Breast Cancer

Key clinical point: Addition of palbociclib to adjuvant endocrine therapy (ET) vs. ET alone failed to improve invasive disease-free survival (IDFS) in patients with early-stage hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2−) breast cancer.

Major finding: At the median follow-up of 23.7 months, 3-year IDFS was similar for palbociclib + ET and ET alone groups (88.2% vs. 88.5%; hazard ratio, 0.93; log-rank P = .51). Serious adverse events occurred in 12.4% of patients on palbociclib + ET vs. 7.6% on ET alone.

Study details: Findings are from the second interim analysis of the ongoing phase 3 PALLAS trial that randomly allocated 5,760 patients with stage II-III HR+ and HER2− breast cancer to receive either 2 years of palbociclib in addition to ongoing standard adjuvant ET (n = 2,883) or ongoing standard adjuvant ET alone (n = 2,877).

Disclosures: PALLAS trial was cosponsored by the Alliance Foundation Trials and the Austrian Breast and Colorectal Cancer Study Group, in collaboration with Eastern Cooperative Oncology Group, the National Surgical Adjuvant Breast and Bowel Project, the German Breast Group, and the Breast International Group, with funding from Pfizer. The lead author reported receiving personal fees from Eisai, Lilly, and Novartis. Some of the coinvestigators reported ties with various pharmaceutical companies including Pfizer.

Source: Mayer EL et al. Lancet Oncol. 2021 Jan 15. doi: 10.1016/S1470-2045(20)30642-2.

Key clinical point: Addition of palbociclib to adjuvant endocrine therapy (ET) vs. ET alone failed to improve invasive disease-free survival (IDFS) in patients with early-stage hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2−) breast cancer.

Major finding: At the median follow-up of 23.7 months, 3-year IDFS was similar for palbociclib + ET and ET alone groups (88.2% vs. 88.5%; hazard ratio, 0.93; log-rank P = .51). Serious adverse events occurred in 12.4% of patients on palbociclib + ET vs. 7.6% on ET alone.

Study details: Findings are from the second interim analysis of the ongoing phase 3 PALLAS trial that randomly allocated 5,760 patients with stage II-III HR+ and HER2− breast cancer to receive either 2 years of palbociclib in addition to ongoing standard adjuvant ET (n = 2,883) or ongoing standard adjuvant ET alone (n = 2,877).

Disclosures: PALLAS trial was cosponsored by the Alliance Foundation Trials and the Austrian Breast and Colorectal Cancer Study Group, in collaboration with Eastern Cooperative Oncology Group, the National Surgical Adjuvant Breast and Bowel Project, the German Breast Group, and the Breast International Group, with funding from Pfizer. The lead author reported receiving personal fees from Eisai, Lilly, and Novartis. Some of the coinvestigators reported ties with various pharmaceutical companies including Pfizer.

Source: Mayer EL et al. Lancet Oncol. 2021 Jan 15. doi: 10.1016/S1470-2045(20)30642-2.

Key clinical point: Addition of palbociclib to adjuvant endocrine therapy (ET) vs. ET alone failed to improve invasive disease-free survival (IDFS) in patients with early-stage hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2−) breast cancer.

Major finding: At the median follow-up of 23.7 months, 3-year IDFS was similar for palbociclib + ET and ET alone groups (88.2% vs. 88.5%; hazard ratio, 0.93; log-rank P = .51). Serious adverse events occurred in 12.4% of patients on palbociclib + ET vs. 7.6% on ET alone.

Study details: Findings are from the second interim analysis of the ongoing phase 3 PALLAS trial that randomly allocated 5,760 patients with stage II-III HR+ and HER2− breast cancer to receive either 2 years of palbociclib in addition to ongoing standard adjuvant ET (n = 2,883) or ongoing standard adjuvant ET alone (n = 2,877).

Disclosures: PALLAS trial was cosponsored by the Alliance Foundation Trials and the Austrian Breast and Colorectal Cancer Study Group, in collaboration with Eastern Cooperative Oncology Group, the National Surgical Adjuvant Breast and Bowel Project, the German Breast Group, and the Breast International Group, with funding from Pfizer. The lead author reported receiving personal fees from Eisai, Lilly, and Novartis. Some of the coinvestigators reported ties with various pharmaceutical companies including Pfizer.

Source: Mayer EL et al. Lancet Oncol. 2021 Jan 15. doi: 10.1016/S1470-2045(20)30642-2.

