Breast Cancer ICYMI

Key clinical point: Immediate reconstruction after neoadjuvant chemotherapy in women with T4 breast cancer is associated with higher odds for complication resulting in unplanned reoperations and a longer time to postmastectomy radiotherapy.

Major finding: Unplanned reoperations for complications were more common after immediate vs. delayed and no reconstruction (22% vs. 7.3% and 4.4%, respectively; P less than .001). The median time to initiation of postmastectomy radiotherapy was longer after immediate reconstruction vs. delayed and no reconstruction (60 days vs. 42 days and 49 days, respectively; P less than .001). The median time to the first recurrence was 18 months and was not significantly different between the groups (P = .13).

Study details: A retrospective study of 269 consecutive women with stage T4 breast cancer treated with surgery, chemotherapy, and radiotherapy between 2007 and 2019.

Disclosure: This study was supported in part by the National Institutes of Health. Dr. Morrow received speaking honoraria from Roche. The other authors did not disclose any conflicts of interest.

Source: Pawloski KR et al. J Am Coll Surg. 2021 Apr 24. doi: 10.1016/j.jamcollsurg.2021.04.016.

Key clinical point: Immediate reconstruction after neoadjuvant chemotherapy in women with T4 breast cancer is associated with higher odds for complication resulting in unplanned reoperations and a longer time to postmastectomy radiotherapy.

Major finding: Unplanned reoperations for complications were more common after immediate vs. delayed and no reconstruction (22% vs. 7.3% and 4.4%, respectively; P less than .001). The median time to initiation of postmastectomy radiotherapy was longer after immediate reconstruction vs. delayed and no reconstruction (60 days vs. 42 days and 49 days, respectively; P less than .001). The median time to the first recurrence was 18 months and was not significantly different between the groups (P = .13).

Study details: A retrospective study of 269 consecutive women with stage T4 breast cancer treated with surgery, chemotherapy, and radiotherapy between 2007 and 2019.

Disclosure: This study was supported in part by the National Institutes of Health. Dr. Morrow received speaking honoraria from Roche. The other authors did not disclose any conflicts of interest.

Source: Pawloski KR et al. J Am Coll Surg. 2021 Apr 24. doi: 10.1016/j.jamcollsurg.2021.04.016.

Key clinical point: Immediate reconstruction after neoadjuvant chemotherapy in women with T4 breast cancer is associated with higher odds for complication resulting in unplanned reoperations and a longer time to postmastectomy radiotherapy.

Major finding: Unplanned reoperations for complications were more common after immediate vs. delayed and no reconstruction (22% vs. 7.3% and 4.4%, respectively; P less than .001). The median time to initiation of postmastectomy radiotherapy was longer after immediate reconstruction vs. delayed and no reconstruction (60 days vs. 42 days and 49 days, respectively; P less than .001). The median time to the first recurrence was 18 months and was not significantly different between the groups (P = .13).

Study details: A retrospective study of 269 consecutive women with stage T4 breast cancer treated with surgery, chemotherapy, and radiotherapy between 2007 and 2019.

Disclosure: This study was supported in part by the National Institutes of Health. Dr. Morrow received speaking honoraria from Roche. The other authors did not disclose any conflicts of interest.

Source: Pawloski KR et al. J Am Coll Surg. 2021 Apr 24. doi: 10.1016/j.jamcollsurg.2021.04.016.

Key clinical point: The presence and extent of coronary artery calcium (CAC), as automatically quantified on routinely performed computed tomography scans, are associated with cardiovascular and coronary artery diseases.

Major finding: The risk for cardiovascular disease increased with a higher CAC score (adjusted hazard ratio, 1.8, 2.1, and 3.4 for CAC scores 11-100, 101-400, and greater than 400, respectively). The risk for coronary artery disease also increased with an increase in CAC score (adjusted hazard ratio, 2.8, 4.3, and 7.8 for CAC scores 11-100, 101-400, and greater than 400, respectively).

Study details: A multicenter cohort study of 15,915 patients with breast cancer who received radiotherapy between 2005 and 2016. The CAC scores were automatically extracted from computed tomography scans using a deep learning algorithm.

Disclosure: This study was funded by the Dutch Cancer Society. The authors received grants, lecture fees, and research support from various sources. Dr. Leiner and Dr. Isgum owned shares of Quantib-U BV and/or a patent with royalties planned. No other conflicts of interest were reported.

Source: Gal R et al. JAMA Oncol. 2021 May 6. doi: 10.1001/jamaoncol.2021.1144.

Key clinical point: The presence and extent of coronary artery calcium (CAC), as automatically quantified on routinely performed computed tomography scans, are associated with cardiovascular and coronary artery diseases.

Major finding: The risk for cardiovascular disease increased with a higher CAC score (adjusted hazard ratio, 1.8, 2.1, and 3.4 for CAC scores 11-100, 101-400, and greater than 400, respectively). The risk for coronary artery disease also increased with an increase in CAC score (adjusted hazard ratio, 2.8, 4.3, and 7.8 for CAC scores 11-100, 101-400, and greater than 400, respectively).

Study details: A multicenter cohort study of 15,915 patients with breast cancer who received radiotherapy between 2005 and 2016. The CAC scores were automatically extracted from computed tomography scans using a deep learning algorithm.

Disclosure: This study was funded by the Dutch Cancer Society. The authors received grants, lecture fees, and research support from various sources. Dr. Leiner and Dr. Isgum owned shares of Quantib-U BV and/or a patent with royalties planned. No other conflicts of interest were reported.

Source: Gal R et al. JAMA Oncol. 2021 May 6. doi: 10.1001/jamaoncol.2021.1144.

Key clinical point: The presence and extent of coronary artery calcium (CAC), as automatically quantified on routinely performed computed tomography scans, are associated with cardiovascular and coronary artery diseases.

Major finding: The risk for cardiovascular disease increased with a higher CAC score (adjusted hazard ratio, 1.8, 2.1, and 3.4 for CAC scores 11-100, 101-400, and greater than 400, respectively). The risk for coronary artery disease also increased with an increase in CAC score (adjusted hazard ratio, 2.8, 4.3, and 7.8 for CAC scores 11-100, 101-400, and greater than 400, respectively).

Study details: A multicenter cohort study of 15,915 patients with breast cancer who received radiotherapy between 2005 and 2016. The CAC scores were automatically extracted from computed tomography scans using a deep learning algorithm.

Disclosure: This study was funded by the Dutch Cancer Society. The authors received grants, lecture fees, and research support from various sources. Dr. Leiner and Dr. Isgum owned shares of Quantib-U BV and/or a patent with royalties planned. No other conflicts of interest were reported.

Source: Gal R et al. JAMA Oncol. 2021 May 6. doi: 10.1001/jamaoncol.2021.1144.

Key clinical point: Breast-conserving surgery (BCS) with radiotherapy yields superior survival vs. mastectomy in patients with early-stage breast cancer.

Major finding: At a median follow-up of 6.28 years, mastectomy without radiotherapy vs. BCS with radiotherapy was associated with worse overall survival (OS; hazard ratio [HR], 1.79; P less than .001) and breast cancer-specific survival (BCSS; HR, 1.66; P less than .001). Mastectomy with radiotherapy also showed lower OS (HR, 1.24; P less than .001) and BCSS (HR, 1.28; P=.001) vs. BCS and radiotherapy.

Study details: A cohort study of 48,986 patients with primary invasive T1-2 N0-2 breast cancer who underwent breast surgery between 2008 and 2017.

Disclosure: This work was funded by the Swedish Breast Cancer Association. Dr de Boniface was supported by an investigator award from the Swedish Cancer Society, and Ms Johansson was supported by a research grant from the Swedish Research Council. The authors did not declare any conflict of interest.

Source: de Boniface J et al. JAMA Surg. 2021 May 5. doi: 10.1001/jamasurg.2021.1438.

Key clinical point: Breast-conserving surgery (BCS) with radiotherapy yields superior survival vs. mastectomy in patients with early-stage breast cancer.

Major finding: At a median follow-up of 6.28 years, mastectomy without radiotherapy vs. BCS with radiotherapy was associated with worse overall survival (OS; hazard ratio [HR], 1.79; P less than .001) and breast cancer-specific survival (BCSS; HR, 1.66; P less than .001). Mastectomy with radiotherapy also showed lower OS (HR, 1.24; P less than .001) and BCSS (HR, 1.28; P=.001) vs. BCS and radiotherapy.

Study details: A cohort study of 48,986 patients with primary invasive T1-2 N0-2 breast cancer who underwent breast surgery between 2008 and 2017.

Disclosure: This work was funded by the Swedish Breast Cancer Association. Dr de Boniface was supported by an investigator award from the Swedish Cancer Society, and Ms Johansson was supported by a research grant from the Swedish Research Council. The authors did not declare any conflict of interest.

Source: de Boniface J et al. JAMA Surg. 2021 May 5. doi: 10.1001/jamasurg.2021.1438.

Key clinical point: Breast-conserving surgery (BCS) with radiotherapy yields superior survival vs. mastectomy in patients with early-stage breast cancer.

Major finding: At a median follow-up of 6.28 years, mastectomy without radiotherapy vs. BCS with radiotherapy was associated with worse overall survival (OS; hazard ratio [HR], 1.79; P less than .001) and breast cancer-specific survival (BCSS; HR, 1.66; P less than .001). Mastectomy with radiotherapy also showed lower OS (HR, 1.24; P less than .001) and BCSS (HR, 1.28; P=.001) vs. BCS and radiotherapy.

Study details: A cohort study of 48,986 patients with primary invasive T1-2 N0-2 breast cancer who underwent breast surgery between 2008 and 2017.

Disclosure: This work was funded by the Swedish Breast Cancer Association. Dr de Boniface was supported by an investigator award from the Swedish Cancer Society, and Ms Johansson was supported by a research grant from the Swedish Research Council. The authors did not declare any conflict of interest.

Source: de Boniface J et al. JAMA Surg. 2021 May 5. doi: 10.1001/jamasurg.2021.1438.

Adjuvant T-DM1 is recommended for patients with HER2-positive early breast cancer with residual disease after neoadjuvant therapy based on phase 3 results. The KATHERINE study found a significant reduction for the risk of recurrence and death with adjuvant T-DM1 vs trastuzumab. Subgroup analyses from KATHERINE showed similar benefits with T-DM1 irrespective of type of neoadjuvant regimen. Furthermore, T-DM1 appeared to benefit small node-negative tumors and particularly those tumors considered high-risk (Mamounas). In the phase 3 TRAIN-2 study, similar pCR rates (68% vs 67%), as well as 3 year event-free (94% vs 93%) and overall (98% vs 98%) survival, were observed for non-anthracycline and anthracycline-containing regimens. These findings highlight the broad applicability of T-DM1 in the adjuvant setting, the rationale to support de-escalation and omission of anthracyclines for HER2-positive tumors, and the importance of tailoring therapy based on response.

