Clinical Edge Journal Scan Commentary

Patients receive the full range of contraception options when providers are educated on the proper use and spectrum of contraceptive options. When an educational intervention was introduced in three countries (Democratic Republic of Congo, Somalia, and Pakistan), aimed at training providers on counseling and provision of immediate postpartum LARC, a significant number of women opted for LARC. This was in comparison to countries that did not implement this educational intervention (Rwanda, Syria, Yemen). The rate of LARC adoption was 10.01% versus 0.77%, respectively in countries providing the educational intervention versus those that did not. 

The copper IUD has long been utilized for emergency contraception, providing nearly 100% efficacy in pregnancy prevention, as well as long-acting, reversible contraception. Recently, the levonorgestrel (LNG) IUD was considered for similar use as emergency contraception. Turok et al studied the pregnancy rate of the LNG IUD compared the copper IUD and found that the LNG IUD was noninferior to the copper IUD when used for emergency contraception, with pregnancy rates of 1 in 317 (LNG) compared to 0 in 321 (copper). LNG IUDs are often more readily available in OBGYN offices and could improve access to higher efficacy emergency contraception compared to traditional emergency contraceptive pills.

When placing IUDs, providers have a range of devices to measure the length of the uterus for correct IUD placement, including endometrial biopsy pipelles, uterine sounds, both plastic and metal, as well as the device inserters. In a biomechanical ex vivo analysis, Duncan et al examined the maximum force generated for IUD placement with the levonorgestrel placement instrument, the copper IUD placement instrument, and a metal sound. Using their model, the investigators found that the metal sound caused uterine perforation, but the plastic IUD placement device did not. Although the study authors utilized the device inserters themselves, we recommend the use of plastic uterine sounds or biopsy pipelles over the device inserters in accordance with IUD packaging instructions.  IUD packaging should not be opened until both the ability to access the uterine cavity and appropriate uterine size are determined to avoid needing to discard the IUD.

Patients receive the full range of contraception options when providers are educated on the proper use and spectrum of contraceptive options. When an educational intervention was introduced in three countries (Democratic Republic of Congo, Somalia, and Pakistan), aimed at training providers on counseling and provision of immediate postpartum LARC, a significant number of women opted for LARC. This was in comparison to countries that did not implement this educational intervention (Rwanda, Syria, Yemen). The rate of LARC adoption was 10.01% versus 0.77%, respectively in countries providing the educational intervention versus those that did not. 

The copper IUD has long been utilized for emergency contraception, providing nearly 100% efficacy in pregnancy prevention, as well as long-acting, reversible contraception. Recently, the levonorgestrel (LNG) IUD was considered for similar use as emergency contraception. Turok et al studied the pregnancy rate of the LNG IUD compared the copper IUD and found that the LNG IUD was noninferior to the copper IUD when used for emergency contraception, with pregnancy rates of 1 in 317 (LNG) compared to 0 in 321 (copper). LNG IUDs are often more readily available in OBGYN offices and could improve access to higher efficacy emergency contraception compared to traditional emergency contraceptive pills.

When placing IUDs, providers have a range of devices to measure the length of the uterus for correct IUD placement, including endometrial biopsy pipelles, uterine sounds, both plastic and metal, as well as the device inserters. In a biomechanical ex vivo analysis, Duncan et al examined the maximum force generated for IUD placement with the levonorgestrel placement instrument, the copper IUD placement instrument, and a metal sound. Using their model, the investigators found that the metal sound caused uterine perforation, but the plastic IUD placement device did not. Although the study authors utilized the device inserters themselves, we recommend the use of plastic uterine sounds or biopsy pipelles over the device inserters in accordance with IUD packaging instructions.  IUD packaging should not be opened until both the ability to access the uterine cavity and appropriate uterine size are determined to avoid needing to discard the IUD.

Patients receive the full range of contraception options when providers are educated on the proper use and spectrum of contraceptive options. When an educational intervention was introduced in three countries (Democratic Republic of Congo, Somalia, and Pakistan), aimed at training providers on counseling and provision of immediate postpartum LARC, a significant number of women opted for LARC. This was in comparison to countries that did not implement this educational intervention (Rwanda, Syria, Yemen). The rate of LARC adoption was 10.01% versus 0.77%, respectively in countries providing the educational intervention versus those that did not. 

The copper IUD has long been utilized for emergency contraception, providing nearly 100% efficacy in pregnancy prevention, as well as long-acting, reversible contraception. Recently, the levonorgestrel (LNG) IUD was considered for similar use as emergency contraception. Turok et al studied the pregnancy rate of the LNG IUD compared the copper IUD and found that the LNG IUD was noninferior to the copper IUD when used for emergency contraception, with pregnancy rates of 1 in 317 (LNG) compared to 0 in 321 (copper). LNG IUDs are often more readily available in OBGYN offices and could improve access to higher efficacy emergency contraception compared to traditional emergency contraceptive pills.

When placing IUDs, providers have a range of devices to measure the length of the uterus for correct IUD placement, including endometrial biopsy pipelles, uterine sounds, both plastic and metal, as well as the device inserters. In a biomechanical ex vivo analysis, Duncan et al examined the maximum force generated for IUD placement with the levonorgestrel placement instrument, the copper IUD placement instrument, and a metal sound. Using their model, the investigators found that the metal sound caused uterine perforation, but the plastic IUD placement device did not. Although the study authors utilized the device inserters themselves, we recommend the use of plastic uterine sounds or biopsy pipelles over the device inserters in accordance with IUD packaging instructions.  IUD packaging should not be opened until both the ability to access the uterine cavity and appropriate uterine size are determined to avoid needing to discard the IUD.

In a study by Trembely et al. sponsored by Pfizer, an indirect comparison of both studies was performed using a simulated treatment comparison to account for differences in patient characteristics. As expected, the overall response rates were higher in the venetoclax study compared to the glasdegib study (48% vs. 24%), but overall survival was similar (hazard ratio 0.75 vs. HR 0.46). This study demonstrates again that CR/CRi cannot be used as a surrogate endpoint for survival in AML. In addition, with the negative study of V-LDAC vs. LDAC and the improved overall survival of the combination of azacytidine + venetoclax (Aza-ven) vs. azacitdine, the current standard of care of newly diagnosed patients with AML unbale to tolerate intensive chemotherapy is Aza-ven and V-LDAC is rarely used.

The success of Aza-ven is not without side effects. This was demonstrated recently in a retrospective study by Feld et al. In that study 72 patients with newly diagnosed AML (26), relapsed refractory AML (39) and MDS (7) received azacitdine + venetoclax. The main side effect was myelosuppression with only 15% of patients who were transfusion dependent become transfusion independent. In addition, 46% of patients had a neutropenic fever and 43.7% of patients requiring admission. Most patients (54.9%) required treatment interruption and 35.2% stopped venetoclax for toxicity.

This study highlighted that the optimal dose and frequency of venetoclax remains unclear. A shorted duration or lower dose of venetoclax maybe more ideal, however that may lead to less efficacy. In addition, bone marrow evaluation to assess for cellularity on D21 to D28 of the first cycle may help guide dose adjustments. Finally with the high CR/CRi rates in AML and short duration of response further studies are ongoing to further define molecular abnormalities that may refine prognosis or guide therapy. Two of those studies recently reported identified a prognostic and possible therapeutic role for both EZH2 and the PI3 kinase mTOR pathway.

In a study by Trembely et al. sponsored by Pfizer, an indirect comparison of both studies was performed using a simulated treatment comparison to account for differences in patient characteristics. As expected, the overall response rates were higher in the venetoclax study compared to the glasdegib study (48% vs. 24%), but overall survival was similar (hazard ratio 0.75 vs. HR 0.46). This study demonstrates again that CR/CRi cannot be used as a surrogate endpoint for survival in AML. In addition, with the negative study of V-LDAC vs. LDAC and the improved overall survival of the combination of azacytidine + venetoclax (Aza-ven) vs. azacitdine, the current standard of care of newly diagnosed patients with AML unbale to tolerate intensive chemotherapy is Aza-ven and V-LDAC is rarely used.

The success of Aza-ven is not without side effects. This was demonstrated recently in a retrospective study by Feld et al. In that study 72 patients with newly diagnosed AML (26), relapsed refractory AML (39) and MDS (7) received azacitdine + venetoclax. The main side effect was myelosuppression with only 15% of patients who were transfusion dependent become transfusion independent. In addition, 46% of patients had a neutropenic fever and 43.7% of patients requiring admission. Most patients (54.9%) required treatment interruption and 35.2% stopped venetoclax for toxicity.

This study highlighted that the optimal dose and frequency of venetoclax remains unclear. A shorted duration or lower dose of venetoclax maybe more ideal, however that may lead to less efficacy. In addition, bone marrow evaluation to assess for cellularity on D21 to D28 of the first cycle may help guide dose adjustments. Finally with the high CR/CRi rates in AML and short duration of response further studies are ongoing to further define molecular abnormalities that may refine prognosis or guide therapy. Two of those studies recently reported identified a prognostic and possible therapeutic role for both EZH2 and the PI3 kinase mTOR pathway.

In a study by Trembely et al. sponsored by Pfizer, an indirect comparison of both studies was performed using a simulated treatment comparison to account for differences in patient characteristics. As expected, the overall response rates were higher in the venetoclax study compared to the glasdegib study (48% vs. 24%), but overall survival was similar (hazard ratio 0.75 vs. HR 0.46). This study demonstrates again that CR/CRi cannot be used as a surrogate endpoint for survival in AML. In addition, with the negative study of V-LDAC vs. LDAC and the improved overall survival of the combination of azacytidine + venetoclax (Aza-ven) vs. azacitdine, the current standard of care of newly diagnosed patients with AML unbale to tolerate intensive chemotherapy is Aza-ven and V-LDAC is rarely used.