Key clinical point: Margetuximab + chemotherapy vs. trastuzumab + chemotherapy improved progression-free survival (PFS) with an acceptable safety profile in patients with ERBB2-positive advanced breast cancer (ERBB2+ ABC) who progressed on 2 or more prior anti-ERBB2 therapies.

Major finding: Margetuximab + chemotherapy prolonged PFS with a 24% relative risk reduction vs. trastuzumab + chemotherapy (median PFS, 5.8 vs. 4.9 months; hazard ratio, 0.76; P = .03). Safety was comparable between the groups. Infusion-related reactions were higher with margetuximab vs. trastuzumab (13.3% vs. 3.4%; P less than .001) but were mostly prevalent at cycle 1 and resolved within 24 hours.

Study details: Findings are from the phase 3 SOPHIA trial including 536 patients with ERBB2+ ABC who had progressive disease after 2 or more prior anti-ERBB2 therapies. Patients were randomly allocated to receive either margetuximab + chemotherapy (n = 266) or trastuzumab + chemotherapy (n = 270).

Disclosures: This study was supported by MacroGenics, Inc. The lead author reported ties with MacroGenics, Roche, Pfizer, Novartis, Lilly, Merck, Seattle Genetics, Odonate Therapeutics, Eisai, Sermonix Pharmaceuticals, Immunomedics, Daiichi Sankyo, Puma, and Samsung. Other investigators reported owning stocks of, being an employee of, receiving support from, and/or consulting for various pharmaceutical companies including MacroGenics.

Source: Rugo HS et al. JAMA Oncol. 2021 Jan 22. doi: 10.1001/jamaoncol.2020.7932.

Key clinical point: Margetuximab + chemotherapy vs. trastuzumab + chemotherapy improved progression-free survival (PFS) with an acceptable safety profile in patients with ERBB2-positive advanced breast cancer (ERBB2+ ABC) who progressed on 2 or more prior anti-ERBB2 therapies.

Major finding: Margetuximab + chemotherapy prolonged PFS with a 24% relative risk reduction vs. trastuzumab + chemotherapy (median PFS, 5.8 vs. 4.9 months; hazard ratio, 0.76; P = .03). Safety was comparable between the groups. Infusion-related reactions were higher with margetuximab vs. trastuzumab (13.3% vs. 3.4%; P less than .001) but were mostly prevalent at cycle 1 and resolved within 24 hours.

Study details: Findings are from the phase 3 SOPHIA trial including 536 patients with ERBB2+ ABC who had progressive disease after 2 or more prior anti-ERBB2 therapies. Patients were randomly allocated to receive either margetuximab + chemotherapy (n = 266) or trastuzumab + chemotherapy (n = 270).

Disclosures: This study was supported by MacroGenics, Inc. The lead author reported ties with MacroGenics, Roche, Pfizer, Novartis, Lilly, Merck, Seattle Genetics, Odonate Therapeutics, Eisai, Sermonix Pharmaceuticals, Immunomedics, Daiichi Sankyo, Puma, and Samsung. Other investigators reported owning stocks of, being an employee of, receiving support from, and/or consulting for various pharmaceutical companies including MacroGenics.

Source: Rugo HS et al. JAMA Oncol. 2021 Jan 22. doi: 10.1001/jamaoncol.2020.7932.

Key clinical point: Margetuximab + chemotherapy vs. trastuzumab + chemotherapy improved progression-free survival (PFS) with an acceptable safety profile in patients with ERBB2-positive advanced breast cancer (ERBB2+ ABC) who progressed on 2 or more prior anti-ERBB2 therapies.

Major finding: Margetuximab + chemotherapy prolonged PFS with a 24% relative risk reduction vs. trastuzumab + chemotherapy (median PFS, 5.8 vs. 4.9 months; hazard ratio, 0.76; P = .03). Safety was comparable between the groups. Infusion-related reactions were higher with margetuximab vs. trastuzumab (13.3% vs. 3.4%; P less than .001) but were mostly prevalent at cycle 1 and resolved within 24 hours.

Study details: Findings are from the phase 3 SOPHIA trial including 536 patients with ERBB2+ ABC who had progressive disease after 2 or more prior anti-ERBB2 therapies. Patients were randomly allocated to receive either margetuximab + chemotherapy (n = 266) or trastuzumab + chemotherapy (n = 270).