Brain metastases occur in up to 50% of patients with HER2-positive metastatic breast cancer (MBC). Effective therapies for this population represent an unmet clinical need. The phase 2 PATRICIA study demonstrated activity of pertuzumab plus high-dose trastuzumab (6mg/kg weekly) for patients with HER2-positive MBC and central nervous system (CNS) progression after radiotherapy. In 37 patients evaluable for efficacy, the CNS objective response rate was 11%, clinical benefit rate at 4 and 6 months was 68% and 51%, respectively, and 2 patients had stable disease for over 2 years (Lin). Data supports the role of other HER2-targeted therapies for CNS disease including T-DM1, neratinib, and tucatinib. Among 291 patients with brain metastases in HER2CLIMB, the combination of tucatinib, capecitabine, and trastuzumab improved median overall survival (18 vs 12 months) and CNS progression-free survival (9.9 vs 4.2 months), compared with capecitabine plus trastuzumab. Further investigation exploring other novel therapy combinations and biomarkers will help further improve outcomes for these patients.

Adjuvant endocrine therapy decreases the risk for recurrence and improves survival for women diagnosed with HR-positive breast cancer. For young women, endocrine therapy options include tamoxifen, as well as ovarian suppression plus tamoxifen, or an aromatase inhibitor. Recommended duration of therapy is at least 5 years and can extend to 10 years. These treatments and duration may present challenges related to childbearing attempts and raise fertility concerns among young women.  In the Young Women’s Breast Cancer Study, among 643 women aged 40 years or younger and diagnosed with early stage HR-positive breast cancer, one-third reported fertility concerns impacting endocrine therapy decisions. Those who reported fertility concerns were more likely to exhibit non-initiation or non-persistence to endocrine therapy (40% vs 20%). Among women with fertility concerns, 7% did not initiate endocrine therapy, and 33% were non-persistent over 5 years (Sella). It is essential to integrate early oncofertility dialogue to help achieve optimal endocrine therapy and address family planning goals.

Studies have shown sugar-sweetened beverages (SSB) increase the risk for insulin resistance, diabetes, and heart disease. In a subsample of Women’s Health Initiative participants, higher levels of insulin resistance were shown to be linked to an increased incidence of breast cancer and all-cause mortality after breast cancer. Researchers found that among 8,863 women diagnosed with early breast cancer, those who consumed SSB after diagnosis had higher breast cancer-specific mortality and all-cause mortality. Additionally, replacing SSB with coffee, tea or water was linked to a decrease in mortality (Farvid). These findings support discussion of lifestyle and dietary behaviors in the survivorship setting, as these modifiable risk factors can potentially have significant health implications.

References:

van der Voort A, van Ramshorst MS, van Werkhoven ED, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): A randomized phase III trial. J Clin Oncol. 2020;38S:ASCO #501.

Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619.

Pan K, Chlebowski RT, Mortimer JE, et al. Insulin resistance and breast cancer incidence and mortality in postmenopausal women in the Women's Health Initiative. Cancer. 2020;126(16):3638-3647.

Adjuvant T-DM1 is recommended for patients with HER2-positive early breast cancer with residual disease after neoadjuvant therapy based on phase 3 results. The KATHERINE study found a significant reduction for the risk of recurrence and death with adjuvant T-DM1 vs trastuzumab. Subgroup analyses from KATHERINE showed similar benefits with T-DM1 irrespective of type of neoadjuvant regimen. Furthermore, T-DM1 appeared to benefit small node-negative tumors and particularly those tumors considered high-risk (Mamounas). In the phase 3 TRAIN-2 study, similar pCR rates (68% vs 67%), as well as 3 year event-free (94% vs 93%) and overall (98% vs 98%) survival, were observed for non-anthracycline and anthracycline-containing regimens. These findings highlight the broad applicability of T-DM1 in the adjuvant setting, the rationale to support de-escalation and omission of anthracyclines for HER2-positive tumors, and the importance of tailoring therapy based on response.

Brain metastases occur in up to 50% of patients with HER2-positive metastatic breast cancer (MBC). Effective therapies for this population represent an unmet clinical need. The phase 2 PATRICIA study demonstrated activity of pertuzumab plus high-dose trastuzumab (6mg/kg weekly) for patients with HER2-positive MBC and central nervous system (CNS) progression after radiotherapy. In 37 patients evaluable for efficacy, the CNS objective response rate was 11%, clinical benefit rate at 4 and 6 months was 68% and 51%, respectively, and 2 patients had stable disease for over 2 years (Lin). Data supports the role of other HER2-targeted therapies for CNS disease including T-DM1, neratinib, and tucatinib. Among 291 patients with brain metastases in HER2CLIMB, the combination of tucatinib, capecitabine, and trastuzumab improved median overall survival (18 vs 12 months) and CNS progression-free survival (9.9 vs 4.2 months), compared with capecitabine plus trastuzumab. Further investigation exploring other novel therapy combinations and biomarkers will help further improve outcomes for these patients.

Adjuvant endocrine therapy decreases the risk for recurrence and improves survival for women diagnosed with HR-positive breast cancer. For young women, endocrine therapy options include tamoxifen, as well as ovarian suppression plus tamoxifen, or an aromatase inhibitor. Recommended duration of therapy is at least 5 years and can extend to 10 years. These treatments and duration may present challenges related to childbearing attempts and raise fertility concerns among young women.  In the Young Women’s Breast Cancer Study, among 643 women aged 40 years or younger and diagnosed with early stage HR-positive breast cancer, one-third reported fertility concerns impacting endocrine therapy decisions. Those who reported fertility concerns were more likely to exhibit non-initiation or non-persistence to endocrine therapy (40% vs 20%). Among women with fertility concerns, 7% did not initiate endocrine therapy, and 33% were non-persistent over 5 years (Sella). It is essential to integrate early oncofertility dialogue to help achieve optimal endocrine therapy and address family planning goals.

Studies have shown sugar-sweetened beverages (SSB) increase the risk for insulin resistance, diabetes, and heart disease. In a subsample of Women’s Health Initiative participants, higher levels of insulin resistance were shown to be linked to an increased incidence of breast cancer and all-cause mortality after breast cancer. Researchers found that among 8,863 women diagnosed with early breast cancer, those who consumed SSB after diagnosis had higher breast cancer-specific mortality and all-cause mortality. Additionally, replacing SSB with coffee, tea or water was linked to a decrease in mortality (Farvid). These findings support discussion of lifestyle and dietary behaviors in the survivorship setting, as these modifiable risk factors can potentially have significant health implications.

References:

van der Voort A, van Ramshorst MS, van Werkhoven ED, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): A randomized phase III trial. J Clin Oncol. 2020;38S:ASCO #501.

Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619.

Pan K, Chlebowski RT, Mortimer JE, et al. Insulin resistance and breast cancer incidence and mortality in postmenopausal women in the Women's Health Initiative. Cancer. 2020;126(16):3638-3647.

Adjuvant T-DM1 is recommended for patients with HER2-positive early breast cancer with residual disease after neoadjuvant therapy based on phase 3 results. The KATHERINE study found a significant reduction for the risk of recurrence and death with adjuvant T-DM1 vs trastuzumab. Subgroup analyses from KATHERINE showed similar benefits with T-DM1 irrespective of type of neoadjuvant regimen. Furthermore, T-DM1 appeared to benefit small node-negative tumors and particularly those tumors considered high-risk (Mamounas). In the phase 3 TRAIN-2 study, similar pCR rates (68% vs 67%), as well as 3 year event-free (94% vs 93%) and overall (98% vs 98%) survival, were observed for non-anthracycline and anthracycline-containing regimens. These findings highlight the broad applicability of T-DM1 in the adjuvant setting, the rationale to support de-escalation and omission of anthracyclines for HER2-positive tumors, and the importance of tailoring therapy based on response.

Brain metastases occur in up to 50% of patients with HER2-positive metastatic breast cancer (MBC). Effective therapies for this population represent an unmet clinical need. The phase 2 PATRICIA study demonstrated activity of pertuzumab plus high-dose trastuzumab (6mg/kg weekly) for patients with HER2-positive MBC and central nervous system (CNS) progression after radiotherapy. In 37 patients evaluable for efficacy, the CNS objective response rate was 11%, clinical benefit rate at 4 and 6 months was 68% and 51%, respectively, and 2 patients had stable disease for over 2 years (Lin). Data supports the role of other HER2-targeted therapies for CNS disease including T-DM1, neratinib, and tucatinib. Among 291 patients with brain metastases in HER2CLIMB, the combination of tucatinib, capecitabine, and trastuzumab improved median overall survival (18 vs 12 months) and CNS progression-free survival (9.9 vs 4.2 months), compared with capecitabine plus trastuzumab. Further investigation exploring other novel therapy combinations and biomarkers will help further improve outcomes for these patients.

Adjuvant endocrine therapy decreases the risk for recurrence and improves survival for women diagnosed with HR-positive breast cancer. For young women, endocrine therapy options include tamoxifen, as well as ovarian suppression plus tamoxifen, or an aromatase inhibitor. Recommended duration of therapy is at least 5 years and can extend to 10 years. These treatments and duration may present challenges related to childbearing attempts and raise fertility concerns among young women.  In the Young Women’s Breast Cancer Study, among 643 women aged 40 years or younger and diagnosed with early stage HR-positive breast cancer, one-third reported fertility concerns impacting endocrine therapy decisions. Those who reported fertility concerns were more likely to exhibit non-initiation or non-persistence to endocrine therapy (40% vs 20%). Among women with fertility concerns, 7% did not initiate endocrine therapy, and 33% were non-persistent over 5 years (Sella). It is essential to integrate early oncofertility dialogue to help achieve optimal endocrine therapy and address family planning goals.

Studies have shown sugar-sweetened beverages (SSB) increase the risk for insulin resistance, diabetes, and heart disease. In a subsample of Women’s Health Initiative participants, higher levels of insulin resistance were shown to be linked to an increased incidence of breast cancer and all-cause mortality after breast cancer. Researchers found that among 8,863 women diagnosed with early breast cancer, those who consumed SSB after diagnosis had higher breast cancer-specific mortality and all-cause mortality. Additionally, replacing SSB with coffee, tea or water was linked to a decrease in mortality (Farvid). These findings support discussion of lifestyle and dietary behaviors in the survivorship setting, as these modifiable risk factors can potentially have significant health implications.

References:

van der Voort A, van Ramshorst MS, van Werkhoven ED, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): A randomized phase III trial. J Clin Oncol. 2020;38S:ASCO #501.

Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619.

Pan K, Chlebowski RT, Mortimer JE, et al. Insulin resistance and breast cancer incidence and mortality in postmenopausal women in the Women's Health Initiative. Cancer. 2020;126(16):3638-3647.

Although rates are generally low, interstitial lung disease (ILD) can occur at any point in the first year of treatment with trastuzumab deruxtecan (T-DXd) for HER2-positive metastatic breast cancer (MBC).

That’s according to a pooled analysis of three early clinical trials with the drug that was reported at the European Society for Medical Oncology (ESMO): Breast Cancer virtual meeting.

Over a 5-year analysis period, the rate of any grade of ILD was 15.5%. The majority (79%) of those events were grade 1 or 2, observed pulmonologist Charles A. Powell, MD, of Icahn School of Medicine at Mount Sinai in New York, who presented the findings.

Of the 245 patients who were included in the analysis, 38 had an ILD event deemed related to treatment. A respective 9 (3.7%) and 21 (8.6%) had events graded as 1 or 2, 1 patient each (0.4%) had a grade 3 or 4 event, and 6 (2.4%) patients had a grade 5 event.