The success of Aza-ven is not without side effects. This was demonstrated recently in a retrospective study by Feld et al. In that study 72 patients with newly diagnosed AML (26), relapsed refractory AML (39) and MDS (7) received azacitdine + venetoclax. The main side effect was myelosuppression with only 15% of patients who were transfusion dependent become transfusion independent. In addition, 46% of patients had a neutropenic fever and 43.7% of patients requiring admission. Most patients (54.9%) required treatment interruption and 35.2% stopped venetoclax for toxicity.

This study highlighted that the optimal dose and frequency of venetoclax remains unclear. A shorted duration or lower dose of venetoclax maybe more ideal, however that may lead to less efficacy. In addition, bone marrow evaluation to assess for cellularity on D21 to D28 of the first cycle may help guide dose adjustments. Finally with the high CR/CRi rates in AML and short duration of response further studies are ongoing to further define molecular abnormalities that may refine prognosis or guide therapy. Two of those studies recently reported identified a prognostic and possible therapeutic role for both EZH2 and the PI3 kinase mTOR pathway.

ENESTfreedom is an important study that set the current guidelines for TFR. The trial included 190 patients treated with front line nilotinib at 300mg twice daily for two years that had achieved an MR4.5, followed by one year of consolidation maintaining deep molecular response of at least MR4 were allowed to discontinued therapy. A recent 5 year update of the trial showed that 81/190 patients (42.6%) still remained on TFR (MR4) with 76 (40.0%) in MR4.5. From the patients who lost major molecular response (MMR) and were re-treated, 90/91 patients entering this phase (98.9%) regained MMR and 84/91 patients (92.3%) regained MR4.5. More important, no disease progression or CML-related deaths were observed, and the adverse event profile was consistent with that reported previously, including a declined incidence of AEs at 96 weeks of the TFR follow up (with low incidence CV AEs), while an expected increase on those in the treatment re-initiation phase.  As previously has been described in other trials, Low Sokal risk score, BCR-ABL1 IS levels at 48 weeks of TFR and stable MR4.5 response for the first year of TFR were associated with higher TFR rates.

When looking at patients who can be candidates for TFR, it is important to take in consideration the likelihood of successful discontinuation and educate patients on certain factors that may contribute to good outcomes. The Australian CML group had previously reported the importance of the initial decline rate of BCR-ABL1 measured as halving time as an important factor associated to deep molecular response. The same group, in a very interesting publication, reported the impact of halving time as a strong predictor of sustained TFR post-tyrosine kinase inhibitor (TKI) cessation in CML patients treated with front line TKI therapies.

Out of 115 patients who attempted TFR and had ≥12 months of follow-up, 55% sustained TFR, defined as remaining in major molecular response off TKI therapy for 12 months, similar percentage seen in other studies. However, when the time taken for the BCR-ABL1 value to halve was applied, it became the strongest independent predictor of sustained TFR with 80% in patients with a halving time of <9.35 days (first quartile) compared with only 4% if the halving time was >21.85 days (last quartile) (P < .001). The e14a2 BCR-ABL1 transcript type and duration of TKI exposure before attempting TFR were also independent predictors of sustained TFR. However, the BCR-ABL1 value measured at 3 months of TKI was not an independent predictor of sustained TFR.

ENESTfreedom is an important study that set the current guidelines for TFR. The trial included 190 patients treated with front line nilotinib at 300mg twice daily for two years that had achieved an MR4.5, followed by one year of consolidation maintaining deep molecular response of at least MR4 were allowed to discontinued therapy. A recent 5 year update of the trial showed that 81/190 patients (42.6%) still remained on TFR (MR4) with 76 (40.0%) in MR4.5. From the patients who lost major molecular response (MMR) and were re-treated, 90/91 patients entering this phase (98.9%) regained MMR and 84/91 patients (92.3%) regained MR4.5. More important, no disease progression or CML-related deaths were observed, and the adverse event profile was consistent with that reported previously, including a declined incidence of AEs at 96 weeks of the TFR follow up (with low incidence CV AEs), while an expected increase on those in the treatment re-initiation phase.  As previously has been described in other trials, Low Sokal risk score, BCR-ABL1 IS levels at 48 weeks of TFR and stable MR4.5 response for the first year of TFR were associated with higher TFR rates.

When looking at patients who can be candidates for TFR, it is important to take in consideration the likelihood of successful discontinuation and educate patients on certain factors that may contribute to good outcomes. The Australian CML group had previously reported the importance of the initial decline rate of BCR-ABL1 measured as halving time as an important factor associated to deep molecular response. The same group, in a very interesting publication, reported the impact of halving time as a strong predictor of sustained TFR post-tyrosine kinase inhibitor (TKI) cessation in CML patients treated with front line TKI therapies.

Out of 115 patients who attempted TFR and had ≥12 months of follow-up, 55% sustained TFR, defined as remaining in major molecular response off TKI therapy for 12 months, similar percentage seen in other studies. However, when the time taken for the BCR-ABL1 value to halve was applied, it became the strongest independent predictor of sustained TFR with 80% in patients with a halving time of <9.35 days (first quartile) compared with only 4% if the halving time was >21.85 days (last quartile) (P < .001). The e14a2 BCR-ABL1 transcript type and duration of TKI exposure before attempting TFR were also independent predictors of sustained TFR. However, the BCR-ABL1 value measured at 3 months of TKI was not an independent predictor of sustained TFR.

ENESTfreedom is an important study that set the current guidelines for TFR. The trial included 190 patients treated with front line nilotinib at 300mg twice daily for two years that had achieved an MR4.5, followed by one year of consolidation maintaining deep molecular response of at least MR4 were allowed to discontinued therapy. A recent 5 year update of the trial showed that 81/190 patients (42.6%) still remained on TFR (MR4) with 76 (40.0%) in MR4.5. From the patients who lost major molecular response (MMR) and were re-treated, 90/91 patients entering this phase (98.9%) regained MMR and 84/91 patients (92.3%) regained MR4.5. More important, no disease progression or CML-related deaths were observed, and the adverse event profile was consistent with that reported previously, including a declined incidence of AEs at 96 weeks of the TFR follow up (with low incidence CV AEs), while an expected increase on those in the treatment re-initiation phase.  As previously has been described in other trials, Low Sokal risk score, BCR-ABL1 IS levels at 48 weeks of TFR and stable MR4.5 response for the first year of TFR were associated with higher TFR rates.

When looking at patients who can be candidates for TFR, it is important to take in consideration the likelihood of successful discontinuation and educate patients on certain factors that may contribute to good outcomes. The Australian CML group had previously reported the importance of the initial decline rate of BCR-ABL1 measured as halving time as an important factor associated to deep molecular response. The same group, in a very interesting publication, reported the impact of halving time as a strong predictor of sustained TFR post-tyrosine kinase inhibitor (TKI) cessation in CML patients treated with front line TKI therapies.

Out of 115 patients who attempted TFR and had ≥12 months of follow-up, 55% sustained TFR, defined as remaining in major molecular response off TKI therapy for 12 months, similar percentage seen in other studies. However, when the time taken for the BCR-ABL1 value to halve was applied, it became the strongest independent predictor of sustained TFR with 80% in patients with a halving time of <9.35 days (first quartile) compared with only 4% if the halving time was >21.85 days (last quartile) (P < .001). The e14a2 BCR-ABL1 transcript type and duration of TKI exposure before attempting TFR were also independent predictors of sustained TFR. However, the BCR-ABL1 value measured at 3 months of TKI was not an independent predictor of sustained TFR.

Adjuvant endocrine therapy (ET) has been shown to reduce risk of recurrence and improve survival in HR+ early breast cancer (EBC). A retrospective matched cohort analysis of 1,972 patients ≥70 years of age with HR+/HER2-negative, node-negative EBC and multiple medical co-morbidities, demonstrated higher median overall survival (OS) in patients who received ET versus those who did not (79.2 months compared to 67.7 months, p<0.0001). Older women with multiple medical co-morbidities may be at greater risk of toxicities related to ET, which can impact quality of life and adherence. The probability of initiating ET has been shown to be greater among patients who underwent radiation, thus highlighting the need to identify those who will adhere to ET when making decisions regarding radiation therapy to optimize care. ET should be discussed with all women who are candidates for this therapy, with a focus on individualized benefit and risk of these agents.

Studies of immunotherapy in metastatic triple-negative breast cancer have shown promising results, notably in patients with PD-L1 enriched tumors (IMpassion 130 and KEYNOTE-355). KEYNOTE-119 was a phase 3 study including 1,098 patients with metastatic TNBC who had received one or two previous systemic therapies for metastatic disease and progressed on most recent treatment, with randomization to pembrolizumab or physician’s choice chemotherapy . Median OS for pembrolizumab compared to chemotherapy was similar in the overall population (9.9 months versus 10.8 months, HR 0.97) and in patients with PD-L1 CPS score of ≥10 (12.7 months versus 11.6 months, HR 0.78, p=0.057). Although not statistically significant, greater PD-L1 expression was associated with longer median OS with pembrolizumab. Responses to immunotherapy may be durable in select patients, and these agents have an overall favorable toxicity profile. Novel immunotherapy combinations as well as biomarkers to predict response are certainly desired in this space.