Disclosures: This study was supported by MacroGenics, Inc. The lead author reported ties with MacroGenics, Roche, Pfizer, Novartis, Lilly, Merck, Seattle Genetics, Odonate Therapeutics, Eisai, Sermonix Pharmaceuticals, Immunomedics, Daiichi Sankyo, Puma, and Samsung. Other investigators reported owning stocks of, being an employee of, receiving support from, and/or consulting for various pharmaceutical companies including MacroGenics.

Source: Rugo HS et al. JAMA Oncol. 2021 Jan 22. doi: 10.1001/jamaoncol.2020.7932.

Key clinical point: Paclitaxel dose reduction does not necessarily result in improved neuropathy outcomes in patients with breast cancer prescribed weekly paclitaxel schedules.

Major finding: Patients receiving reduced-dose vs. full-dose paclitaxel had worse patient-reported symptom burden (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, 40.2 vs. 45.9) and clinical neuropathy outcomes (Total Neuropathy Score clinical version, 4.3 vs. 3.3; all P less than .05).

Study details: Findings are from the assessment of women with breast cancer prescribed weekly paclitaxel (80 mg/m²) for 12 weeks. Posttreatment outcomes were assessed at 3.6 months in 105 women who underwent subsequent dose reduction.

Disclosures: This study was supported by grants from the Cancer Institute NSW Program and National Health and Medical Research Council of Australia. M Friedlander reported ties with various pharmaceutical companies. The other authors did not have any financial disclosures.

Source: Timmins HC et al. Oncologist. 2021 Feb 1. doi: 10.1002/onco.13697.

Key clinical point: Paclitaxel dose reduction does not necessarily result in improved neuropathy outcomes in patients with breast cancer prescribed weekly paclitaxel schedules.

Major finding: Patients receiving reduced-dose vs. full-dose paclitaxel had worse patient-reported symptom burden (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, 40.2 vs. 45.9) and clinical neuropathy outcomes (Total Neuropathy Score clinical version, 4.3 vs. 3.3; all P less than .05).

Study details: Findings are from the assessment of women with breast cancer prescribed weekly paclitaxel (80 mg/m²) for 12 weeks. Posttreatment outcomes were assessed at 3.6 months in 105 women who underwent subsequent dose reduction.

Disclosures: This study was supported by grants from the Cancer Institute NSW Program and National Health and Medical Research Council of Australia. M Friedlander reported ties with various pharmaceutical companies. The other authors did not have any financial disclosures.

Source: Timmins HC et al. Oncologist. 2021 Feb 1. doi: 10.1002/onco.13697.

Key clinical point: Paclitaxel dose reduction does not necessarily result in improved neuropathy outcomes in patients with breast cancer prescribed weekly paclitaxel schedules.

Major finding: Patients receiving reduced-dose vs. full-dose paclitaxel had worse patient-reported symptom burden (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, 40.2 vs. 45.9) and clinical neuropathy outcomes (Total Neuropathy Score clinical version, 4.3 vs. 3.3; all P less than .05).

Study details: Findings are from the assessment of women with breast cancer prescribed weekly paclitaxel (80 mg/m²) for 12 weeks. Posttreatment outcomes were assessed at 3.6 months in 105 women who underwent subsequent dose reduction.

Disclosures: This study was supported by grants from the Cancer Institute NSW Program and National Health and Medical Research Council of Australia. M Friedlander reported ties with various pharmaceutical companies. The other authors did not have any financial disclosures.

Source: Timmins HC et al. Oncologist. 2021 Feb 1. doi: 10.1002/onco.13697.

Key clinical point: Intensive screening for distant metastasis during posttreatment follow-up was not associated with improved overall survival (OS) in disease-free patients initially diagnosed with nonmetastatic breast cancer.

Major finding: OS was not significantly different among patients receiving intensive vs. less intensive screening (adjusted hazard ratio, 1.21; P = .124).

Study details: This retrospective study evaluated the effect of intensive (n=199) vs. less intensive (n=199) screening on survival in 398 patients initially diagnosed with nonmetastatic, resectable breast cancer who eventually developed distant metastasis after initial curative treatment.

Disclosures: This study was supported by grants received by the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea, and the National Research Foundation of Korea grant funded by the Ministry of Science and ICT, Republic of Korea. The authors declared no conflicts of interest.