The timing of the first identified ILD event varied from 1.1 months to 20.8 months, given a median of 5.6 months overall. “This highlights an opportunity for more timely detection of ILD,” Dr. Powell suggested. He added that in almost all (97%) cases, ILD occurred before 12 months and the risk may even decrease over time “suggesting that the risk is not cumulative.”

He cautioned, however: “It is important to note that this analysis is exploratory and hypothesis generating in nature.”
 

ILD occurs with other cancer drugs

ILD is not just associated with T-DXd treatment, said the invited discussant for the trial, Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

“It’s important for clinicians to remember that ILD/pneumonitis is an uncommon, but potentially very serious side effect that affects many breast cancer treatments,” he said.

That not only includes T-DXd, but other newer drugs such the cyclin dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors, as well as other older more established drugs including taxanes, cyclophosphamide and even the mTOR inhibitor everolimus.

“Both clinicians and patients need to be aware of this risk. It’s part of the differential diagnosis for any patient who develops either ground glass changes or other infiltrates on a CT scan, or who has symptoms,” Dr. Burstein added.
 

Investigating ILD in T-DXd trials

T-DXd (Enhertu) is an anti-HER2-antibody drug conjugate that contains a humanized anti-HER2 IgG1 monoclonal antibody akin to trastuzumab that is linked to DXd, a topoisomerase I inhibitor that is a derivative of exatecan.

It has been approved for use in patients with HER2-positive metastatic breast cancer after two other HER2 treatments fail in the United States and Europe, and after chemotherapy in Japan, noted Dr. Powell. This is largely due to the results from the phase 2, open-label DESTINY-Breast01 trial.

“In breast cancer, T-DXd continues to demonstrate clinically meaningful efficacy with a median duration of response of more than 20 months in a heavily pretreated population,” he said. Objective response rates seen in the DESTINY-Breast01 trial were around 60%, and the median progression-free survival was a little over 19 months.

To look at the issue of drug-related ILD events in patients treated with T-DXd for HER2-positive MBC, an independent adjudication committee was formed to look at all the imaging and clinical data from the DESTINY-Breast01 trial and two single-arm phase 1 trials (NCT02564900 and NCT03383692).

In all, data on 245 patients who had been treated with T-DXd at the approved dose of 5.4 mg/kg in those trials between August 2015 and June 2020 were analyzed.
 

Dealing with lung toxicity

“We are getting new drugs to improve the treatment of cancer, but they always come with a price in terms of toxicity,” observed David Cameron, MD, professor of medical oncology at Edinburgh University in Scotland. Dr. Cameron chaired the session.

“Several measures were taken to identify and mitigate ILD,” across all the T-DXd studies, Dr. Powell explained. As well as the independent adjudication committee, available guidelines were followed and updated on how to diagnose and treat drug-induced lung injuries, and a “safe use” campaign was run in 2019.

Many patients in the early MBC studies were recruited before these measures were in place, such as the use of systemic steroids to manage low-grade events.

The bottom line, however, is that if a patient develops ILD then treatment should be stopped, Dr. Powell said. “Patients with grade 1 events may restart once the ILD has resolved, but those with grade 2 to 4 events must discontinue treatment.”

Dr. Powell concluded: “The overall clinical data support the positive risk-benefit profile of T-DXd. Phase 3 randomized controlled trials in breast cancer are ongoing.”
 

ILD also seen in monarchE trial with abemaciclib

Data on ILD events seen in the phase 3 monarchE trial were also reported separately at the ESMO Breast Cancer virtual meeting. The analysis population included 2,971 patients who had been treated with the CDK 4/6 inhibitor abemaciclib (Verzenio) together with endocrine therapy and 2,800 who had received endocrine therapy alone in the early-stage, adjuvant advanced breast cancer setting.

Most ILD (97%) events that occurred were single occurrences, with any grade of ILD occurring in a higher percentage of patients treated with abemaciclib with endocrine therapy than endocrine therapy alone (2.9% vs. 1.2%). Grade 3 events occurred in a respective 0.4% and 0.0% of patients.
 

So who’s at risk?

The risk factors for ILD and pneumonitis are not well characterized with either of the two drugs discussed, Dr. Burstein observed.

“In the abemaciclib experience, it looked like obesity might be a predisposing factor, with trastuzumab deruxtecan, it looked like patients of Asian ancestry were greater risk, but we need more data to really understand who’s at jeopardy.”

Dr. Burstein observed: “This is something patients need to be aware of as they’re contemplating this treatment.”

While data to prove the benefit of the drug need to mature, Dr. Burstein “would likely discontinue therapy” if a patient were to develop ILD or pneumonitis and treat accordingly.

As for T-DXd, he said: “It’s important that patients know that lung disease is a potentially severe side effect of treatment and that any respiratory symptoms need to be jumped on quickly.”

While prospective studies are now needed, and the phase 3 data should help to better understand the risk of ILD with T-DXd, Dr. Burstein believes it will be important to develop algorithms to ensure the safe administration of the drug.

These algorithms should include “appropriate surveillance and monitoring, especially as we think about trying to move this drug forward into the early stage setting where we’re using it in women who have favorable prognosis, and potentially curative situations for breast cancer.”

The trastuzumab deruxtecan trials were cosponsored by Daiichi Sankyo and AstraZeneca. The monarchE trial was supported by Eli Lilly.

Dr. Powell acknowledged receiving personal fees for acting as an advisory or consultant to both companies as well as to Voluntis. Dr. Burstein had nothing to disclose, and Dr. Cameron had no relevant financial interests in the data being presented.

Although rates are generally low, interstitial lung disease (ILD) can occur at any point in the first year of treatment with trastuzumab deruxtecan (T-DXd) for HER2-positive metastatic breast cancer (MBC).

That’s according to a pooled analysis of three early clinical trials with the drug that was reported at the European Society for Medical Oncology (ESMO): Breast Cancer virtual meeting.

Over a 5-year analysis period, the rate of any grade of ILD was 15.5%. The majority (79%) of those events were grade 1 or 2, observed pulmonologist Charles A. Powell, MD, of Icahn School of Medicine at Mount Sinai in New York, who presented the findings.

Of the 245 patients who were included in the analysis, 38 had an ILD event deemed related to treatment. A respective 9 (3.7%) and 21 (8.6%) had events graded as 1 or 2, 1 patient each (0.4%) had a grade 3 or 4 event, and 6 (2.4%) patients had a grade 5 event.

The timing of the first identified ILD event varied from 1.1 months to 20.8 months, given a median of 5.6 months overall. “This highlights an opportunity for more timely detection of ILD,” Dr. Powell suggested. He added that in almost all (97%) cases, ILD occurred before 12 months and the risk may even decrease over time “suggesting that the risk is not cumulative.”

He cautioned, however: “It is important to note that this analysis is exploratory and hypothesis generating in nature.”
 

ILD occurs with other cancer drugs

ILD is not just associated with T-DXd treatment, said the invited discussant for the trial, Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

“It’s important for clinicians to remember that ILD/pneumonitis is an uncommon, but potentially very serious side effect that affects many breast cancer treatments,” he said.

That not only includes T-DXd, but other newer drugs such the cyclin dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors, as well as other older more established drugs including taxanes, cyclophosphamide and even the mTOR inhibitor everolimus.

“Both clinicians and patients need to be aware of this risk. It’s part of the differential diagnosis for any patient who develops either ground glass changes or other infiltrates on a CT scan, or who has symptoms,” Dr. Burstein added.
 

Investigating ILD in T-DXd trials

T-DXd (Enhertu) is an anti-HER2-antibody drug conjugate that contains a humanized anti-HER2 IgG1 monoclonal antibody akin to trastuzumab that is linked to DXd, a topoisomerase I inhibitor that is a derivative of exatecan.

It has been approved for use in patients with HER2-positive metastatic breast cancer after two other HER2 treatments fail in the United States and Europe, and after chemotherapy in Japan, noted Dr. Powell. This is largely due to the results from the phase 2, open-label DESTINY-Breast01 trial.

“In breast cancer, T-DXd continues to demonstrate clinically meaningful efficacy with a median duration of response of more than 20 months in a heavily pretreated population,” he said. Objective response rates seen in the DESTINY-Breast01 trial were around 60%, and the median progression-free survival was a little over 19 months.

To look at the issue of drug-related ILD events in patients treated with T-DXd for HER2-positive MBC, an independent adjudication committee was formed to look at all the imaging and clinical data from the DESTINY-Breast01 trial and two single-arm phase 1 trials (NCT02564900 and NCT03383692).

In all, data on 245 patients who had been treated with T-DXd at the approved dose of 5.4 mg/kg in those trials between August 2015 and June 2020 were analyzed.
 

Dealing with lung toxicity

“We are getting new drugs to improve the treatment of cancer, but they always come with a price in terms of toxicity,” observed David Cameron, MD, professor of medical oncology at Edinburgh University in Scotland. Dr. Cameron chaired the session.

“Several measures were taken to identify and mitigate ILD,” across all the T-DXd studies, Dr. Powell explained. As well as the independent adjudication committee, available guidelines were followed and updated on how to diagnose and treat drug-induced lung injuries, and a “safe use” campaign was run in 2019.

Many patients in the early MBC studies were recruited before these measures were in place, such as the use of systemic steroids to manage low-grade events.

The bottom line, however, is that if a patient develops ILD then treatment should be stopped, Dr. Powell said. “Patients with grade 1 events may restart once the ILD has resolved, but those with grade 2 to 4 events must discontinue treatment.”

Dr. Powell concluded: “The overall clinical data support the positive risk-benefit profile of T-DXd. Phase 3 randomized controlled trials in breast cancer are ongoing.”
 

ILD also seen in monarchE trial with abemaciclib

Data on ILD events seen in the phase 3 monarchE trial were also reported separately at the ESMO Breast Cancer virtual meeting. The analysis population included 2,971 patients who had been treated with the CDK 4/6 inhibitor abemaciclib (Verzenio) together with endocrine therapy and 2,800 who had received endocrine therapy alone in the early-stage, adjuvant advanced breast cancer setting.

Most ILD (97%) events that occurred were single occurrences, with any grade of ILD occurring in a higher percentage of patients treated with abemaciclib with endocrine therapy than endocrine therapy alone (2.9% vs. 1.2%). Grade 3 events occurred in a respective 0.4% and 0.0% of patients.
 

So who’s at risk?

The risk factors for ILD and pneumonitis are not well characterized with either of the two drugs discussed, Dr. Burstein observed.

“In the abemaciclib experience, it looked like obesity might be a predisposing factor, with trastuzumab deruxtecan, it looked like patients of Asian ancestry were greater risk, but we need more data to really understand who’s at jeopardy.”

Dr. Burstein observed: “This is something patients need to be aware of as they’re contemplating this treatment.”

While data to prove the benefit of the drug need to mature, Dr. Burstein “would likely discontinue therapy” if a patient were to develop ILD or pneumonitis and treat accordingly.

As for T-DXd, he said: “It’s important that patients know that lung disease is a potentially severe side effect of treatment and that any respiratory symptoms need to be jumped on quickly.”