Combination endocrine therapy plus a CDK 4/6 inhibitor is standard first-line treatment for metastatic HR+/HER2-negative breast cancer. Neutropenia is a common adverse event (AE) seen with the CDK 4/6 inhibitor palbociclib, and dosing guidelines provide a clear algorithm for drug monitoring and adjustment for cytopenias. Cutaneous toxicities, although not commonly seen, have been reported in the literature. Chawla and colleagues performed a retrospective analysis including 324 patients with advanced HR+/HER2-negative breast cancer who received palbociclib plus endocrine therapy. Cutaneous AEs were seen in 14.2%, with a significant proportion occurring early (41% occurred during or after the first cycle) and 50% resolved within 14 days (average 43 days). Of those who developed cutaneous AEs (n=46), only 15% and 4% required temporary hold and permanent cessation of therapy, respectively. These findings indicate a low overall incidence of cutaneous AEs associated with palbociclib, however highlight the importance of prompt recognition, management, and dermatology referral as appropriate, to help maintain patients on effective cancer-directed therapy.

References:

Yau C, van der Noordaa M, Wei J, et al. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: a multi-center pooled analysis. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS5-01.

Wei M, Wang X, Zimmerman DN, Burt LM, Haaland B, Henry NL. Endocrine therapy and radiotherapy use among older women with hormone receptor-positive, clinically node-negative breast cancer. Breast Cancer Res Treat. 2021 Jan 9. doi: 10.1007/s10549-020-06071-w.Epub ahead of print.

Emens LA, Adams S, Barrios CH, et al. IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab plus nabpaclitaxel versus placebo plus nabpaclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. Presented at: ESMO Virtual Congress 2020, Ann Oncol. 2020;31S:ESMO #LBA16.

Khan NAJ, Alsharedi M. Bullous Skin Rash: A Rare Case of Palbociclib-Induced Dermatological Toxicity. Cureus. 2020 Sep 3;12(9):e10229. doi: 10.7759/cureus.10229.

Adjuvant endocrine therapy (ET) has been shown to reduce risk of recurrence and improve survival in HR+ early breast cancer (EBC). A retrospective matched cohort analysis of 1,972 patients ≥70 years of age with HR+/HER2-negative, node-negative EBC and multiple medical co-morbidities, demonstrated higher median overall survival (OS) in patients who received ET versus those who did not (79.2 months compared to 67.7 months, p<0.0001). Older women with multiple medical co-morbidities may be at greater risk of toxicities related to ET, which can impact quality of life and adherence. The probability of initiating ET has been shown to be greater among patients who underwent radiation, thus highlighting the need to identify those who will adhere to ET when making decisions regarding radiation therapy to optimize care. ET should be discussed with all women who are candidates for this therapy, with a focus on individualized benefit and risk of these agents.

Studies of immunotherapy in metastatic triple-negative breast cancer have shown promising results, notably in patients with PD-L1 enriched tumors (IMpassion 130 and KEYNOTE-355). KEYNOTE-119 was a phase 3 study including 1,098 patients with metastatic TNBC who had received one or two previous systemic therapies for metastatic disease and progressed on most recent treatment, with randomization to pembrolizumab or physician’s choice chemotherapy . Median OS for pembrolizumab compared to chemotherapy was similar in the overall population (9.9 months versus 10.8 months, HR 0.97) and in patients with PD-L1 CPS score of ≥10 (12.7 months versus 11.6 months, HR 0.78, p=0.057). Although not statistically significant, greater PD-L1 expression was associated with longer median OS with pembrolizumab. Responses to immunotherapy may be durable in select patients, and these agents have an overall favorable toxicity profile. Novel immunotherapy combinations as well as biomarkers to predict response are certainly desired in this space.

Combination endocrine therapy plus a CDK 4/6 inhibitor is standard first-line treatment for metastatic HR+/HER2-negative breast cancer. Neutropenia is a common adverse event (AE) seen with the CDK 4/6 inhibitor palbociclib, and dosing guidelines provide a clear algorithm for drug monitoring and adjustment for cytopenias. Cutaneous toxicities, although not commonly seen, have been reported in the literature. Chawla and colleagues performed a retrospective analysis including 324 patients with advanced HR+/HER2-negative breast cancer who received palbociclib plus endocrine therapy. Cutaneous AEs were seen in 14.2%, with a significant proportion occurring early (41% occurred during or after the first cycle) and 50% resolved within 14 days (average 43 days). Of those who developed cutaneous AEs (n=46), only 15% and 4% required temporary hold and permanent cessation of therapy, respectively. These findings indicate a low overall incidence of cutaneous AEs associated with palbociclib, however highlight the importance of prompt recognition, management, and dermatology referral as appropriate, to help maintain patients on effective cancer-directed therapy.

References:

Yau C, van der Noordaa M, Wei J, et al. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: a multi-center pooled analysis. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS5-01.

Wei M, Wang X, Zimmerman DN, Burt LM, Haaland B, Henry NL. Endocrine therapy and radiotherapy use among older women with hormone receptor-positive, clinically node-negative breast cancer. Breast Cancer Res Treat. 2021 Jan 9. doi: 10.1007/s10549-020-06071-w.Epub ahead of print.

Emens LA, Adams S, Barrios CH, et al. IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab plus nabpaclitaxel versus placebo plus nabpaclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. Presented at: ESMO Virtual Congress 2020, Ann Oncol. 2020;31S:ESMO #LBA16.

Khan NAJ, Alsharedi M. Bullous Skin Rash: A Rare Case of Palbociclib-Induced Dermatological Toxicity. Cureus. 2020 Sep 3;12(9):e10229. doi: 10.7759/cureus.10229.

Adjuvant endocrine therapy (ET) has been shown to reduce risk of recurrence and improve survival in HR+ early breast cancer (EBC). A retrospective matched cohort analysis of 1,972 patients ≥70 years of age with HR+/HER2-negative, node-negative EBC and multiple medical co-morbidities, demonstrated higher median overall survival (OS) in patients who received ET versus those who did not (79.2 months compared to 67.7 months, p<0.0001). Older women with multiple medical co-morbidities may be at greater risk of toxicities related to ET, which can impact quality of life and adherence. The probability of initiating ET has been shown to be greater among patients who underwent radiation, thus highlighting the need to identify those who will adhere to ET when making decisions regarding radiation therapy to optimize care. ET should be discussed with all women who are candidates for this therapy, with a focus on individualized benefit and risk of these agents.

Studies of immunotherapy in metastatic triple-negative breast cancer have shown promising results, notably in patients with PD-L1 enriched tumors (IMpassion 130 and KEYNOTE-355). KEYNOTE-119 was a phase 3 study including 1,098 patients with metastatic TNBC who had received one or two previous systemic therapies for metastatic disease and progressed on most recent treatment, with randomization to pembrolizumab or physician’s choice chemotherapy . Median OS for pembrolizumab compared to chemotherapy was similar in the overall population (9.9 months versus 10.8 months, HR 0.97) and in patients with PD-L1 CPS score of ≥10 (12.7 months versus 11.6 months, HR 0.78, p=0.057). Although not statistically significant, greater PD-L1 expression was associated with longer median OS with pembrolizumab. Responses to immunotherapy may be durable in select patients, and these agents have an overall favorable toxicity profile. Novel immunotherapy combinations as well as biomarkers to predict response are certainly desired in this space.

Combination endocrine therapy plus a CDK 4/6 inhibitor is standard first-line treatment for metastatic HR+/HER2-negative breast cancer. Neutropenia is a common adverse event (AE) seen with the CDK 4/6 inhibitor palbociclib, and dosing guidelines provide a clear algorithm for drug monitoring and adjustment for cytopenias. Cutaneous toxicities, although not commonly seen, have been reported in the literature. Chawla and colleagues performed a retrospective analysis including 324 patients with advanced HR+/HER2-negative breast cancer who received palbociclib plus endocrine therapy. Cutaneous AEs were seen in 14.2%, with a significant proportion occurring early (41% occurred during or after the first cycle) and 50% resolved within 14 days (average 43 days). Of those who developed cutaneous AEs (n=46), only 15% and 4% required temporary hold and permanent cessation of therapy, respectively. These findings indicate a low overall incidence of cutaneous AEs associated with palbociclib, however highlight the importance of prompt recognition, management, and dermatology referral as appropriate, to help maintain patients on effective cancer-directed therapy.

References:

Yau C, van der Noordaa M, Wei J, et al. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: a multi-center pooled analysis. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS5-01.

Wei M, Wang X, Zimmerman DN, Burt LM, Haaland B, Henry NL. Endocrine therapy and radiotherapy use among older women with hormone receptor-positive, clinically node-negative breast cancer. Breast Cancer Res Treat. 2021 Jan 9. doi: 10.1007/s10549-020-06071-w.Epub ahead of print.

Emens LA, Adams S, Barrios CH, et al. IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab plus nabpaclitaxel versus placebo plus nabpaclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. Presented at: ESMO Virtual Congress 2020, Ann Oncol. 2020;31S:ESMO #LBA16.

Khan NAJ, Alsharedi M. Bullous Skin Rash: A Rare Case of Palbociclib-Induced Dermatological Toxicity. Cureus. 2020 Sep 3;12(9):e10229. doi: 10.7759/cureus.10229.

The OS was similar between the two arms, although the analysis was underpowered.  Nausea, diarrhea, and vomiting were the most frequently occurring treatment-emergent adverse events for oral azacitidine vs placebo (76% vs 23%, 68% vs 23%, 63% vs 9%). While oral azacitidine is not approved for MDS and trial was stopped early, it can provide meaningful reduction in RBC transfusions in low grade MDS, and further evaluation is needed in MDS.