Source: Cheun J-H et al. Sci Rep. 2021 Feb 2. doi: 10.1038/s41598-021-82485-w.

Key clinical point: Intensive screening for distant metastasis during posttreatment follow-up was not associated with improved overall survival (OS) in disease-free patients initially diagnosed with nonmetastatic breast cancer.

Major finding: OS was not significantly different among patients receiving intensive vs. less intensive screening (adjusted hazard ratio, 1.21; P = .124).

Study details: This retrospective study evaluated the effect of intensive (n=199) vs. less intensive (n=199) screening on survival in 398 patients initially diagnosed with nonmetastatic, resectable breast cancer who eventually developed distant metastasis after initial curative treatment.

Disclosures: This study was supported by grants received by the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea, and the National Research Foundation of Korea grant funded by the Ministry of Science and ICT, Republic of Korea. The authors declared no conflicts of interest.

Source: Cheun J-H et al. Sci Rep. 2021 Feb 2. doi: 10.1038/s41598-021-82485-w.

Key clinical point: Intensive screening for distant metastasis during posttreatment follow-up was not associated with improved overall survival (OS) in disease-free patients initially diagnosed with nonmetastatic breast cancer.

Major finding: OS was not significantly different among patients receiving intensive vs. less intensive screening (adjusted hazard ratio, 1.21; P = .124).

Study details: This retrospective study evaluated the effect of intensive (n=199) vs. less intensive (n=199) screening on survival in 398 patients initially diagnosed with nonmetastatic, resectable breast cancer who eventually developed distant metastasis after initial curative treatment.

Disclosures: This study was supported by grants received by the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea, and the National Research Foundation of Korea grant funded by the Ministry of Science and ICT, Republic of Korea. The authors declared no conflicts of interest.

Source: Cheun J-H et al. Sci Rep. 2021 Feb 2. doi: 10.1038/s41598-021-82485-w.

Key clinical point: By opting initially for breast-conserving therapy (BCT) over mastectomy, majority of women with T1-2 node-negative breast cancer with positive sentinel lymph node (SLN) can avoid completion axillary lymph node dissection (cALND), often done in mastectomy.

Major finding: Patients treated with mastectomy vs. BCT were more likely to receive cALND after positive SLN (71% vs. 26.6%; P less than .001). Extracapsular extension (ECE) in the SLN was observed in 31.6% of patients treated with mastectomy and cALND. However, remaining 68.4% of patients without ECE in the SLN could have avoided cALND if they had chosen BCT initially.

Study details: Findings are from an analysis of 306 women with T1-2 clinically node-negative breast cancer with metastases in the SLN who were treated with mastectomy (n=107) or BCT (n=199).

Disclosures: Programmatic support was provided by the Fashion Footwear Charitable Foundation of New York, Inc., the Margie and Robert E. Peterson Foundation, and the Linda and Jim Lippman. ML Smidt reported receiving a grant from Servier Pharma. The remaining authors had no disclosures.

Source: Vane MLG et al. Ann Surg Oncol. 2021 Feb 14. doi: 10.1245/s10434-021-09674-9. 

Key clinical point: By opting initially for breast-conserving therapy (BCT) over mastectomy, majority of women with T1-2 node-negative breast cancer with positive sentinel lymph node (SLN) can avoid completion axillary lymph node dissection (cALND), often done in mastectomy.

Major finding: Patients treated with mastectomy vs. BCT were more likely to receive cALND after positive SLN (71% vs. 26.6%; P less than .001). Extracapsular extension (ECE) in the SLN was observed in 31.6% of patients treated with mastectomy and cALND. However, remaining 68.4% of patients without ECE in the SLN could have avoided cALND if they had chosen BCT initially.

Study details: Findings are from an analysis of 306 women with T1-2 clinically node-negative breast cancer with metastases in the SLN who were treated with mastectomy (n=107) or BCT (n=199).

Disclosures: Programmatic support was provided by the Fashion Footwear Charitable Foundation of New York, Inc., the Margie and Robert E. Peterson Foundation, and the Linda and Jim Lippman. ML Smidt reported receiving a grant from Servier Pharma. The remaining authors had no disclosures.

Source: Vane MLG et al. Ann Surg Oncol. 2021 Feb 14. doi: 10.1245/s10434-021-09674-9. 

Key clinical point: By opting initially for breast-conserving therapy (BCT) over mastectomy, majority of women with T1-2 node-negative breast cancer with positive sentinel lymph node (SLN) can avoid completion axillary lymph node dissection (cALND), often done in mastectomy.