While prospective studies are now needed, and the phase 3 data should help to better understand the risk of ILD with T-DXd, Dr. Burstein believes it will be important to develop algorithms to ensure the safe administration of the drug.

These algorithms should include “appropriate surveillance and monitoring, especially as we think about trying to move this drug forward into the early stage setting where we’re using it in women who have favorable prognosis, and potentially curative situations for breast cancer.”

The trastuzumab deruxtecan trials were cosponsored by Daiichi Sankyo and AstraZeneca. The monarchE trial was supported by Eli Lilly.

Dr. Powell acknowledged receiving personal fees for acting as an advisory or consultant to both companies as well as to Voluntis. Dr. Burstein had nothing to disclose, and Dr. Cameron had no relevant financial interests in the data being presented.

Although rates are generally low, interstitial lung disease (ILD) can occur at any point in the first year of treatment with trastuzumab deruxtecan (T-DXd) for HER2-positive metastatic breast cancer (MBC).

That’s according to a pooled analysis of three early clinical trials with the drug that was reported at the European Society for Medical Oncology (ESMO): Breast Cancer virtual meeting.

Over a 5-year analysis period, the rate of any grade of ILD was 15.5%. The majority (79%) of those events were grade 1 or 2, observed pulmonologist Charles A. Powell, MD, of Icahn School of Medicine at Mount Sinai in New York, who presented the findings.

Of the 245 patients who were included in the analysis, 38 had an ILD event deemed related to treatment. A respective 9 (3.7%) and 21 (8.6%) had events graded as 1 or 2, 1 patient each (0.4%) had a grade 3 or 4 event, and 6 (2.4%) patients had a grade 5 event.

The timing of the first identified ILD event varied from 1.1 months to 20.8 months, given a median of 5.6 months overall. “This highlights an opportunity for more timely detection of ILD,” Dr. Powell suggested. He added that in almost all (97%) cases, ILD occurred before 12 months and the risk may even decrease over time “suggesting that the risk is not cumulative.”

He cautioned, however: “It is important to note that this analysis is exploratory and hypothesis generating in nature.”
 

ILD occurs with other cancer drugs

ILD is not just associated with T-DXd treatment, said the invited discussant for the trial, Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

“It’s important for clinicians to remember that ILD/pneumonitis is an uncommon, but potentially very serious side effect that affects many breast cancer treatments,” he said.

That not only includes T-DXd, but other newer drugs such the cyclin dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors, as well as other older more established drugs including taxanes, cyclophosphamide and even the mTOR inhibitor everolimus.

“Both clinicians and patients need to be aware of this risk. It’s part of the differential diagnosis for any patient who develops either ground glass changes or other infiltrates on a CT scan, or who has symptoms,” Dr. Burstein added.
 

Investigating ILD in T-DXd trials

T-DXd (Enhertu) is an anti-HER2-antibody drug conjugate that contains a humanized anti-HER2 IgG1 monoclonal antibody akin to trastuzumab that is linked to DXd, a topoisomerase I inhibitor that is a derivative of exatecan.

It has been approved for use in patients with HER2-positive metastatic breast cancer after two other HER2 treatments fail in the United States and Europe, and after chemotherapy in Japan, noted Dr. Powell. This is largely due to the results from the phase 2, open-label DESTINY-Breast01 trial.

“In breast cancer, T-DXd continues to demonstrate clinically meaningful efficacy with a median duration of response of more than 20 months in a heavily pretreated population,” he said. Objective response rates seen in the DESTINY-Breast01 trial were around 60%, and the median progression-free survival was a little over 19 months.

To look at the issue of drug-related ILD events in patients treated with T-DXd for HER2-positive MBC, an independent adjudication committee was formed to look at all the imaging and clinical data from the DESTINY-Breast01 trial and two single-arm phase 1 trials (NCT02564900 and NCT03383692).

In all, data on 245 patients who had been treated with T-DXd at the approved dose of 5.4 mg/kg in those trials between August 2015 and June 2020 were analyzed.
 

Dealing with lung toxicity

“We are getting new drugs to improve the treatment of cancer, but they always come with a price in terms of toxicity,” observed David Cameron, MD, professor of medical oncology at Edinburgh University in Scotland. Dr. Cameron chaired the session.

“Several measures were taken to identify and mitigate ILD,” across all the T-DXd studies, Dr. Powell explained. As well as the independent adjudication committee, available guidelines were followed and updated on how to diagnose and treat drug-induced lung injuries, and a “safe use” campaign was run in 2019.

Many patients in the early MBC studies were recruited before these measures were in place, such as the use of systemic steroids to manage low-grade events.

The bottom line, however, is that if a patient develops ILD then treatment should be stopped, Dr. Powell said. “Patients with grade 1 events may restart once the ILD has resolved, but those with grade 2 to 4 events must discontinue treatment.”

Dr. Powell concluded: “The overall clinical data support the positive risk-benefit profile of T-DXd. Phase 3 randomized controlled trials in breast cancer are ongoing.”
 

ILD also seen in monarchE trial with abemaciclib

Data on ILD events seen in the phase 3 monarchE trial were also reported separately at the ESMO Breast Cancer virtual meeting. The analysis population included 2,971 patients who had been treated with the CDK 4/6 inhibitor abemaciclib (Verzenio) together with endocrine therapy and 2,800 who had received endocrine therapy alone in the early-stage, adjuvant advanced breast cancer setting.

Most ILD (97%) events that occurred were single occurrences, with any grade of ILD occurring in a higher percentage of patients treated with abemaciclib with endocrine therapy than endocrine therapy alone (2.9% vs. 1.2%). Grade 3 events occurred in a respective 0.4% and 0.0% of patients.
 

So who’s at risk?

The risk factors for ILD and pneumonitis are not well characterized with either of the two drugs discussed, Dr. Burstein observed.

“In the abemaciclib experience, it looked like obesity might be a predisposing factor, with trastuzumab deruxtecan, it looked like patients of Asian ancestry were greater risk, but we need more data to really understand who’s at jeopardy.”

Dr. Burstein observed: “This is something patients need to be aware of as they’re contemplating this treatment.”

While data to prove the benefit of the drug need to mature, Dr. Burstein “would likely discontinue therapy” if a patient were to develop ILD or pneumonitis and treat accordingly.

As for T-DXd, he said: “It’s important that patients know that lung disease is a potentially severe side effect of treatment and that any respiratory symptoms need to be jumped on quickly.”

While prospective studies are now needed, and the phase 3 data should help to better understand the risk of ILD with T-DXd, Dr. Burstein believes it will be important to develop algorithms to ensure the safe administration of the drug.

These algorithms should include “appropriate surveillance and monitoring, especially as we think about trying to move this drug forward into the early stage setting where we’re using it in women who have favorable prognosis, and potentially curative situations for breast cancer.”

The trastuzumab deruxtecan trials were cosponsored by Daiichi Sankyo and AstraZeneca. The monarchE trial was supported by Eli Lilly.

Dr. Powell acknowledged receiving personal fees for acting as an advisory or consultant to both companies as well as to Voluntis. Dr. Burstein had nothing to disclose, and Dr. Cameron had no relevant financial interests in the data being presented.

The U.S. Food and Drug Administration has expanded the indication for rimegepant (Nurtec ODT, Biohaven) to include prevention of migraine in adults. Last year, rimegepant became the first calcitonin gene-related peptide (CGRP) receptor antagonist, available in a fast-acting orally disintegrating tablet, to be approved for the acute treatment of migraine with or without aura in adults.

Rimegepant is currently the only migraine medication approved to both treat acute migraine attacks and help prevent future migraine attacks.

The new indication allows for use of rimegepant for preventive treatment in adults with episodic migraine (more than 15 migraine days per month). Rimegepant may be used for up to 18 doses per month, which includes both acute and preventive therapy.

In a phase 2/3 study, oral rimegepant was superior to placebo in reducing monthly migraine days. About half of adults who took rimegepant experienced a 50% or greater reduction in the number of days of moderate to severe migraines per month.

The most common adverse effects of rimegepant therapy were nausea (2.7%) and stomach pain or indigestion (2.4%).

The FDA approval of rimegepant for the preventive treatment of migraine, along with its acute treatment indication, is “one of the most ground-breaking things to happen to migraine treatment in my 40 years of practicing headache medicine,” Peter J. Goadsby, MD, PhD, an investigator in the prevention study, said in a company news release.   

“To have one medication patients can use to treat and prevent migraine will likely change the treatment paradigm for many of the millions of people who live with migraine,” said Dr. Goadsby, professor of neurology, University of California, Los Angeles and King’s College, London.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has expanded the indication for rimegepant (Nurtec ODT, Biohaven) to include prevention of migraine in adults. Last year, rimegepant became the first calcitonin gene-related peptide (CGRP) receptor antagonist, available in a fast-acting orally disintegrating tablet, to be approved for the acute treatment of migraine with or without aura in adults.

Rimegepant is currently the only migraine medication approved to both treat acute migraine attacks and help prevent future migraine attacks.

The new indication allows for use of rimegepant for preventive treatment in adults with episodic migraine (more than 15 migraine days per month). Rimegepant may be used for up to 18 doses per month, which includes both acute and preventive therapy.

In a phase 2/3 study, oral rimegepant was superior to placebo in reducing monthly migraine days. About half of adults who took rimegepant experienced a 50% or greater reduction in the number of days of moderate to severe migraines per month.

The most common adverse effects of rimegepant therapy were nausea (2.7%) and stomach pain or indigestion (2.4%).

The FDA approval of rimegepant for the preventive treatment of migraine, along with its acute treatment indication, is “one of the most ground-breaking things to happen to migraine treatment in my 40 years of practicing headache medicine,” Peter J. Goadsby, MD, PhD, an investigator in the prevention study, said in a company news release.   

“To have one medication patients can use to treat and prevent migraine will likely change the treatment paradigm for many of the millions of people who live with migraine,” said Dr. Goadsby, professor of neurology, University of California, Los Angeles and King’s College, London.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has expanded the indication for rimegepant (Nurtec ODT, Biohaven) to include prevention of migraine in adults. Last year, rimegepant became the first calcitonin gene-related peptide (CGRP) receptor antagonist, available in a fast-acting orally disintegrating tablet, to be approved for the acute treatment of migraine with or without aura in adults.

Rimegepant is currently the only migraine medication approved to both treat acute migraine attacks and help prevent future migraine attacks.

The new indication allows for use of rimegepant for preventive treatment in adults with episodic migraine (more than 15 migraine days per month). Rimegepant may be used for up to 18 doses per month, which includes both acute and preventive therapy.

In a phase 2/3 study, oral rimegepant was superior to placebo in reducing monthly migraine days. About half of adults who took rimegepant experienced a 50% or greater reduction in the number of days of moderate to severe migraines per month.

The most common adverse effects of rimegepant therapy were nausea (2.7%) and stomach pain or indigestion (2.4%).

The FDA approval of rimegepant for the preventive treatment of migraine, along with its acute treatment indication, is “one of the most ground-breaking things to happen to migraine treatment in my 40 years of practicing headache medicine,” Peter J. Goadsby, MD, PhD, an investigator in the prevention study, said in a company news release.   