Paroxysmal nocturnal hemoglobinuria (PNH) clones have been observed in bone marrow failure syndromes including MDS and aplastic anemia (AA). Fattizzo et al analyzed PNH clone size with clinical outcomes in MDS and AA in a cohort of 3085 patients tested for PNH at King’s College Hospital in London. 20.3% of MDS patients had presence of PNH clone; PNH cases occurred more in hypoplastic MDS, and lower risk IPSS MDS patients. The presence of PNH clone was a predictor of response to immunosuppressive therapy and to allogeneic stem cell transplant (84% vs 45%, p=0.01, 71% vs 57%, p=0.09), but not to azacitidine. MDS patients with PNH clone had lower rate of progression by IPSS and AML transformation, and higher OS accounting for MDS with excess blasts. Each 10% increase in clone size resulted in a 1% decrease in cumulative incidence of death. PNH testing is often done especially in cases with hypoplastic MDS; the underlying mechanism and role for monitoring PNH clones in MDS needs further investigation.

Outcomes in MDS patients after azacitidine therapy are generally poor. Clavio et al analyzed outcomes of 402 MDS patients post-azacitidine in the Italian MDS Registry. At azacitidine discontinuation, 20% of patients still derived response to azacitidine, 35% had primary resistance, and 44% had adaptive resistance, which was defined as loss of response or progression after achievement of a response. As expected, OS was longer for patients who stopped treatment due to planned allogeneic stem cell transplant (median OS not reached), compared to patients with primary resistance (median OS 4 months), or adaptive resistance (median OS 5 months), or patients intolerant or noncompliant to azacitidine (median OS 4 months, p=0.004). The North American MDS Consortium scoring system was evaluated in the study cohort; patients with high risk had worse OS than low risk (3 and 7 months, p<0.001). This retrospective analysis confirms the poor outlook of MDS patients after treatment of azacitidine, and effective therapy in this patient population is an unmet need.

The OS was similar between the two arms, although the analysis was underpowered.  Nausea, diarrhea, and vomiting were the most frequently occurring treatment-emergent adverse events for oral azacitidine vs placebo (76% vs 23%, 68% vs 23%, 63% vs 9%). While oral azacitidine is not approved for MDS and trial was stopped early, it can provide meaningful reduction in RBC transfusions in low grade MDS, and further evaluation is needed in MDS.

Paroxysmal nocturnal hemoglobinuria (PNH) clones have been observed in bone marrow failure syndromes including MDS and aplastic anemia (AA). Fattizzo et al analyzed PNH clone size with clinical outcomes in MDS and AA in a cohort of 3085 patients tested for PNH at King’s College Hospital in London. 20.3% of MDS patients had presence of PNH clone; PNH cases occurred more in hypoplastic MDS, and lower risk IPSS MDS patients. The presence of PNH clone was a predictor of response to immunosuppressive therapy and to allogeneic stem cell transplant (84% vs 45%, p=0.01, 71% vs 57%, p=0.09), but not to azacitidine. MDS patients with PNH clone had lower rate of progression by IPSS and AML transformation, and higher OS accounting for MDS with excess blasts. Each 10% increase in clone size resulted in a 1% decrease in cumulative incidence of death. PNH testing is often done especially in cases with hypoplastic MDS; the underlying mechanism and role for monitoring PNH clones in MDS needs further investigation.

Outcomes in MDS patients after azacitidine therapy are generally poor. Clavio et al analyzed outcomes of 402 MDS patients post-azacitidine in the Italian MDS Registry. At azacitidine discontinuation, 20% of patients still derived response to azacitidine, 35% had primary resistance, and 44% had adaptive resistance, which was defined as loss of response or progression after achievement of a response. As expected, OS was longer for patients who stopped treatment due to planned allogeneic stem cell transplant (median OS not reached), compared to patients with primary resistance (median OS 4 months), or adaptive resistance (median OS 5 months), or patients intolerant or noncompliant to azacitidine (median OS 4 months, p=0.004). The North American MDS Consortium scoring system was evaluated in the study cohort; patients with high risk had worse OS than low risk (3 and 7 months, p<0.001). This retrospective analysis confirms the poor outlook of MDS patients after treatment of azacitidine, and effective therapy in this patient population is an unmet need.

The OS was similar between the two arms, although the analysis was underpowered.  Nausea, diarrhea, and vomiting were the most frequently occurring treatment-emergent adverse events for oral azacitidine vs placebo (76% vs 23%, 68% vs 23%, 63% vs 9%). While oral azacitidine is not approved for MDS and trial was stopped early, it can provide meaningful reduction in RBC transfusions in low grade MDS, and further evaluation is needed in MDS.

Paroxysmal nocturnal hemoglobinuria (PNH) clones have been observed in bone marrow failure syndromes including MDS and aplastic anemia (AA). Fattizzo et al analyzed PNH clone size with clinical outcomes in MDS and AA in a cohort of 3085 patients tested for PNH at King’s College Hospital in London. 20.3% of MDS patients had presence of PNH clone; PNH cases occurred more in hypoplastic MDS, and lower risk IPSS MDS patients. The presence of PNH clone was a predictor of response to immunosuppressive therapy and to allogeneic stem cell transplant (84% vs 45%, p=0.01, 71% vs 57%, p=0.09), but not to azacitidine. MDS patients with PNH clone had lower rate of progression by IPSS and AML transformation, and higher OS accounting for MDS with excess blasts. Each 10% increase in clone size resulted in a 1% decrease in cumulative incidence of death. PNH testing is often done especially in cases with hypoplastic MDS; the underlying mechanism and role for monitoring PNH clones in MDS needs further investigation.

Outcomes in MDS patients after azacitidine therapy are generally poor. Clavio et al analyzed outcomes of 402 MDS patients post-azacitidine in the Italian MDS Registry. At azacitidine discontinuation, 20% of patients still derived response to azacitidine, 35% had primary resistance, and 44% had adaptive resistance, which was defined as loss of response or progression after achievement of a response. As expected, OS was longer for patients who stopped treatment due to planned allogeneic stem cell transplant (median OS not reached), compared to patients with primary resistance (median OS 4 months), or adaptive resistance (median OS 5 months), or patients intolerant or noncompliant to azacitidine (median OS 4 months, p=0.004). The North American MDS Consortium scoring system was evaluated in the study cohort; patients with high risk had worse OS than low risk (3 and 7 months, p<0.001). This retrospective analysis confirms the poor outlook of MDS patients after treatment of azacitidine, and effective therapy in this patient population is an unmet need.

The following two studies are related to additional at-risk patient populations for exocrine pancreatic insufficiency. In a single-center cross-sectional study out of Italy, researchers demonstrated that EPI is a feature of type 1 diabetes—compared with healthy individuals, fecal elastase-1 levels were significantly lower in participants with new-onset and long-standing T1D (P = .0070 and .0010, respectively). Notably the study showed correlation between progressive exocrine and endocrine function throughout the natural history of disease. Certainly, further research is needed to clarify the pathogenesis and role of EPI in type 1 diabetes.

Lastly the final selection comes from AIIMS in India, where they assessed endocrine and exocrine function in patients following pancreatic trauma. Notably, of the 20 patients studied with trauma, 11 of them (55%) had evidence of pancreatic exocrine insufficiency by fecal elastase measurement. 4 patients had severe pancreatic insufficiency, 3 of which had partial pancreatectomy (with mean pancreatic volume of 48.65cm3 following surgery). Classic teaching is that EPI develops when exocrine function is impaired by ~90%, however in the resection groups, they have demonstrated severe EPI in patients with roughly 50% retained pancreatic volume.   

The following two studies are related to additional at-risk patient populations for exocrine pancreatic insufficiency. In a single-center cross-sectional study out of Italy, researchers demonstrated that EPI is a feature of type 1 diabetes—compared with healthy individuals, fecal elastase-1 levels were significantly lower in participants with new-onset and long-standing T1D (P = .0070 and .0010, respectively). Notably the study showed correlation between progressive exocrine and endocrine function throughout the natural history of disease. Certainly, further research is needed to clarify the pathogenesis and role of EPI in type 1 diabetes.

Lastly the final selection comes from AIIMS in India, where they assessed endocrine and exocrine function in patients following pancreatic trauma. Notably, of the 20 patients studied with trauma, 11 of them (55%) had evidence of pancreatic exocrine insufficiency by fecal elastase measurement. 4 patients had severe pancreatic insufficiency, 3 of which had partial pancreatectomy (with mean pancreatic volume of 48.65cm3 following surgery). Classic teaching is that EPI develops when exocrine function is impaired by ~90%, however in the resection groups, they have demonstrated severe EPI in patients with roughly 50% retained pancreatic volume.   

The following two studies are related to additional at-risk patient populations for exocrine pancreatic insufficiency. In a single-center cross-sectional study out of Italy, researchers demonstrated that EPI is a feature of type 1 diabetes—compared with healthy individuals, fecal elastase-1 levels were significantly lower in participants with new-onset and long-standing T1D (P = .0070 and .0010, respectively). Notably the study showed correlation between progressive exocrine and endocrine function throughout the natural history of disease. Certainly, further research is needed to clarify the pathogenesis and role of EPI in type 1 diabetes.