Major finding: Patients treated with mastectomy vs. BCT were more likely to receive cALND after positive SLN (71% vs. 26.6%; P less than .001). Extracapsular extension (ECE) in the SLN was observed in 31.6% of patients treated with mastectomy and cALND. However, remaining 68.4% of patients without ECE in the SLN could have avoided cALND if they had chosen BCT initially.

Study details: Findings are from an analysis of 306 women with T1-2 clinically node-negative breast cancer with metastases in the SLN who were treated with mastectomy (n=107) or BCT (n=199).

Disclosures: Programmatic support was provided by the Fashion Footwear Charitable Foundation of New York, Inc., the Margie and Robert E. Peterson Foundation, and the Linda and Jim Lippman. ML Smidt reported receiving a grant from Servier Pharma. The remaining authors had no disclosures.

Source: Vane MLG et al. Ann Surg Oncol. 2021 Feb 14. doi: 10.1245/s10434-021-09674-9. 

Key clinical point: The 6-year follow-up data from APHINITY trial confirm invasive disease-free survival (IDFS) benefits of adding pertuzumab to adjuvant trastuzumab and chemotherapy in node-positive human epidermal growth factor receptor 2-positive (HER2+) early breast cancer.

Major finding: At 6 years, IDFS was longer in pertuzumab vs. placebo (91% vs. 88%; hazard ratio [HR], 0.76; 95% CI, 0.64-0.91) group, particularly in node-positive cohort (HR, 0.72; 95% CI, 0.59-0.87) but not in node-negative cohort. The overall survival analysis did not reach the required statistical significance (HR, 0.85; P = .17).

Study details: Findings are from a second interim analysis of the phase 3 APHINITY trial including 4,805 patients with node-positive or high-risk node-negative HER2+ breast cancer randomly allocated to receive chemotherapy with either 1 year of trastuzumab + placebo (n = 2,404) or trastuzumab + pertuzumab (n = 2,400) post-surgery.

Disclosures: This study was supported by F. Hoffmann-La Roche Ltd/Genentech. The lead author reported ties with AstraZeneca, Lilly, MSD, Novartis, Pfizer, Debiopharm Group, Odonate Therapeutics, Menarini, Seattle Genetics, Camel-IDS, Immunomedics, Roche/Genentech, Immutep, Radius Health, Synthon, Servier, Oncolytics, and EU Cancer Mission Board. Other investigators declared ties with various pharmaceutical companies including Roche/Genentech.

Source: Piccart M et al. J Clin Oncol. 2021 Feb 4. doi: 10.1200/JCO.20.01204.

Key clinical point: The 6-year follow-up data from APHINITY trial confirm invasive disease-free survival (IDFS) benefits of adding pertuzumab to adjuvant trastuzumab and chemotherapy in node-positive human epidermal growth factor receptor 2-positive (HER2+) early breast cancer.

Major finding: At 6 years, IDFS was longer in pertuzumab vs. placebo (91% vs. 88%; hazard ratio [HR], 0.76; 95% CI, 0.64-0.91) group, particularly in node-positive cohort (HR, 0.72; 95% CI, 0.59-0.87) but not in node-negative cohort. The overall survival analysis did not reach the required statistical significance (HR, 0.85; P = .17).

Study details: Findings are from a second interim analysis of the phase 3 APHINITY trial including 4,805 patients with node-positive or high-risk node-negative HER2+ breast cancer randomly allocated to receive chemotherapy with either 1 year of trastuzumab + placebo (n = 2,404) or trastuzumab + pertuzumab (n = 2,400) post-surgery.

Disclosures: This study was supported by F. Hoffmann-La Roche Ltd/Genentech. The lead author reported ties with AstraZeneca, Lilly, MSD, Novartis, Pfizer, Debiopharm Group, Odonate Therapeutics, Menarini, Seattle Genetics, Camel-IDS, Immunomedics, Roche/Genentech, Immutep, Radius Health, Synthon, Servier, Oncolytics, and EU Cancer Mission Board. Other investigators declared ties with various pharmaceutical companies including Roche/Genentech.

Source: Piccart M et al. J Clin Oncol. 2021 Feb 4. doi: 10.1200/JCO.20.01204.