“To have one medication patients can use to treat and prevent migraine will likely change the treatment paradigm for many of the millions of people who live with migraine,” said Dr. Goadsby, professor of neurology, University of California, Los Angeles and King’s College, London.

A version of this article first appeared on Medscape.com.

In the past, chemotherapy was the go-to treatment for patients with HR+/HER2- breast cancer with visceral metastases, which most commonly involve lung and liver. Dr Adam M. Brufsky, of the University of Pittsburgh School of Medicine, reports that the advent of CDK4/6 inhibitors offers an opportunity for several different courses of action appropriate to subgroups within this population of patients.

Three CDK4/6 inhibitors are FDA approved for clinical practice. Dr Brufsky summarizes results from three studies of CDK4/6 inhibitors — abemaciclib, ribociclib, and palbociclib — where these agents were used as second-line therapy after progression on a nonsteroidal aromatase inhibitor. In combination with fulvestrant, all three offered significant benefits in progression-free survival (PFS) and two in overall survival (OS). Among those who derived survival benefit were patients who had visceral metatases, who constituted 56%, 27% and 60% of the respective studies.

For patients who show progression on CDK4/6 inhibitors, additional treatment can be determined by genomic sequencing. Combination therapy with alpelisib and fulvestrant has been shown to lengthen PFS in patients whose tumors have PIK3 mutations. Patients without PIK3 mutations can be treated with fulvestrant or a combination of fulvestrant and everolimus.

--

Adam M. Brufsky, MD, PhD, Professor, Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine; Associate Chief, Department of Medicine, Division of Hematology-Oncology, UPMC-Hillman Cancer Center, Pittsburgh, Pennsylvania. 

Adam M. Brufsky, MD, PhD, has disclosed the following relevant financial relationships: 
Received income in an amount equal to or greater than $250 from: Seattle Genetics; Roche; AstraZeneca; Puma; Daiichi Sankyo.

In the past, chemotherapy was the go-to treatment for patients with HR+/HER2- breast cancer with visceral metastases, which most commonly involve lung and liver. Dr Adam M. Brufsky, of the University of Pittsburgh School of Medicine, reports that the advent of CDK4/6 inhibitors offers an opportunity for several different courses of action appropriate to subgroups within this population of patients.

Three CDK4/6 inhibitors are FDA approved for clinical practice. Dr Brufsky summarizes results from three studies of CDK4/6 inhibitors — abemaciclib, ribociclib, and palbociclib — where these agents were used as second-line therapy after progression on a nonsteroidal aromatase inhibitor. In combination with fulvestrant, all three offered significant benefits in progression-free survival (PFS) and two in overall survival (OS). Among those who derived survival benefit were patients who had visceral metatases, who constituted 56%, 27% and 60% of the respective studies.

For patients who show progression on CDK4/6 inhibitors, additional treatment can be determined by genomic sequencing. Combination therapy with alpelisib and fulvestrant has been shown to lengthen PFS in patients whose tumors have PIK3 mutations. Patients without PIK3 mutations can be treated with fulvestrant or a combination of fulvestrant and everolimus.

--

Adam M. Brufsky, MD, PhD, Professor, Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine; Associate Chief, Department of Medicine, Division of Hematology-Oncology, UPMC-Hillman Cancer Center, Pittsburgh, Pennsylvania. 

Adam M. Brufsky, MD, PhD, has disclosed the following relevant financial relationships: 
Received income in an amount equal to or greater than $250 from: Seattle Genetics; Roche; AstraZeneca; Puma; Daiichi Sankyo.

In the past, chemotherapy was the go-to treatment for patients with HR+/HER2- breast cancer with visceral metastases, which most commonly involve lung and liver. Dr Adam M. Brufsky, of the University of Pittsburgh School of Medicine, reports that the advent of CDK4/6 inhibitors offers an opportunity for several different courses of action appropriate to subgroups within this population of patients.

Three CDK4/6 inhibitors are FDA approved for clinical practice. Dr Brufsky summarizes results from three studies of CDK4/6 inhibitors — abemaciclib, ribociclib, and palbociclib — where these agents were used as second-line therapy after progression on a nonsteroidal aromatase inhibitor. In combination with fulvestrant, all three offered significant benefits in progression-free survival (PFS) and two in overall survival (OS). Among those who derived survival benefit were patients who had visceral metatases, who constituted 56%, 27% and 60% of the respective studies.

For patients who show progression on CDK4/6 inhibitors, additional treatment can be determined by genomic sequencing. Combination therapy with alpelisib and fulvestrant has been shown to lengthen PFS in patients whose tumors have PIK3 mutations. Patients without PIK3 mutations can be treated with fulvestrant or a combination of fulvestrant and everolimus.

--

Adam M. Brufsky, MD, PhD, Professor, Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine; Associate Chief, Department of Medicine, Division of Hematology-Oncology, UPMC-Hillman Cancer Center, Pittsburgh, Pennsylvania. 

Adam M. Brufsky, MD, PhD, has disclosed the following relevant financial relationships: 
Received income in an amount equal to or greater than $250 from: Seattle Genetics; Roche; AstraZeneca; Puma; Daiichi Sankyo.

The long-term benefits of endocrine therapy in premenopausal breast cancer appear to differ according to whether patients are categorized as high or low molecular risk using the 70-gene signature (MammaPrint).

Based upon data from patients who had participated in the Stockholm tamoxifen (STO-5) trial, high-risk patients significantly benefited from goserelin treatment, whereas low-risk patients benefited more from tamoxifen treatment when compared with no endocrine therapy.

“Goserelin, tamoxifen, and the combination of the two, reduced the 20-year risk of distant occurrences and fatal breast cancer, compared to no endocrine therapy,” Annelie Johansson, MSc, said at the European Society for Medical Oncology: Breast Cancer virtual meeting.

“Our findings indicate that the long-term endocrine therapy benefit in premenopausal patients is influenced by molecular risk classification and thus tumor characteristics,” she added.

Ms. Johansson, a postdoctoral researcher in genomic breast cancer at the Karolinska Institutet in Stockholm, reported the results of the analysis as a late-breaking abstract at the meeting.

“I think this is an innovative translational study trying to use the multigene assay results to look at differential endocrine therapy effects,” said Prudence Francis, MD, the invited discussant for study.

However, there are relatively few patients in the various subgroups being tested, she added. “We’ve also got short duration of tamoxifen, only 2 years, we’ve got prior chemotherapy in some patients and absence of HER2 therapy, all of which might influence outcomes.”

As a result, Dr. Francis, who is head of medical oncology at the Peter MacCallum Cancer Centre and a consultant Medical Oncologist at St. Vincent’s Hospital Melbourne, called the findings purely “hypothesis generating.”
 

Study details and results

The analysis was based on data from the STO-5 trial, which had recruited just over 900 patients between 1990 and 1997. Patients were stratified according to their lymph node status and some received chemotherapy with or without locoregional radiotherapy before being randomized to one of four study arms: goserelin alone, tamoxifen alone, the combination of the two, or no endocrine therapy.

Ms. Johansson noted that they were able to obtain the primary tumor blocks from 729 patients in the past year, of whom 610 were estrogen receptor positive. The analysis according to the 70-gene signature was then based on data from 465 patients: 131 had been treated with goserelin, 105 with tamoxifen, 120 with both, and 109 had received no endocrine treatment.

We have complete 20-year follow-up from high-quality Swedish National registries,” Ms. Johansson said, observing that the median age in the trial was 46 years.

Before stratifying patients into high and low risk using the 70-gene signature, the risk for having a distant recurrence, compared with no endocrine therapy was reduced by 52% with goserelin (hazard ratio, .48), 41% with tamoxifen (HR, 0.59), and 33% with both in combination (HR, 0.67).

After stratification, however, goserelin was associated with a 78% reduction of distant recurrence versus no endocrine treatment in high-risk patients (HR, 0.22) and a 20% reduction in low-risk patients (HR, 0.80).

Results in high- and low-risk patients with tamoxifen versus no endocrine treatment were a respective 31% reduction (HR, 0.69) and 62% reduction (HR, 0.38), and a respective 36% (HR, 0.64) and 28% (HR, 0.72) for the combination.

A further analysis was performed to compare between the active treatment arms, and this suggested a greater benefit of goserelin in patients at high risk when compared with both tamoxifen (HR, 0.30) and the combination (HR, 0.33).

Dr. Francis commented: “it is a bit surprising to find that goserelin appeared to be also better than the combination,” and it is something that the research team is looking into.

“One hypothesis might be if you look how the different treatments are working,” Ms. Johansson said. “Goserelin is very efficient in lowering the estrogen levels in premenopausal patients, suppressing the ovarian production of estrogen whereas tamoxifen can act both as an antagonist and agonist.

“So, we are thinking that maybe the addition of tamoxifen, with the agonistic properties of tamoxifen, might then make the goserelin not as efficient. But that’s of course, just a hypothesis right now and we need to look into this further,” she said.

The work was funded by The Swedish Research Council (Vetenskapsrådet), The Swedish Research Council for Health, Working life and Welfare, and the Swedish Cancer Society (Cancerfonden). Ms. Johansson had no personal disclosures; one of the coauthors was a coinventor of MammaPrint. Dr. Francis disclosed receiving travel support for overseas lectures from Ipsen and Novartis and acting as a medical oncology editor for Elsevier.

The long-term benefits of endocrine therapy in premenopausal breast cancer appear to differ according to whether patients are categorized as high or low molecular risk using the 70-gene signature (MammaPrint).

Based upon data from patients who had participated in the Stockholm tamoxifen (STO-5) trial, high-risk patients significantly benefited from goserelin treatment, whereas low-risk patients benefited more from tamoxifen treatment when compared with no endocrine therapy.

“Goserelin, tamoxifen, and the combination of the two, reduced the 20-year risk of distant occurrences and fatal breast cancer, compared to no endocrine therapy,” Annelie Johansson, MSc, said at the European Society for Medical Oncology: Breast Cancer virtual meeting.

“Our findings indicate that the long-term endocrine therapy benefit in premenopausal patients is influenced by molecular risk classification and thus tumor characteristics,” she added.

Ms. Johansson, a postdoctoral researcher in genomic breast cancer at the Karolinska Institutet in Stockholm, reported the results of the analysis as a late-breaking abstract at the meeting.

“I think this is an innovative translational study trying to use the multigene assay results to look at differential endocrine therapy effects,” said Prudence Francis, MD, the invited discussant for study.

However, there are relatively few patients in the various subgroups being tested, she added. “We’ve also got short duration of tamoxifen, only 2 years, we’ve got prior chemotherapy in some patients and absence of HER2 therapy, all of which might influence outcomes.”

As a result, Dr. Francis, who is head of medical oncology at the Peter MacCallum Cancer Centre and a consultant Medical Oncologist at St. Vincent’s Hospital Melbourne, called the findings purely “hypothesis generating.”
 

Study details and results

The analysis was based on data from the STO-5 trial, which had recruited just over 900 patients between 1990 and 1997. Patients were stratified according to their lymph node status and some received chemotherapy with or without locoregional radiotherapy before being randomized to one of four study arms: goserelin alone, tamoxifen alone, the combination of the two, or no endocrine therapy.