Lastly the final selection comes from AIIMS in India, where they assessed endocrine and exocrine function in patients following pancreatic trauma. Notably, of the 20 patients studied with trauma, 11 of them (55%) had evidence of pancreatic exocrine insufficiency by fecal elastase measurement. 4 patients had severe pancreatic insufficiency, 3 of which had partial pancreatectomy (with mean pancreatic volume of 48.65cm3 following surgery). Classic teaching is that EPI develops when exocrine function is impaired by ~90%, however in the resection groups, they have demonstrated severe EPI in patients with roughly 50% retained pancreatic volume.   

Although TFR is a reality on today's management of CML patients, it is important to emphasize a proper molecular monitoring after TKI discontinuation following the current NCCN and ELN guidelines. However, late relapses may occur after one year of therapy, although there are uncommon. In a recent letter to the editor in the journal Leukemia, investigators that participated in the EURO-SKI trial planned to follow patients beyond the 3 years scheduled in the trial and they reported the outcomes in what they called the AFTER-SKI trial. With a follow-up of 72 months, 12 out of 111 patients (10.8%) who were in TFR at 36 months, subsequently lost MMR. What is interesting is that the molecular status at 36 months appears highly predictive of later relapse, as only 1 patient out of 98 in MR4 at month 36 lost MMR in the following 3 years. Conversely, 11 of the 13 patients not in MR4 at month 36 lost MMR during follow-up.

For older CML patients not eligible for TFR or after TFR failure, long term therapy with TKI is the only option. However, we know that many patients can suffer from chronic AEs that will impact long term quality of life. A recent publication of the Italian phase III multicentric randomized OPTkIMA study aimed to evaluate if a progressive de‐escalation of TKIs was able to maintain the molecular response (MR^3.0) and improve Health Related Quality of Life (HRQoL). 166 elderly CML patients in stable MR^3.0/MR^4.0completed the first year of any TKI intermittent schedule, 1 month ON and 1 month OFF. The first-year probability of maintaining the MR^3.0 was 81%. No patients progressed to accelerated/blastic phase. All patients who lost the molecular response regained the MR^3.0 after resuming TKI continuously, and none suffered from TKI withdrawn syndrome. However, data related with quality of life was confounded by several factors and non-conclusive, for which longer follow up will be needed.
 

Although TFR is a reality on today's management of CML patients, it is important to emphasize a proper molecular monitoring after TKI discontinuation following the current NCCN and ELN guidelines. However, late relapses may occur after one year of therapy, although there are uncommon. In a recent letter to the editor in the journal Leukemia, investigators that participated in the EURO-SKI trial planned to follow patients beyond the 3 years scheduled in the trial and they reported the outcomes in what they called the AFTER-SKI trial. With a follow-up of 72 months, 12 out of 111 patients (10.8%) who were in TFR at 36 months, subsequently lost MMR. What is interesting is that the molecular status at 36 months appears highly predictive of later relapse, as only 1 patient out of 98 in MR4 at month 36 lost MMR in the following 3 years. Conversely, 11 of the 13 patients not in MR4 at month 36 lost MMR during follow-up.

For older CML patients not eligible for TFR or after TFR failure, long term therapy with TKI is the only option. However, we know that many patients can suffer from chronic AEs that will impact long term quality of life. A recent publication of the Italian phase III multicentric randomized OPTkIMA study aimed to evaluate if a progressive de‐escalation of TKIs was able to maintain the molecular response (MR^3.0) and improve Health Related Quality of Life (HRQoL). 166 elderly CML patients in stable MR^3.0/MR^4.0completed the first year of any TKI intermittent schedule, 1 month ON and 1 month OFF. The first-year probability of maintaining the MR^3.0 was 81%. No patients progressed to accelerated/blastic phase. All patients who lost the molecular response regained the MR^3.0 after resuming TKI continuously, and none suffered from TKI withdrawn syndrome. However, data related with quality of life was confounded by several factors and non-conclusive, for which longer follow up will be needed.
 

Although TFR is a reality on today's management of CML patients, it is important to emphasize a proper molecular monitoring after TKI discontinuation following the current NCCN and ELN guidelines. However, late relapses may occur after one year of therapy, although there are uncommon. In a recent letter to the editor in the journal Leukemia, investigators that participated in the EURO-SKI trial planned to follow patients beyond the 3 years scheduled in the trial and they reported the outcomes in what they called the AFTER-SKI trial. With a follow-up of 72 months, 12 out of 111 patients (10.8%) who were in TFR at 36 months, subsequently lost MMR. What is interesting is that the molecular status at 36 months appears highly predictive of later relapse, as only 1 patient out of 98 in MR4 at month 36 lost MMR in the following 3 years. Conversely, 11 of the 13 patients not in MR4 at month 36 lost MMR during follow-up.

For older CML patients not eligible for TFR or after TFR failure, long term therapy with TKI is the only option. However, we know that many patients can suffer from chronic AEs that will impact long term quality of life. A recent publication of the Italian phase III multicentric randomized OPTkIMA study aimed to evaluate if a progressive de‐escalation of TKIs was able to maintain the molecular response (MR^3.0) and improve Health Related Quality of Life (HRQoL). 166 elderly CML patients in stable MR^3.0/MR^4.0completed the first year of any TKI intermittent schedule, 1 month ON and 1 month OFF. The first-year probability of maintaining the MR^3.0 was 81%. No patients progressed to accelerated/blastic phase. All patients who lost the molecular response regained the MR^3.0 after resuming TKI continuously, and none suffered from TKI withdrawn syndrome. However, data related with quality of life was confounded by several factors and non-conclusive, for which longer follow up will be needed.
 

Peripheral neuropathy is a well-recognized complication of taxane therapy that can impact functioning and quality of life. Dose-reductions are applied in an effort to continue treatment and minimize risk of worsening neuropathy. In a prospective analysis of breast cancer patients receiving weekly paclitaxel, Timmins et al showed neuropathy symptoms affected 85% with severe symptoms in 38%, and about half of the cohort had persistent symptoms up to 12 months post-chemotherapy. Patients who received dose reductions reported worse neuropathy and symptom burden compared to those who received full dose paclitaxel chemotherapy. It is challenging to predict with certainty which patients may experience significant neuropathy, and important to acknowledge individual patients factors such as age and other medical co-morbidities. Additional research is warranted to refine individual risk assessment as well as prevention and management strategies.

The treatment landscape for metastatic HER2-positive breast cancer is evolving at a rapid pace. Margetuximab is a chimeric antibody with similar epitope specificity to trastuzumab, but with an engineered Fc region that enhances immune activation. The phase 3 SOPHIA trial included 536 patients with pretreated HER2-positive advanced breast cancer and demonstrated modest improvement in progression free-survival with margetuximab plus chemotherapy compared to trastuzumab plus chemotherapy (median PFS 5.8 versus 4.9 months; HR 0.76, p=0.03). The introduction of other therapies in this space (tucatinib, trastuzumab deruxtecan, neratinib) provides patients with many options, but simultaneously creates a complex treatment algorithm when it comes to therapy selection. Toxicity profiles and sites of metastases should be taken into consideration when deciding on best therapy for an individual patient.

Given the impressive outcomes seen with endocrine therapy plus CDK 4/6 inhibitors in the advanced HR+/HER2- population, these combinations are being studied in the curative setting. The phase 3 PALLAS study randomized 5,760 patients with stage I-III HR+/HER2- breast cancer to ongoing endocrine therapy with or without palbociclib for 2 years. Data from the second interim analysis of this trial showed similar invasive disease-free survival rates for the two arms (3 years iDFS 88.2% for palbociclib plus endocrine therapy versus 88.5% for endocrine therapy alone; HR 0.93, p=0.51). In contrast, the phase 3 monarchE trial showed improvement in iDFS with abemaciclib for 2 years with ongoing endocrine therapy compared to endocrine therapy alone (2 year iDFS rate of 92.3% versus 89.3%; HR 0.713, p=0.0009). Differences in study populations, mechanism of action of various CDK 4/6 inhibitors, dosing and drug exposure, may possibly impact results. Long-term follow-up and biomarker studies are desired to further delineate the role of CDK 4/6 inhibitors in this setting.

References:

Runowicz CD, Leach CR, Henry NL, Henry KS, Mackey HT, Cowens-Alvarado RL, Cannady RS, Pratt-Chapman ML, Edge SB, Jacobs LA, Hurria A, Marks LB, LaMonte SJ, Warner E, Lyman GH, Ganz PA. American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. J Clin Oncol. 2016;34:611-35.

Ghoreishi Z, Keshavarz S, Asghari Jafarabadi M, Fathifar Z, Goodman KA, Esfahani A. Risk factors for paclitaxel-induced peripheral neuropathy in patients with breast cancer. BMC Cancer. 2018;18:958.

O'Shaughnessy JA, Johnston S, Harbeck N, Toi M, Im Y-H, Reinisch M, Shao Z, Kellokumpu Lehtinen PL, Huang C-S, Tryakin A, Goetz M, Rugo HS, Senkus E, Testa L, Andersson M, Tamura K, Steger GG, Del Mastro L, Cox J, Forrester T, Sherwood S, Li X, Wei R, Martin M, Rastogi P. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. Presented at: 2020 Virtual San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract GS1-01.

Peripheral neuropathy is a well-recognized complication of taxane therapy that can impact functioning and quality of life. Dose-reductions are applied in an effort to continue treatment and minimize risk of worsening neuropathy. In a prospective analysis of breast cancer patients receiving weekly paclitaxel, Timmins et al showed neuropathy symptoms affected 85% with severe symptoms in 38%, and about half of the cohort had persistent symptoms up to 12 months post-chemotherapy. Patients who received dose reductions reported worse neuropathy and symptom burden compared to those who received full dose paclitaxel chemotherapy. It is challenging to predict with certainty which patients may experience significant neuropathy, and important to acknowledge individual patients factors such as age and other medical co-morbidities. Additional research is warranted to refine individual risk assessment as well as prevention and management strategies.