Key clinical point: The 6-year follow-up data from APHINITY trial confirm invasive disease-free survival (IDFS) benefits of adding pertuzumab to adjuvant trastuzumab and chemotherapy in node-positive human epidermal growth factor receptor 2-positive (HER2+) early breast cancer.

Major finding: At 6 years, IDFS was longer in pertuzumab vs. placebo (91% vs. 88%; hazard ratio [HR], 0.76; 95% CI, 0.64-0.91) group, particularly in node-positive cohort (HR, 0.72; 95% CI, 0.59-0.87) but not in node-negative cohort. The overall survival analysis did not reach the required statistical significance (HR, 0.85; P = .17).

Study details: Findings are from a second interim analysis of the phase 3 APHINITY trial including 4,805 patients with node-positive or high-risk node-negative HER2+ breast cancer randomly allocated to receive chemotherapy with either 1 year of trastuzumab + placebo (n = 2,404) or trastuzumab + pertuzumab (n = 2,400) post-surgery.

Disclosures: This study was supported by F. Hoffmann-La Roche Ltd/Genentech. The lead author reported ties with AstraZeneca, Lilly, MSD, Novartis, Pfizer, Debiopharm Group, Odonate Therapeutics, Menarini, Seattle Genetics, Camel-IDS, Immunomedics, Roche/Genentech, Immutep, Radius Health, Synthon, Servier, Oncolytics, and EU Cancer Mission Board. Other investigators declared ties with various pharmaceutical companies including Roche/Genentech.

Source: Piccart M et al. J Clin Oncol. 2021 Feb 4. doi: 10.1200/JCO.20.01204.

Key clinical point: Pyrotinib+capecitabine significantly improved progression-free survival (PFS) vs. lapatinib+capecitabine with manageable toxicity in women with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) after treatment with trastuzumab and taxanes.

Major finding: Median PFS was significantly longer in the pyrotinib+capecitabine vs. lapatinib+capecitabine group (12.5 vs. 6.8 months; hazard ratio, 0.39; one-sided P less than .0001). Serious adverse events were reported by 10% vs. 8% of patients in the pyrotinib vs. lapatinib group.

Study details: Findings are from an interim analysis of the phase 3 PHOEBE trial including 267 patients with HER2+ MBC previously treated with trastuzumab and taxanes randomly allocated to receive either pyrotinib+capecitabine (n=134) or lapatinib+capecitabine (n=132).

Disclosures: This study was funded by Jiangsu Hengrui Medicine and the National Key R&D Program of China. The lead author reported ties with Hengrui, Novartis, Roche, AstraZeneca, Pfizer, and Eisai. Some other investigators also reported employment or receiving grants and fees from various pharmaceutical companies including Hengrui.

Source: Xu B et al. Lancet Oncol. 2021 Feb 11. doi: 10.1016/S1470-2045(20)30702-6.

Key clinical point: Pyrotinib+capecitabine significantly improved progression-free survival (PFS) vs. lapatinib+capecitabine with manageable toxicity in women with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) after treatment with trastuzumab and taxanes.

Major finding: Median PFS was significantly longer in the pyrotinib+capecitabine vs. lapatinib+capecitabine group (12.5 vs. 6.8 months; hazard ratio, 0.39; one-sided P less than .0001). Serious adverse events were reported by 10% vs. 8% of patients in the pyrotinib vs. lapatinib group.

Study details: Findings are from an interim analysis of the phase 3 PHOEBE trial including 267 patients with HER2+ MBC previously treated with trastuzumab and taxanes randomly allocated to receive either pyrotinib+capecitabine (n=134) or lapatinib+capecitabine (n=132).

Disclosures: This study was funded by Jiangsu Hengrui Medicine and the National Key R&D Program of China. The lead author reported ties with Hengrui, Novartis, Roche, AstraZeneca, Pfizer, and Eisai. Some other investigators also reported employment or receiving grants and fees from various pharmaceutical companies including Hengrui.

Source: Xu B et al. Lancet Oncol. 2021 Feb 11. doi: 10.1016/S1470-2045(20)30702-6.

Key clinical point: Pyrotinib+capecitabine significantly improved progression-free survival (PFS) vs. lapatinib+capecitabine with manageable toxicity in women with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) after treatment with trastuzumab and taxanes.

Major finding: Median PFS was significantly longer in the pyrotinib+capecitabine vs. lapatinib+capecitabine group (12.5 vs. 6.8 months; hazard ratio, 0.39; one-sided P less than .0001). Serious adverse events were reported by 10% vs. 8% of patients in the pyrotinib vs. lapatinib group.