Ms. Johansson noted that they were able to obtain the primary tumor blocks from 729 patients in the past year, of whom 610 were estrogen receptor positive. The analysis according to the 70-gene signature was then based on data from 465 patients: 131 had been treated with goserelin, 105 with tamoxifen, 120 with both, and 109 had received no endocrine treatment.

We have complete 20-year follow-up from high-quality Swedish National registries,” Ms. Johansson said, observing that the median age in the trial was 46 years.

Before stratifying patients into high and low risk using the 70-gene signature, the risk for having a distant recurrence, compared with no endocrine therapy was reduced by 52% with goserelin (hazard ratio, .48), 41% with tamoxifen (HR, 0.59), and 33% with both in combination (HR, 0.67).

After stratification, however, goserelin was associated with a 78% reduction of distant recurrence versus no endocrine treatment in high-risk patients (HR, 0.22) and a 20% reduction in low-risk patients (HR, 0.80).

Results in high- and low-risk patients with tamoxifen versus no endocrine treatment were a respective 31% reduction (HR, 0.69) and 62% reduction (HR, 0.38), and a respective 36% (HR, 0.64) and 28% (HR, 0.72) for the combination.

A further analysis was performed to compare between the active treatment arms, and this suggested a greater benefit of goserelin in patients at high risk when compared with both tamoxifen (HR, 0.30) and the combination (HR, 0.33).

Dr. Francis commented: “it is a bit surprising to find that goserelin appeared to be also better than the combination,” and it is something that the research team is looking into.

“One hypothesis might be if you look how the different treatments are working,” Ms. Johansson said. “Goserelin is very efficient in lowering the estrogen levels in premenopausal patients, suppressing the ovarian production of estrogen whereas tamoxifen can act both as an antagonist and agonist.

“So, we are thinking that maybe the addition of tamoxifen, with the agonistic properties of tamoxifen, might then make the goserelin not as efficient. But that’s of course, just a hypothesis right now and we need to look into this further,” she said.

The work was funded by The Swedish Research Council (Vetenskapsrådet), The Swedish Research Council for Health, Working life and Welfare, and the Swedish Cancer Society (Cancerfonden). Ms. Johansson had no personal disclosures; one of the coauthors was a coinventor of MammaPrint. Dr. Francis disclosed receiving travel support for overseas lectures from Ipsen and Novartis and acting as a medical oncology editor for Elsevier.

The long-term benefits of endocrine therapy in premenopausal breast cancer appear to differ according to whether patients are categorized as high or low molecular risk using the 70-gene signature (MammaPrint).

Based upon data from patients who had participated in the Stockholm tamoxifen (STO-5) trial, high-risk patients significantly benefited from goserelin treatment, whereas low-risk patients benefited more from tamoxifen treatment when compared with no endocrine therapy.

“Goserelin, tamoxifen, and the combination of the two, reduced the 20-year risk of distant occurrences and fatal breast cancer, compared to no endocrine therapy,” Annelie Johansson, MSc, said at the European Society for Medical Oncology: Breast Cancer virtual meeting.

“Our findings indicate that the long-term endocrine therapy benefit in premenopausal patients is influenced by molecular risk classification and thus tumor characteristics,” she added.

Ms. Johansson, a postdoctoral researcher in genomic breast cancer at the Karolinska Institutet in Stockholm, reported the results of the analysis as a late-breaking abstract at the meeting.

“I think this is an innovative translational study trying to use the multigene assay results to look at differential endocrine therapy effects,” said Prudence Francis, MD, the invited discussant for study.

However, there are relatively few patients in the various subgroups being tested, she added. “We’ve also got short duration of tamoxifen, only 2 years, we’ve got prior chemotherapy in some patients and absence of HER2 therapy, all of which might influence outcomes.”

As a result, Dr. Francis, who is head of medical oncology at the Peter MacCallum Cancer Centre and a consultant Medical Oncologist at St. Vincent’s Hospital Melbourne, called the findings purely “hypothesis generating.”
 

Study details and results

The analysis was based on data from the STO-5 trial, which had recruited just over 900 patients between 1990 and 1997. Patients were stratified according to their lymph node status and some received chemotherapy with or without locoregional radiotherapy before being randomized to one of four study arms: goserelin alone, tamoxifen alone, the combination of the two, or no endocrine therapy.

Ms. Johansson noted that they were able to obtain the primary tumor blocks from 729 patients in the past year, of whom 610 were estrogen receptor positive. The analysis according to the 70-gene signature was then based on data from 465 patients: 131 had been treated with goserelin, 105 with tamoxifen, 120 with both, and 109 had received no endocrine treatment.

We have complete 20-year follow-up from high-quality Swedish National registries,” Ms. Johansson said, observing that the median age in the trial was 46 years.

Before stratifying patients into high and low risk using the 70-gene signature, the risk for having a distant recurrence, compared with no endocrine therapy was reduced by 52% with goserelin (hazard ratio, .48), 41% with tamoxifen (HR, 0.59), and 33% with both in combination (HR, 0.67).

After stratification, however, goserelin was associated with a 78% reduction of distant recurrence versus no endocrine treatment in high-risk patients (HR, 0.22) and a 20% reduction in low-risk patients (HR, 0.80).

Results in high- and low-risk patients with tamoxifen versus no endocrine treatment were a respective 31% reduction (HR, 0.69) and 62% reduction (HR, 0.38), and a respective 36% (HR, 0.64) and 28% (HR, 0.72) for the combination.

A further analysis was performed to compare between the active treatment arms, and this suggested a greater benefit of goserelin in patients at high risk when compared with both tamoxifen (HR, 0.30) and the combination (HR, 0.33).

Dr. Francis commented: “it is a bit surprising to find that goserelin appeared to be also better than the combination,” and it is something that the research team is looking into.

“One hypothesis might be if you look how the different treatments are working,” Ms. Johansson said. “Goserelin is very efficient in lowering the estrogen levels in premenopausal patients, suppressing the ovarian production of estrogen whereas tamoxifen can act both as an antagonist and agonist.

“So, we are thinking that maybe the addition of tamoxifen, with the agonistic properties of tamoxifen, might then make the goserelin not as efficient. But that’s of course, just a hypothesis right now and we need to look into this further,” she said.

The work was funded by The Swedish Research Council (Vetenskapsrådet), The Swedish Research Council for Health, Working life and Welfare, and the Swedish Cancer Society (Cancerfonden). Ms. Johansson had no personal disclosures; one of the coauthors was a coinventor of MammaPrint. Dr. Francis disclosed receiving travel support for overseas lectures from Ipsen and Novartis and acting as a medical oncology editor for Elsevier.

For children with spinal muscular atrophy (SMA), gene therapy with onasemnogene abeparvovec (Zolgensma, Novartis) provides long-lasting benefits with a favorable safety profile, new long-term follow-up data show. At a median of 5.2 years since receiving the approved therapeutic dose, onasemnogene abeparvovec provided “sustained, durable efficacy, with all patients alive and without the need for permanent ventilation,” reported Jerry Mendell, MD, with the Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, Ohio, and colleagues.

The study was published online May 17 in JAMA Neurology.
 

Single infusion

SMA is a rare genetic disease that can lead to paralysis, breathing difficulty, and death. The disorder is caused by a mutation in the survival motor neuron 1 (SMN1) gene, which encodes the SMN protein critical for maintenance and function of motor neurons.

In 2019, Zolgensma was approved in the United States for children with SMA and younger than 2 years of age.

Zolgensma is an adeno-associated virus vector-based gene therapy that addresses the genetic root cause of SMA by replacing the defective or missing SMN1 gene to halt disease progression. A single, one-time intravenous infusion results in expression of the SMN protein motor neurons, which improves chances of survival, as well as muscle movement and function.

In the phase 1 START study, 15 infants with SMA type 1 were treated with either a low or therapeutic dose of Zolgensma at Nationwide Children’s Hospital between 2014 and 2017.

The START long-term follow-up study (START LTFU) is an ongoing, observational study assessing safety and durability of response over 15 years in 13 of the infants; three infants received the low dose and 10 received the approved high dose.

Prior to baseline, four patients (40%) in the therapeutic dose cohort required noninvasive ventilatory support, and six (60%) did not require regular ventilatory support, which did not change in long-term follow-up.

All 10 patients who received the therapeutic dose remained alive and without the need for permanent ventilation up to 6.2 years after dosing, Dr. Mendell and colleagues report.

These patients also maintained previously acquired motor milestones. Two patients attained the new milestone of “standing with assistance” without the use of nusinersen (Spinraza, Biogen). 

Serious adverse events occurred in eight patients (62%), none of which resulted in study discontinuation or death. The most common serious adverse events were related to the underlying SMA disease process and included acute respiratory failure (31%), pneumonia (31%), dehydration (23%), respiratory distress (15%), and bronchiolitis (15%).

Importantly, the investigators noted, no new safety signals or “adverse events of special interest” emerged during follow-up, including liver function enzyme elevations, new incidences of malignancy or hematologic disorders, and new incidences or exacerbations of existing neurologic or autoimmune disorders.

The investigators acknowledged that this follow-up study is limited by the small sample size of the patient population and confounded by treatment with nusinersen in several patients. “However, given that the two patients who acquired the new motor milestone of standing with assistance did not receive nusinersen at any time, this benefit can be attributed solely to onasemnogene abeparvovec,” Dr. Mendell and colleagues said. 

The study was supported by Novartis Gene Therapies. Dr. Mendell and several co-investigators have disclosed financial relationships with the company.

A version of this article first appeared on Medscape.com.

For children with spinal muscular atrophy (SMA), gene therapy with onasemnogene abeparvovec (Zolgensma, Novartis) provides long-lasting benefits with a favorable safety profile, new long-term follow-up data show. At a median of 5.2 years since receiving the approved therapeutic dose, onasemnogene abeparvovec provided “sustained, durable efficacy, with all patients alive and without the need for permanent ventilation,” reported Jerry Mendell, MD, with the Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, Ohio, and colleagues.

The study was published online May 17 in JAMA Neurology.
 

Single infusion

SMA is a rare genetic disease that can lead to paralysis, breathing difficulty, and death. The disorder is caused by a mutation in the survival motor neuron 1 (SMN1) gene, which encodes the SMN protein critical for maintenance and function of motor neurons.

In 2019, Zolgensma was approved in the United States for children with SMA and younger than 2 years of age.

Zolgensma is an adeno-associated virus vector-based gene therapy that addresses the genetic root cause of SMA by replacing the defective or missing SMN1 gene to halt disease progression. A single, one-time intravenous infusion results in expression of the SMN protein motor neurons, which improves chances of survival, as well as muscle movement and function.

In the phase 1 START study, 15 infants with SMA type 1 were treated with either a low or therapeutic dose of Zolgensma at Nationwide Children’s Hospital between 2014 and 2017.

The START long-term follow-up study (START LTFU) is an ongoing, observational study assessing safety and durability of response over 15 years in 13 of the infants; three infants received the low dose and 10 received the approved high dose.

Prior to baseline, four patients (40%) in the therapeutic dose cohort required noninvasive ventilatory support, and six (60%) did not require regular ventilatory support, which did not change in long-term follow-up.

All 10 patients who received the therapeutic dose remained alive and without the need for permanent ventilation up to 6.2 years after dosing, Dr. Mendell and colleagues report.