The treatment landscape for metastatic HER2-positive breast cancer is evolving at a rapid pace. Margetuximab is a chimeric antibody with similar epitope specificity to trastuzumab, but with an engineered Fc region that enhances immune activation. The phase 3 SOPHIA trial included 536 patients with pretreated HER2-positive advanced breast cancer and demonstrated modest improvement in progression free-survival with margetuximab plus chemotherapy compared to trastuzumab plus chemotherapy (median PFS 5.8 versus 4.9 months; HR 0.76, p=0.03). The introduction of other therapies in this space (tucatinib, trastuzumab deruxtecan, neratinib) provides patients with many options, but simultaneously creates a complex treatment algorithm when it comes to therapy selection. Toxicity profiles and sites of metastases should be taken into consideration when deciding on best therapy for an individual patient.

Given the impressive outcomes seen with endocrine therapy plus CDK 4/6 inhibitors in the advanced HR+/HER2- population, these combinations are being studied in the curative setting. The phase 3 PALLAS study randomized 5,760 patients with stage I-III HR+/HER2- breast cancer to ongoing endocrine therapy with or without palbociclib for 2 years. Data from the second interim analysis of this trial showed similar invasive disease-free survival rates for the two arms (3 years iDFS 88.2% for palbociclib plus endocrine therapy versus 88.5% for endocrine therapy alone; HR 0.93, p=0.51). In contrast, the phase 3 monarchE trial showed improvement in iDFS with abemaciclib for 2 years with ongoing endocrine therapy compared to endocrine therapy alone (2 year iDFS rate of 92.3% versus 89.3%; HR 0.713, p=0.0009). Differences in study populations, mechanism of action of various CDK 4/6 inhibitors, dosing and drug exposure, may possibly impact results. Long-term follow-up and biomarker studies are desired to further delineate the role of CDK 4/6 inhibitors in this setting.

References:

Runowicz CD, Leach CR, Henry NL, Henry KS, Mackey HT, Cowens-Alvarado RL, Cannady RS, Pratt-Chapman ML, Edge SB, Jacobs LA, Hurria A, Marks LB, LaMonte SJ, Warner E, Lyman GH, Ganz PA. American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. J Clin Oncol. 2016;34:611-35.

Ghoreishi Z, Keshavarz S, Asghari Jafarabadi M, Fathifar Z, Goodman KA, Esfahani A. Risk factors for paclitaxel-induced peripheral neuropathy in patients with breast cancer. BMC Cancer. 2018;18:958.

O'Shaughnessy JA, Johnston S, Harbeck N, Toi M, Im Y-H, Reinisch M, Shao Z, Kellokumpu Lehtinen PL, Huang C-S, Tryakin A, Goetz M, Rugo HS, Senkus E, Testa L, Andersson M, Tamura K, Steger GG, Del Mastro L, Cox J, Forrester T, Sherwood S, Li X, Wei R, Martin M, Rastogi P. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. Presented at: 2020 Virtual San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract GS1-01.

Peripheral neuropathy is a well-recognized complication of taxane therapy that can impact functioning and quality of life. Dose-reductions are applied in an effort to continue treatment and minimize risk of worsening neuropathy. In a prospective analysis of breast cancer patients receiving weekly paclitaxel, Timmins et al showed neuropathy symptoms affected 85% with severe symptoms in 38%, and about half of the cohort had persistent symptoms up to 12 months post-chemotherapy. Patients who received dose reductions reported worse neuropathy and symptom burden compared to those who received full dose paclitaxel chemotherapy. It is challenging to predict with certainty which patients may experience significant neuropathy, and important to acknowledge individual patients factors such as age and other medical co-morbidities. Additional research is warranted to refine individual risk assessment as well as prevention and management strategies.

The treatment landscape for metastatic HER2-positive breast cancer is evolving at a rapid pace. Margetuximab is a chimeric antibody with similar epitope specificity to trastuzumab, but with an engineered Fc region that enhances immune activation. The phase 3 SOPHIA trial included 536 patients with pretreated HER2-positive advanced breast cancer and demonstrated modest improvement in progression free-survival with margetuximab plus chemotherapy compared to trastuzumab plus chemotherapy (median PFS 5.8 versus 4.9 months; HR 0.76, p=0.03). The introduction of other therapies in this space (tucatinib, trastuzumab deruxtecan, neratinib) provides patients with many options, but simultaneously creates a complex treatment algorithm when it comes to therapy selection. Toxicity profiles and sites of metastases should be taken into consideration when deciding on best therapy for an individual patient.

Given the impressive outcomes seen with endocrine therapy plus CDK 4/6 inhibitors in the advanced HR+/HER2- population, these combinations are being studied in the curative setting. The phase 3 PALLAS study randomized 5,760 patients with stage I-III HR+/HER2- breast cancer to ongoing endocrine therapy with or without palbociclib for 2 years. Data from the second interim analysis of this trial showed similar invasive disease-free survival rates for the two arms (3 years iDFS 88.2% for palbociclib plus endocrine therapy versus 88.5% for endocrine therapy alone; HR 0.93, p=0.51). In contrast, the phase 3 monarchE trial showed improvement in iDFS with abemaciclib for 2 years with ongoing endocrine therapy compared to endocrine therapy alone (2 year iDFS rate of 92.3% versus 89.3%; HR 0.713, p=0.0009). Differences in study populations, mechanism of action of various CDK 4/6 inhibitors, dosing and drug exposure, may possibly impact results. Long-term follow-up and biomarker studies are desired to further delineate the role of CDK 4/6 inhibitors in this setting.

References:

Runowicz CD, Leach CR, Henry NL, Henry KS, Mackey HT, Cowens-Alvarado RL, Cannady RS, Pratt-Chapman ML, Edge SB, Jacobs LA, Hurria A, Marks LB, LaMonte SJ, Warner E, Lyman GH, Ganz PA. American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. J Clin Oncol. 2016;34:611-35.

Ghoreishi Z, Keshavarz S, Asghari Jafarabadi M, Fathifar Z, Goodman KA, Esfahani A. Risk factors for paclitaxel-induced peripheral neuropathy in patients with breast cancer. BMC Cancer. 2018;18:958.

O'Shaughnessy JA, Johnston S, Harbeck N, Toi M, Im Y-H, Reinisch M, Shao Z, Kellokumpu Lehtinen PL, Huang C-S, Tryakin A, Goetz M, Rugo HS, Senkus E, Testa L, Andersson M, Tamura K, Steger GG, Del Mastro L, Cox J, Forrester T, Sherwood S, Li X, Wei R, Martin M, Rastogi P. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. Presented at: 2020 Virtual San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract GS1-01.

For patients with myelodysplastic syndromes (MDS), allogeneic stem cell transplantation (SCT) is currently the only curative treatment, however, is associated with risk of transplant-related mortality, as well as relapse. Reduced intensity conditioning (RIC) regimens may decrease toxicity yet there may be increased risk of relapse compared to myeloablative conditioning (MAC) regimens. In an analysis of MDS patients enrolled on the BMT CTN 0901 study, which was a phase III randomized clinical trial comparing outcomes by conditioning intensity prior to allogeneic stem cell transplantation in adult patients with myeloid malignancy, 42% of patients had detectable mutations in a set of 10 genes prior to conditioning with RIC or MAC. Presence of mutations prior to conditioning was associated with increased risk of relapse (3 year relapse, 40% vs 11%, p=0.022) and decreased overall survival (3 year OS 55% vs 79%, p=0.045). Among those with detectable mutations, receiving RIC had higher relapse rates (3 year relapse 75% vs 17%, p=0.003) and lower relapse-free survival (3 year RFS 13% vs 49%, p=0.003) compared to receiving MAC, although there was no difference in overall survival. Further investigation is warranted given small sample size of MDS patients, however, there may be benefit of considering MAC conditioning in MDS patients with detectable mutations prior to conditioning for allogeneic SCT.

TP53 mutations are found in 10-20% of patients with MDS and confer worse outcomes. Eprenetapopt (APR-246) is a small molecule inhibitor that stabilizes mutant p53 and induces apoptosis in TP53-mutant cells. In a phase Ib/II study of eprenatapopt combined with azacitidine in patients with TP53-mutatnt MDS or acute myeloid leukemia (AML), overall response in MDS patients (n=40) was 73%, with 50% achieving complete remission and 58% achieving a cytogenetic response. Median overall survival was 10.8 months, and no dose limiting toxicities were observed. Despite the promising early trial results, the phase 3 clinical trial evaluating eprenetapopt with azacitidine compared to azacitidine in MDS patients with TP53 mutation did not meet the primary endpoint of complete remission rate (33.3% vs 22.4%, p=0.13) (Aprea Press Release, 12/28/2020). Further results including secondary endpoints from the phase 3 trial will be reported in the future. 