These patients also maintained previously acquired motor milestones. Two patients attained the new milestone of “standing with assistance” without the use of nusinersen (Spinraza, Biogen). 

Serious adverse events occurred in eight patients (62%), none of which resulted in study discontinuation or death. The most common serious adverse events were related to the underlying SMA disease process and included acute respiratory failure (31%), pneumonia (31%), dehydration (23%), respiratory distress (15%), and bronchiolitis (15%).

Importantly, the investigators noted, no new safety signals or “adverse events of special interest” emerged during follow-up, including liver function enzyme elevations, new incidences of malignancy or hematologic disorders, and new incidences or exacerbations of existing neurologic or autoimmune disorders.

The investigators acknowledged that this follow-up study is limited by the small sample size of the patient population and confounded by treatment with nusinersen in several patients. “However, given that the two patients who acquired the new motor milestone of standing with assistance did not receive nusinersen at any time, this benefit can be attributed solely to onasemnogene abeparvovec,” Dr. Mendell and colleagues said. 

The study was supported by Novartis Gene Therapies. Dr. Mendell and several co-investigators have disclosed financial relationships with the company.

A version of this article first appeared on Medscape.com.

For children with spinal muscular atrophy (SMA), gene therapy with onasemnogene abeparvovec (Zolgensma, Novartis) provides long-lasting benefits with a favorable safety profile, new long-term follow-up data show. At a median of 5.2 years since receiving the approved therapeutic dose, onasemnogene abeparvovec provided “sustained, durable efficacy, with all patients alive and without the need for permanent ventilation,” reported Jerry Mendell, MD, with the Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, Ohio, and colleagues.

The study was published online May 17 in JAMA Neurology.
 

Single infusion

SMA is a rare genetic disease that can lead to paralysis, breathing difficulty, and death. The disorder is caused by a mutation in the survival motor neuron 1 (SMN1) gene, which encodes the SMN protein critical for maintenance and function of motor neurons.

In 2019, Zolgensma was approved in the United States for children with SMA and younger than 2 years of age.

Zolgensma is an adeno-associated virus vector-based gene therapy that addresses the genetic root cause of SMA by replacing the defective or missing SMN1 gene to halt disease progression. A single, one-time intravenous infusion results in expression of the SMN protein motor neurons, which improves chances of survival, as well as muscle movement and function.

In the phase 1 START study, 15 infants with SMA type 1 were treated with either a low or therapeutic dose of Zolgensma at Nationwide Children’s Hospital between 2014 and 2017.

The START long-term follow-up study (START LTFU) is an ongoing, observational study assessing safety and durability of response over 15 years in 13 of the infants; three infants received the low dose and 10 received the approved high dose.

Prior to baseline, four patients (40%) in the therapeutic dose cohort required noninvasive ventilatory support, and six (60%) did not require regular ventilatory support, which did not change in long-term follow-up.

All 10 patients who received the therapeutic dose remained alive and without the need for permanent ventilation up to 6.2 years after dosing, Dr. Mendell and colleagues report.

These patients also maintained previously acquired motor milestones. Two patients attained the new milestone of “standing with assistance” without the use of nusinersen (Spinraza, Biogen). 

Serious adverse events occurred in eight patients (62%), none of which resulted in study discontinuation or death. The most common serious adverse events were related to the underlying SMA disease process and included acute respiratory failure (31%), pneumonia (31%), dehydration (23%), respiratory distress (15%), and bronchiolitis (15%).

Importantly, the investigators noted, no new safety signals or “adverse events of special interest” emerged during follow-up, including liver function enzyme elevations, new incidences of malignancy or hematologic disorders, and new incidences or exacerbations of existing neurologic or autoimmune disorders.

The investigators acknowledged that this follow-up study is limited by the small sample size of the patient population and confounded by treatment with nusinersen in several patients. “However, given that the two patients who acquired the new motor milestone of standing with assistance did not receive nusinersen at any time, this benefit can be attributed solely to onasemnogene abeparvovec,” Dr. Mendell and colleagues said. 

The study was supported by Novartis Gene Therapies. Dr. Mendell and several co-investigators have disclosed financial relationships with the company.

A version of this article first appeared on Medscape.com.

The first cases of large vessel arterial occlusion strokes linked to the AstraZeneca COVID-19 vaccine have been described in the United Kingdom. The three cases (one of which was fatal) occurred in two women and one man in their 30s or 40s and involved blockages of the carotid and middle cerebral artery. Two of the three patients also had venous thrombosis involving the portal and cerebral venous system. All three also had extremely low platelet counts, confirmed antibodies to platelet factor 4, and raised D-dimer levels, all characteristic of the vaccine-induced immune thrombotic thrombocytopenia (VITT) reaction associated with the AstraZeneca vaccine.  

They are described in detail in a letter published online on May 25 in the Journal of Neurology, Neurosurgery & Psychiatry

“These are [the] first detailed reports of arterial stroke believed to be caused by VITT after the AstraZeneca COVID vaccine, although stroke has been mentioned previously in the VITT data,” said senior author David Werring, PhD, FRCP.

“VITT has more commonly presented as CVST [Cerebral venous sinus thrombosis] which is stroke caused by a venous thrombosis; these cases are showing that it can also cause stroke caused by an arterial thrombosis,” explained Dr. Werring, professor of clinical neurology at the Stroke Research Centre, University College London.

“In patients who present with ischemic stroke, especially younger patients, and who have had the AstraZeneca vaccine within the past month, clinicians need to consider VITT as a possible cause, as there is a specific treatment needed for this syndrome,” he said.  

Young patients presenting with ischemic stroke after receiving the AstraZeneca vaccine should urgently be evaluated for VITT with laboratory tests, including platelet count, D-dimers, fibrinogen, and anti-PF4 antibodies, the authors wrote, and then managed by a multidisciplinary team, including hematology, neurology, stroke, neurosurgery, and neuroradiology, for rapid access to treatments including intravenous immune globulin, methylprednisolone, plasmapheresis, and nonheparin anticoagulants such as fondaparinux, argatroban, or direct oral anticoagulants.

Dr. Werring noted that these reports do not add anything to the overall risk/benefit of the vaccine, as they are only describing three cases. “While VITT is very serious, the benefit of the vaccine still outweighs its risks,” he said. “Around 40% of patients hospitalized with COVID-19 experience some sort of thrombosis and about 1.5% have an ischemic stroke. Whereas latest figures from the U.K. estimate the incidence of VITT with the AstraZeneca vaccine of 1 in 50,000 to 1 in 100,000.

“Our report doesn’t suggest that VITT is more common than these latest figures estimate, but we are just drawing attention to an alternative presentation,” he added.  
 

Three cases

The first patient in the current case series, a woman in her 30s, experienced an intermittent headache on the right side and around her eyes 6 days after the vaccine. Five days later, she awoke feeling drowsy and with weakness to her left face, arm, and leg.

Imaging revealed a blocked right middle cerebral artery with brain infarction and clots in the right portal vein. She underwent brain surgery to reduce the pressure in her skull, plasma removal and replacement, and received the anticoagulant fondaparinux, but she still unfortunately died.

The second patient, a woman in her late 30s, presented with headache, confusion, weakness in her left arm, and loss of vision on the left side 12 days after having received the vaccine. Imaging showed occlusion of both carotid arteries, as well as pulmonary embolism and a left cerebral venous sinus thrombosis.  

Her platelet count increased following plasma removal and replacement and intravenous corticosteroids, and her condition improved after fondaparinux treatment.

The third patient, a man in his early 40s, presented 3 weeks after receiving his vaccination with problems speaking. Imaging showed a clot in the left middle cerebral artery, but there was no evidence of clots in the cerebral venous sinuses. He received a platelet and plasma transfusion, and fondaparinux, and remains stable.
 

High index of suspicion required

In a linked commentary, Hugh Markus, PhD, FRCP, professor of stroke medicine at the University of Cambridge, United Kingdom, wrote: “This report emphasizes that the immune mediated coagulopathy can also cause arterial thrombosis, including ischemic stroke, although venous thrombosis and especially cerebral venous sinus thrombosis appear more frequent.

“During the current period of COVID vaccination, a high index of suspicion is required to identify thrombotic episodes following vaccination,” he added. “However, it is important to remember that these side effects are rare and much less common than both cerebral venous thrombosis and ischemic stroke associated with COVID-19 infection itself.”
 

Risk/benefit unaltered

Several experts who commented on these reports for the Science Media Centre all agreed with Dr. Werring and Dr. Markus that these reports do not alter the current risk/benefit estimates with the vaccine.

Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, who sits on the U.K.’s Medicines and Healthcare Products Regulatory Agency’s Pharmacovigilance Expert Advisory Group, said: “The picture regarding the rare syndrome of blood clots combined with low platelet counts associated with the AstraZeneca vaccine is becoming clearer. Until now, the cases described have tended to involve clots in veins such as cerebral vein thrombosis. In this series of three case reports, we now have some evidence that the types of blood vessels affected include arteries as well as veins.”  

“It’s important to stress that such cases remain very rare, and it’s certainly much rarer in people who have had the AstraZeneca vaccine than it is in people affected by COVID-19 itself,” Dr. Douglas emphasized.

“The description of the cases suggests the patients involved presented with the same kind of symptoms as already described in cases involving cerebral vein thrombosis, and they don’t suggest patients need to be on the alert for anything different,” he added.

“However, the emergence of details like this will help guide health professionals who may be faced with similar cases in future; the sooner such cases are recognized, the more chance they will quickly receive the right kind of treatment, hopefully leading to better outcomes.”

Will Lester, MBChB, PhD, consultant hematologist, University Hospitals Birmingham NHS Foundation Trust, said: “VITT remains a rare complication, and patients with a history of thrombosis, including stroke, should not consider themselves to be at any higher risk of this type of rare thrombosis after vaccination, and COVID infection itself is a significant risk for stroke and other types of thrombosis.”

Many countries have paused use of the AstraZeneca vaccine because of its link to the VITT syndrome or restricted its use to older people as the VITT reaction appears to be slightly more common in younger people. In the United Kingdom, the current recommendation is that individuals under 40 years of age should be offered an alternative to the AstraZeneca vaccine where possible.

A version of this article first appeared on Medscape.com.

The first cases of large vessel arterial occlusion strokes linked to the AstraZeneca COVID-19 vaccine have been described in the United Kingdom. The three cases (one of which was fatal) occurred in two women and one man in their 30s or 40s and involved blockages of the carotid and middle cerebral artery. Two of the three patients also had venous thrombosis involving the portal and cerebral venous system. All three also had extremely low platelet counts, confirmed antibodies to platelet factor 4, and raised D-dimer levels, all characteristic of the vaccine-induced immune thrombotic thrombocytopenia (VITT) reaction associated with the AstraZeneca vaccine.  

They are described in detail in a letter published online on May 25 in the Journal of Neurology, Neurosurgery & Psychiatry

“These are [the] first detailed reports of arterial stroke believed to be caused by VITT after the AstraZeneca COVID vaccine, although stroke has been mentioned previously in the VITT data,” said senior author David Werring, PhD, FRCP.