For patients with myelodysplastic syndromes (MDS), allogeneic stem cell transplantation (SCT) is currently the only curative treatment, however, is associated with risk of transplant-related mortality, as well as relapse. Reduced intensity conditioning (RIC) regimens may decrease toxicity yet there may be increased risk of relapse compared to myeloablative conditioning (MAC) regimens. In an analysis of MDS patients enrolled on the BMT CTN 0901 study, which was a phase III randomized clinical trial comparing outcomes by conditioning intensity prior to allogeneic stem cell transplantation in adult patients with myeloid malignancy, 42% of patients had detectable mutations in a set of 10 genes prior to conditioning with RIC or MAC. Presence of mutations prior to conditioning was associated with increased risk of relapse (3 year relapse, 40% vs 11%, p=0.022) and decreased overall survival (3 year OS 55% vs 79%, p=0.045). Among those with detectable mutations, receiving RIC had higher relapse rates (3 year relapse 75% vs 17%, p=0.003) and lower relapse-free survival (3 year RFS 13% vs 49%, p=0.003) compared to receiving MAC, although there was no difference in overall survival. Further investigation is warranted given small sample size of MDS patients, however, there may be benefit of considering MAC conditioning in MDS patients with detectable mutations prior to conditioning for allogeneic SCT.

TP53 mutations are found in 10-20% of patients with MDS and confer worse outcomes. Eprenetapopt (APR-246) is a small molecule inhibitor that stabilizes mutant p53 and induces apoptosis in TP53-mutant cells. In a phase Ib/II study of eprenatapopt combined with azacitidine in patients with TP53-mutatnt MDS or acute myeloid leukemia (AML), overall response in MDS patients (n=40) was 73%, with 50% achieving complete remission and 58% achieving a cytogenetic response. Median overall survival was 10.8 months, and no dose limiting toxicities were observed. Despite the promising early trial results, the phase 3 clinical trial evaluating eprenetapopt with azacitidine compared to azacitidine in MDS patients with TP53 mutation did not meet the primary endpoint of complete remission rate (33.3% vs 22.4%, p=0.13) (Aprea Press Release, 12/28/2020). Further results including secondary endpoints from the phase 3 trial will be reported in the future. 

For patients with myelodysplastic syndromes (MDS), allogeneic stem cell transplantation (SCT) is currently the only curative treatment, however, is associated with risk of transplant-related mortality, as well as relapse. Reduced intensity conditioning (RIC) regimens may decrease toxicity yet there may be increased risk of relapse compared to myeloablative conditioning (MAC) regimens. In an analysis of MDS patients enrolled on the BMT CTN 0901 study, which was a phase III randomized clinical trial comparing outcomes by conditioning intensity prior to allogeneic stem cell transplantation in adult patients with myeloid malignancy, 42% of patients had detectable mutations in a set of 10 genes prior to conditioning with RIC or MAC. Presence of mutations prior to conditioning was associated with increased risk of relapse (3 year relapse, 40% vs 11%, p=0.022) and decreased overall survival (3 year OS 55% vs 79%, p=0.045). Among those with detectable mutations, receiving RIC had higher relapse rates (3 year relapse 75% vs 17%, p=0.003) and lower relapse-free survival (3 year RFS 13% vs 49%, p=0.003) compared to receiving MAC, although there was no difference in overall survival. Further investigation is warranted given small sample size of MDS patients, however, there may be benefit of considering MAC conditioning in MDS patients with detectable mutations prior to conditioning for allogeneic SCT.

TP53 mutations are found in 10-20% of patients with MDS and confer worse outcomes. Eprenetapopt (APR-246) is a small molecule inhibitor that stabilizes mutant p53 and induces apoptosis in TP53-mutant cells. In a phase Ib/II study of eprenatapopt combined with azacitidine in patients with TP53-mutatnt MDS or acute myeloid leukemia (AML), overall response in MDS patients (n=40) was 73%, with 50% achieving complete remission and 58% achieving a cytogenetic response. Median overall survival was 10.8 months, and no dose limiting toxicities were observed. Despite the promising early trial results, the phase 3 clinical trial evaluating eprenetapopt with azacitidine compared to azacitidine in MDS patients with TP53 mutation did not meet the primary endpoint of complete remission rate (33.3% vs 22.4%, p=0.13) (Aprea Press Release, 12/28/2020). Further results including secondary endpoints from the phase 3 trial will be reported in the future. 

Systemic therapy advances for metastatic breast cancer (MBC) have led to improved overall survival; however, the CNS sanctuary site can be challenging to treat and cause significant neurologic symptoms. Kuksis and colleagues reported that HER2-positive and triple-negative breast MBC subtypes have high incidence of brain metastases, with pooled cumulative incidences of 31% and 32%, respectively. The incidence per patient-year was 13% for both subtypes. The treatment landscape for HER2-positive MBC is rapidly evolving. The combination of tucatinib/capecitabine/trastuzumab demonstrated reduced risk of intracranial progression or death (HR 0.32), improvement in intracranial objective response rate (47.3% versus 20.0%) and reduced risk of death (0.58) in the HER2CLIMB study. An MRI screening program may enhance early detection and study prevention of brain metastases.

Trastuzumab and pertuzumab have significantly improved outcomes in early-stage and advanced HER2-positive breast cancer. These monoclonal antibodies are given with chemotherapy initially, followed by dual antibody therapy to complete one year for curative treatment and until disease progression in the metastatic setting. The FeDeriCa randomized phase 3 study demonstrated that fixed-dose subcutaneous combination of pertuzumab and trastuzumab was non-inferior to intravenous formulations with a geometric mean ratio of cycle 7 pertuzumab serum trough concentration of 1.22 (90% CI 1.14-1.31). Furthermore, efficacy appeared similar with pathologic complete response rates of 60% for both groups. Trastuzumab and pertuzumab administration in an infusion center requires hospital resources, cost, and patient’s time. The MetasphHER study showed that patients preferred subcutaneous trastuzumab compared to IV, and further investigation into long-term outcomes and impact on quality of life and resource allocation is desired.

The phase 3 CLEOPATRA study demonstrated improvement in overall survival with the addition of pertuzumab to docetaxel and trastuzumab in patients with HER2-positive MBC. Rash and diarrhea are well-recognized potential side effects related to pertuzumab. Ferreira et al demonstrated that rash was prognostic for PFS and OS both during and after docetaxel discontinuation, while diarrhea was only prognostic after docetaxel. Neither rash nor diarrhea were predictive of pertuzumab benefit. Studies have shown that patients who developed immune-related adverse events during anti-PD-1 treatment had PFS and OS benefit compared to those who did not. These results may help inform and encourage patients and providers regarding benefit of various treatments in the setting of toxicities. Future research exploring biomarker prognostic and predictive capability is certainly warranted. 

Endocrine therapy plus a CDK 4/6 inhibitor is standard first-line treatment for hormone receptor-positive MBC. Progression that occurs rapidly or through multiple lines of endocrine therapy combinations, may indicate endocrine resistance. The phase 3 PEARL trial did not demonstrate superior PFS among patients with wild type ESR1 AI-resistant MBC with palbociclib/endocrine therapy compared to capecitabine (mPFS 8.0 vs 10.6 months, adjusted HR 1.11; p=0.404); similar PFS and aHR were seen in palbociclib/fulvestrant versus capecitabine cohort. Therapy sequencing in HR+/HER2-negative MBC is indeed relevant, and a previous meta-analysis demonstrated chemotherapy was not better than endocrine therapy plus CDK 4/6 inhibitor in first- or second-line setting. Importantly, palbociclib plus endocrine therapy was associated with better tolerability and quality of life, which should be considered when selecting treatment with similar PFS outcomes.

References:

Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, Hurvitz S, Loi S, Okines A, Abramson V, Bedard PL, Oliveira M, Mueller V, Zelnak A, DiGiovanna MP, Bachelot T, Chien AJ, O'Regan R, Wardley A, Conlin A, Cameron D, Carey L, Curigliano G, Gelmon K, Loibl S, Mayor J, McGoldrick S, An X, Winer EP. 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;38:2610-2619.

Pivot X, Spano JP, Espie M, Cottu P, Jouannaud C, Pottier V, Moreau L, Extra JM, Lortholary A, Rivera P, Spaeth D, Attar-Rabia H, Benkanoun C, Dima-Martinez L, Esposito N, Gligorov J. Patients' preference of trastuzumab administration (subcutaneous versus intravenous) in HER2-positive metastatic breast cancer: Results of the randomised MetaspHer study. Eur J Cancer. 2017;82:230-236.

Das S, Ciombor KK, Haraldsdottir S, Pumpalova Y, Sahin IH, Pineda G, Shyr Y, Lin EP, Hsu CY, Chu SK, Goff LW, Cardin DB, Bilen MA, Fisher GA, Wu C, Berlin J. Immune-related adverse events and immune checkpoint inhibitor efficacy in patients with gastrointestinal cancer with Food and Drug Administration-approved indications for immunotherapy. Oncologist. 2020;25:669-679.

Giuliano M, Schettini F, Rognoni C, Milani M, Jerusalem G, Bachelot T, De Laurentiis M, Thomas G, De Placido P, Arpino G, De Placido S, Cristofanilli M, Giordano A, Puglisi F, Pistilli B, Prat A, Del Mastro L, Venturini S, Generali D. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis. Lancet Oncol. 2019;20:1360-1369.

Systemic therapy advances for metastatic breast cancer (MBC) have led to improved overall survival; however, the CNS sanctuary site can be challenging to treat and cause significant neurologic symptoms. Kuksis and colleagues reported that HER2-positive and triple-negative breast MBC subtypes have high incidence of brain metastases, with pooled cumulative incidences of 31% and 32%, respectively. The incidence per patient-year was 13% for both subtypes. The treatment landscape for HER2-positive MBC is rapidly evolving. The combination of tucatinib/capecitabine/trastuzumab demonstrated reduced risk of intracranial progression or death (HR 0.32), improvement in intracranial objective response rate (47.3% versus 20.0%) and reduced risk of death (0.58) in the HER2CLIMB study. An MRI screening program may enhance early detection and study prevention of brain metastases.

Trastuzumab and pertuzumab have significantly improved outcomes in early-stage and advanced HER2-positive breast cancer. These monoclonal antibodies are given with chemotherapy initially, followed by dual antibody therapy to complete one year for curative treatment and until disease progression in the metastatic setting. The FeDeriCa randomized phase 3 study demonstrated that fixed-dose subcutaneous combination of pertuzumab and trastuzumab was non-inferior to intravenous formulations with a geometric mean ratio of cycle 7 pertuzumab serum trough concentration of 1.22 (90% CI 1.14-1.31). Furthermore, efficacy appeared similar with pathologic complete response rates of 60% for both groups. Trastuzumab and pertuzumab administration in an infusion center requires hospital resources, cost, and patient’s time. The MetasphHER study showed that patients preferred subcutaneous trastuzumab compared to IV, and further investigation into long-term outcomes and impact on quality of life and resource allocation is desired.

The phase 3 CLEOPATRA study demonstrated improvement in overall survival with the addition of pertuzumab to docetaxel and trastuzumab in patients with HER2-positive MBC. Rash and diarrhea are well-recognized potential side effects related to pertuzumab. Ferreira et al demonstrated that rash was prognostic for PFS and OS both during and after docetaxel discontinuation, while diarrhea was only prognostic after docetaxel. Neither rash nor diarrhea were predictive of pertuzumab benefit. Studies have shown that patients who developed immune-related adverse events during anti-PD-1 treatment had PFS and OS benefit compared to those who did not. These results may help inform and encourage patients and providers regarding benefit of various treatments in the setting of toxicities. Future research exploring biomarker prognostic and predictive capability is certainly warranted. 

Endocrine therapy plus a CDK 4/6 inhibitor is standard first-line treatment for hormone receptor-positive MBC. Progression that occurs rapidly or through multiple lines of endocrine therapy combinations, may indicate endocrine resistance. The phase 3 PEARL trial did not demonstrate superior PFS among patients with wild type ESR1 AI-resistant MBC with palbociclib/endocrine therapy compared to capecitabine (mPFS 8.0 vs 10.6 months, adjusted HR 1.11; p=0.404); similar PFS and aHR were seen in palbociclib/fulvestrant versus capecitabine cohort. Therapy sequencing in HR+/HER2-negative MBC is indeed relevant, and a previous meta-analysis demonstrated chemotherapy was not better than endocrine therapy plus CDK 4/6 inhibitor in first- or second-line setting. Importantly, palbociclib plus endocrine therapy was associated with better tolerability and quality of life, which should be considered when selecting treatment with similar PFS outcomes.

References:

Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, Hurvitz S, Loi S, Okines A, Abramson V, Bedard PL, Oliveira M, Mueller V, Zelnak A, DiGiovanna MP, Bachelot T, Chien AJ, O'Regan R, Wardley A, Conlin A, Cameron D, Carey L, Curigliano G, Gelmon K, Loibl S, Mayor J, McGoldrick S, An X, Winer EP. 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;38:2610-2619.

Pivot X, Spano JP, Espie M, Cottu P, Jouannaud C, Pottier V, Moreau L, Extra JM, Lortholary A, Rivera P, Spaeth D, Attar-Rabia H, Benkanoun C, Dima-Martinez L, Esposito N, Gligorov J. Patients' preference of trastuzumab administration (subcutaneous versus intravenous) in HER2-positive metastatic breast cancer: Results of the randomised MetaspHer study. Eur J Cancer. 2017;82:230-236.

Das S, Ciombor KK, Haraldsdottir S, Pumpalova Y, Sahin IH, Pineda G, Shyr Y, Lin EP, Hsu CY, Chu SK, Goff LW, Cardin DB, Bilen MA, Fisher GA, Wu C, Berlin J. Immune-related adverse events and immune checkpoint inhibitor efficacy in patients with gastrointestinal cancer with Food and Drug Administration-approved indications for immunotherapy. Oncologist. 2020;25:669-679.

Giuliano M, Schettini F, Rognoni C, Milani M, Jerusalem G, Bachelot T, De Laurentiis M, Thomas G, De Placido P, Arpino G, De Placido S, Cristofanilli M, Giordano A, Puglisi F, Pistilli B, Prat A, Del Mastro L, Venturini S, Generali D. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis. Lancet Oncol. 2019;20:1360-1369.

Systemic therapy advances for metastatic breast cancer (MBC) have led to improved overall survival; however, the CNS sanctuary site can be challenging to treat and cause significant neurologic symptoms. Kuksis and colleagues reported that HER2-positive and triple-negative breast MBC subtypes have high incidence of brain metastases, with pooled cumulative incidences of 31% and 32%, respectively. The incidence per patient-year was 13% for both subtypes. The treatment landscape for HER2-positive MBC is rapidly evolving. The combination of tucatinib/capecitabine/trastuzumab demonstrated reduced risk of intracranial progression or death (HR 0.32), improvement in intracranial objective response rate (47.3% versus 20.0%) and reduced risk of death (0.58) in the HER2CLIMB study. An MRI screening program may enhance early detection and study prevention of brain metastases.

Trastuzumab and pertuzumab have significantly improved outcomes in early-stage and advanced HER2-positive breast cancer. These monoclonal antibodies are given with chemotherapy initially, followed by dual antibody therapy to complete one year for curative treatment and until disease progression in the metastatic setting. The FeDeriCa randomized phase 3 study demonstrated that fixed-dose subcutaneous combination of pertuzumab and trastuzumab was non-inferior to intravenous formulations with a geometric mean ratio of cycle 7 pertuzumab serum trough concentration of 1.22 (90% CI 1.14-1.31). Furthermore, efficacy appeared similar with pathologic complete response rates of 60% for both groups. Trastuzumab and pertuzumab administration in an infusion center requires hospital resources, cost, and patient’s time. The MetasphHER study showed that patients preferred subcutaneous trastuzumab compared to IV, and further investigation into long-term outcomes and impact on quality of life and resource allocation is desired.

The phase 3 CLEOPATRA study demonstrated improvement in overall survival with the addition of pertuzumab to docetaxel and trastuzumab in patients with HER2-positive MBC. Rash and diarrhea are well-recognized potential side effects related to pertuzumab. Ferreira et al demonstrated that rash was prognostic for PFS and OS both during and after docetaxel discontinuation, while diarrhea was only prognostic after docetaxel. Neither rash nor diarrhea were predictive of pertuzumab benefit. Studies have shown that patients who developed immune-related adverse events during anti-PD-1 treatment had PFS and OS benefit compared to those who did not. These results may help inform and encourage patients and providers regarding benefit of various treatments in the setting of toxicities. Future research exploring biomarker prognostic and predictive capability is certainly warranted. 

Endocrine therapy plus a CDK 4/6 inhibitor is standard first-line treatment for hormone receptor-positive MBC. Progression that occurs rapidly or through multiple lines of endocrine therapy combinations, may indicate endocrine resistance. The phase 3 PEARL trial did not demonstrate superior PFS among patients with wild type ESR1 AI-resistant MBC with palbociclib/endocrine therapy compared to capecitabine (mPFS 8.0 vs 10.6 months, adjusted HR 1.11; p=0.404); similar PFS and aHR were seen in palbociclib/fulvestrant versus capecitabine cohort. Therapy sequencing in HR+/HER2-negative MBC is indeed relevant, and a previous meta-analysis demonstrated chemotherapy was not better than endocrine therapy plus CDK 4/6 inhibitor in first- or second-line setting. Importantly, palbociclib plus endocrine therapy was associated with better tolerability and quality of life, which should be considered when selecting treatment with similar PFS outcomes.

References:

Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, Hurvitz S, Loi S, Okines A, Abramson V, Bedard PL, Oliveira M, Mueller V, Zelnak A, DiGiovanna MP, Bachelot T, Chien AJ, O'Regan R, Wardley A, Conlin A, Cameron D, Carey L, Curigliano G, Gelmon K, Loibl S, Mayor J, McGoldrick S, An X, Winer EP. 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;38:2610-2619.

Pivot X, Spano JP, Espie M, Cottu P, Jouannaud C, Pottier V, Moreau L, Extra JM, Lortholary A, Rivera P, Spaeth D, Attar-Rabia H, Benkanoun C, Dima-Martinez L, Esposito N, Gligorov J. Patients' preference of trastuzumab administration (subcutaneous versus intravenous) in HER2-positive metastatic breast cancer: Results of the randomised MetaspHer study. Eur J Cancer. 2017;82:230-236.

Das S, Ciombor KK, Haraldsdottir S, Pumpalova Y, Sahin IH, Pineda G, Shyr Y, Lin EP, Hsu CY, Chu SK, Goff LW, Cardin DB, Bilen MA, Fisher GA, Wu C, Berlin J. Immune-related adverse events and immune checkpoint inhibitor efficacy in patients with gastrointestinal cancer with Food and Drug Administration-approved indications for immunotherapy. Oncologist. 2020;25:669-679.

Giuliano M, Schettini F, Rognoni C, Milani M, Jerusalem G, Bachelot T, De Laurentiis M, Thomas G, De Placido P, Arpino G, De Placido S, Cristofanilli M, Giordano A, Puglisi F, Pistilli B, Prat A, Del Mastro L, Venturini S, Generali D. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis. Lancet Oncol. 2019;20:1360-1369.