“VITT has more commonly presented as CVST [Cerebral venous sinus thrombosis] which is stroke caused by a venous thrombosis; these cases are showing that it can also cause stroke caused by an arterial thrombosis,” explained Dr. Werring, professor of clinical neurology at the Stroke Research Centre, University College London.

“In patients who present with ischemic stroke, especially younger patients, and who have had the AstraZeneca vaccine within the past month, clinicians need to consider VITT as a possible cause, as there is a specific treatment needed for this syndrome,” he said.  

Young patients presenting with ischemic stroke after receiving the AstraZeneca vaccine should urgently be evaluated for VITT with laboratory tests, including platelet count, D-dimers, fibrinogen, and anti-PF4 antibodies, the authors wrote, and then managed by a multidisciplinary team, including hematology, neurology, stroke, neurosurgery, and neuroradiology, for rapid access to treatments including intravenous immune globulin, methylprednisolone, plasmapheresis, and nonheparin anticoagulants such as fondaparinux, argatroban, or direct oral anticoagulants.

Dr. Werring noted that these reports do not add anything to the overall risk/benefit of the vaccine, as they are only describing three cases. “While VITT is very serious, the benefit of the vaccine still outweighs its risks,” he said. “Around 40% of patients hospitalized with COVID-19 experience some sort of thrombosis and about 1.5% have an ischemic stroke. Whereas latest figures from the U.K. estimate the incidence of VITT with the AstraZeneca vaccine of 1 in 50,000 to 1 in 100,000.

“Our report doesn’t suggest that VITT is more common than these latest figures estimate, but we are just drawing attention to an alternative presentation,” he added.  
 

Three cases

The first patient in the current case series, a woman in her 30s, experienced an intermittent headache on the right side and around her eyes 6 days after the vaccine. Five days later, she awoke feeling drowsy and with weakness to her left face, arm, and leg.

Imaging revealed a blocked right middle cerebral artery with brain infarction and clots in the right portal vein. She underwent brain surgery to reduce the pressure in her skull, plasma removal and replacement, and received the anticoagulant fondaparinux, but she still unfortunately died.

The second patient, a woman in her late 30s, presented with headache, confusion, weakness in her left arm, and loss of vision on the left side 12 days after having received the vaccine. Imaging showed occlusion of both carotid arteries, as well as pulmonary embolism and a left cerebral venous sinus thrombosis.  

Her platelet count increased following plasma removal and replacement and intravenous corticosteroids, and her condition improved after fondaparinux treatment.

The third patient, a man in his early 40s, presented 3 weeks after receiving his vaccination with problems speaking. Imaging showed a clot in the left middle cerebral artery, but there was no evidence of clots in the cerebral venous sinuses. He received a platelet and plasma transfusion, and fondaparinux, and remains stable.
 

High index of suspicion required

In a linked commentary, Hugh Markus, PhD, FRCP, professor of stroke medicine at the University of Cambridge, United Kingdom, wrote: “This report emphasizes that the immune mediated coagulopathy can also cause arterial thrombosis, including ischemic stroke, although venous thrombosis and especially cerebral venous sinus thrombosis appear more frequent.

“During the current period of COVID vaccination, a high index of suspicion is required to identify thrombotic episodes following vaccination,” he added. “However, it is important to remember that these side effects are rare and much less common than both cerebral venous thrombosis and ischemic stroke associated with COVID-19 infection itself.”
 

Risk/benefit unaltered

Several experts who commented on these reports for the Science Media Centre all agreed with Dr. Werring and Dr. Markus that these reports do not alter the current risk/benefit estimates with the vaccine.

Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, who sits on the U.K.’s Medicines and Healthcare Products Regulatory Agency’s Pharmacovigilance Expert Advisory Group, said: “The picture regarding the rare syndrome of blood clots combined with low platelet counts associated with the AstraZeneca vaccine is becoming clearer. Until now, the cases described have tended to involve clots in veins such as cerebral vein thrombosis. In this series of three case reports, we now have some evidence that the types of blood vessels affected include arteries as well as veins.”  

“It’s important to stress that such cases remain very rare, and it’s certainly much rarer in people who have had the AstraZeneca vaccine than it is in people affected by COVID-19 itself,” Dr. Douglas emphasized.

“The description of the cases suggests the patients involved presented with the same kind of symptoms as already described in cases involving cerebral vein thrombosis, and they don’t suggest patients need to be on the alert for anything different,” he added.

“However, the emergence of details like this will help guide health professionals who may be faced with similar cases in future; the sooner such cases are recognized, the more chance they will quickly receive the right kind of treatment, hopefully leading to better outcomes.”

Will Lester, MBChB, PhD, consultant hematologist, University Hospitals Birmingham NHS Foundation Trust, said: “VITT remains a rare complication, and patients with a history of thrombosis, including stroke, should not consider themselves to be at any higher risk of this type of rare thrombosis after vaccination, and COVID infection itself is a significant risk for stroke and other types of thrombosis.”

Many countries have paused use of the AstraZeneca vaccine because of its link to the VITT syndrome or restricted its use to older people as the VITT reaction appears to be slightly more common in younger people. In the United Kingdom, the current recommendation is that individuals under 40 years of age should be offered an alternative to the AstraZeneca vaccine where possible.

A version of this article first appeared on Medscape.com.

The first cases of large vessel arterial occlusion strokes linked to the AstraZeneca COVID-19 vaccine have been described in the United Kingdom. The three cases (one of which was fatal) occurred in two women and one man in their 30s or 40s and involved blockages of the carotid and middle cerebral artery. Two of the three patients also had venous thrombosis involving the portal and cerebral venous system. All three also had extremely low platelet counts, confirmed antibodies to platelet factor 4, and raised D-dimer levels, all characteristic of the vaccine-induced immune thrombotic thrombocytopenia (VITT) reaction associated with the AstraZeneca vaccine.  

They are described in detail in a letter published online on May 25 in the Journal of Neurology, Neurosurgery & Psychiatry

“These are [the] first detailed reports of arterial stroke believed to be caused by VITT after the AstraZeneca COVID vaccine, although stroke has been mentioned previously in the VITT data,” said senior author David Werring, PhD, FRCP.

“VITT has more commonly presented as CVST [Cerebral venous sinus thrombosis] which is stroke caused by a venous thrombosis; these cases are showing that it can also cause stroke caused by an arterial thrombosis,” explained Dr. Werring, professor of clinical neurology at the Stroke Research Centre, University College London.

“In patients who present with ischemic stroke, especially younger patients, and who have had the AstraZeneca vaccine within the past month, clinicians need to consider VITT as a possible cause, as there is a specific treatment needed for this syndrome,” he said.  

Young patients presenting with ischemic stroke after receiving the AstraZeneca vaccine should urgently be evaluated for VITT with laboratory tests, including platelet count, D-dimers, fibrinogen, and anti-PF4 antibodies, the authors wrote, and then managed by a multidisciplinary team, including hematology, neurology, stroke, neurosurgery, and neuroradiology, for rapid access to treatments including intravenous immune globulin, methylprednisolone, plasmapheresis, and nonheparin anticoagulants such as fondaparinux, argatroban, or direct oral anticoagulants.

Dr. Werring noted that these reports do not add anything to the overall risk/benefit of the vaccine, as they are only describing three cases. “While VITT is very serious, the benefit of the vaccine still outweighs its risks,” he said. “Around 40% of patients hospitalized with COVID-19 experience some sort of thrombosis and about 1.5% have an ischemic stroke. Whereas latest figures from the U.K. estimate the incidence of VITT with the AstraZeneca vaccine of 1 in 50,000 to 1 in 100,000.

“Our report doesn’t suggest that VITT is more common than these latest figures estimate, but we are just drawing attention to an alternative presentation,” he added.  
 

Three cases

The first patient in the current case series, a woman in her 30s, experienced an intermittent headache on the right side and around her eyes 6 days after the vaccine. Five days later, she awoke feeling drowsy and with weakness to her left face, arm, and leg.

Imaging revealed a blocked right middle cerebral artery with brain infarction and clots in the right portal vein. She underwent brain surgery to reduce the pressure in her skull, plasma removal and replacement, and received the anticoagulant fondaparinux, but she still unfortunately died.

The second patient, a woman in her late 30s, presented with headache, confusion, weakness in her left arm, and loss of vision on the left side 12 days after having received the vaccine. Imaging showed occlusion of both carotid arteries, as well as pulmonary embolism and a left cerebral venous sinus thrombosis.  

Her platelet count increased following plasma removal and replacement and intravenous corticosteroids, and her condition improved after fondaparinux treatment.

The third patient, a man in his early 40s, presented 3 weeks after receiving his vaccination with problems speaking. Imaging showed a clot in the left middle cerebral artery, but there was no evidence of clots in the cerebral venous sinuses. He received a platelet and plasma transfusion, and fondaparinux, and remains stable.
 

High index of suspicion required

In a linked commentary, Hugh Markus, PhD, FRCP, professor of stroke medicine at the University of Cambridge, United Kingdom, wrote: “This report emphasizes that the immune mediated coagulopathy can also cause arterial thrombosis, including ischemic stroke, although venous thrombosis and especially cerebral venous sinus thrombosis appear more frequent.

“During the current period of COVID vaccination, a high index of suspicion is required to identify thrombotic episodes following vaccination,” he added. “However, it is important to remember that these side effects are rare and much less common than both cerebral venous thrombosis and ischemic stroke associated with COVID-19 infection itself.”
 

Risk/benefit unaltered

Several experts who commented on these reports for the Science Media Centre all agreed with Dr. Werring and Dr. Markus that these reports do not alter the current risk/benefit estimates with the vaccine.

Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, who sits on the U.K.’s Medicines and Healthcare Products Regulatory Agency’s Pharmacovigilance Expert Advisory Group, said: “The picture regarding the rare syndrome of blood clots combined with low platelet counts associated with the AstraZeneca vaccine is becoming clearer. Until now, the cases described have tended to involve clots in veins such as cerebral vein thrombosis. In this series of three case reports, we now have some evidence that the types of blood vessels affected include arteries as well as veins.”  

“It’s important to stress that such cases remain very rare, and it’s certainly much rarer in people who have had the AstraZeneca vaccine than it is in people affected by COVID-19 itself,” Dr. Douglas emphasized.

“The description of the cases suggests the patients involved presented with the same kind of symptoms as already described in cases involving cerebral vein thrombosis, and they don’t suggest patients need to be on the alert for anything different,” he added.

“However, the emergence of details like this will help guide health professionals who may be faced with similar cases in future; the sooner such cases are recognized, the more chance they will quickly receive the right kind of treatment, hopefully leading to better outcomes.”

Will Lester, MBChB, PhD, consultant hematologist, University Hospitals Birmingham NHS Foundation Trust, said: “VITT remains a rare complication, and patients with a history of thrombosis, including stroke, should not consider themselves to be at any higher risk of this type of rare thrombosis after vaccination, and COVID infection itself is a significant risk for stroke and other types of thrombosis.”

Many countries have paused use of the AstraZeneca vaccine because of its link to the VITT syndrome or restricted its use to older people as the VITT reaction appears to be slightly more common in younger people. In the United Kingdom, the current recommendation is that individuals under 40 years of age should be offered an alternative to the AstraZeneca vaccine where possible.

A version of this article first appeared on Medscape.com.