Study details: Findings are from an interim analysis of the phase 3 PHOEBE trial including 267 patients with HER2+ MBC previously treated with trastuzumab and taxanes randomly allocated to receive either pyrotinib+capecitabine (n=134) or lapatinib+capecitabine (n=132).

Disclosures: This study was funded by Jiangsu Hengrui Medicine and the National Key R&D Program of China. The lead author reported ties with Hengrui, Novartis, Roche, AstraZeneca, Pfizer, and Eisai. Some other investigators also reported employment or receiving grants and fees from various pharmaceutical companies including Hengrui.

Source: Xu B et al. Lancet Oncol. 2021 Feb 11. doi: 10.1016/S1470-2045(20)30702-6.

For patients with triple-negative breast cancer (TNBC), neoadjuvant carboplatin plus docetaxel yields the same pathologic complete response and survival rates as a standard anthracycline-based neoadjuvant regimen – carboplatin and paclitaxel followed by doxorubicin/cyclophosphamide – but with less toxicity, higher completion rates, and at lower cost.

The results come from a phase 2 trial that involved 100 women. The study was published online in February in Clinical Cancer Research.

The doublet provides a safe, effective alternative for patients who are not candidates for treatment with anthracyclines and should be explored further for neoadjuvant deescalation, according to investigators led by Priyanka Sharma, MD, TNBC specialist and professor at the University of Kansas Medical Center, Westwood.

The trial wasn’t powered to demonstrate noninferiority, so it “probably does not provide enough evidence to state that [taxane/platinum] should replace other regimens,” Dr. Sharma said in an interview.

A proper noninferiority trial would require more than 2,500 participants, she said, adding that such a trial is unlikely, because companies are focused on immunotherapies for neoadjuvant TNBC.

“Our study does, however, provide a very effective alternative for patients and providers who want to use or prefer an anthracycline-sparing neoadjuvant chemotherapy regimen. We are very encouraged” by the findings, Dr. Sharma said.

This is “a provocative study that should make us pause and reevaluate our current approach. Further study of this approach in early-stage TNBC is warranted,” Melinda L. Telli, MD, associate professor of medicine and director of the breast cancer program at Stanford (Calif.) University, said when asked for comment.

Avoiding the risks associated with anthracycline “is great. I would be particularly enthusiastic using this regimen in patients with known increased risk of cardiac toxicity,” said Amy Tiersten, MD, a breast cancer specialist and professor at Mount Sinai Hospital, New York.

Anthracycline-based regimens are the standard of care for neoadjuvant TNBC. They typically include a taxane with or without carboplatin plus an anthracycline/cyclophosphamide combination. The regimen is highly active, but there is a small but serious risk for cardiomyopathy and leukemia with anthracycline/cyclophosphamide. In the current trial, one woman in the anthracycline arm died of secondary acute myeloid leukemia.

Given its tolerability and effectiveness, a taxane/carboplatin doublet might serve as a good backbone for the addition of novel immunotherapies in trials. Dr. Sharma is the principal investigator in one such trial, a phase 2 trial of carboplatin/docetaxel plus pembrolizumab for stage I–III TNBC.
 

Study details

The Neoadjuvant Study of Two Platinum Regimens in Stage I–III Triple Negative Breast Cancer (NeoSTOP) involved 100 women with stage I–III TNBC.

In the experimental arm, 52 women received carboplatin AUC 6 plus docetaxel 75 mg/m² every 21 days for six cycles.

In the standard-of-care anthracycline arm, 48 women received carboplatin AUC 6 every 21 days for four cycles plus paclitaxel 80 mg/m² weekly for 12 weeks, followed by doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² every 2 weeks for four cycles.

Docetaxel and paclitaxel in the two regimens are interchangeable because they have shown equal efficacy in adjuvant trials, Dr. Sharma said.

At surgery, 54% of women in both arms had a breast/axilla pathologic complete response – the primary endpoint – and 67% in both arms had a residual cancer burden of 0-1. Event-free and overall survival (about 55% at 3 years for both) were similar with the two regimens.

Grade 3/4 adverse events were more common in the anthracycline arm. They included neutropenia, which occurred in 60% of women in the anthracycline arm, vs. 8% with the doublet; and febrile neutropenia, which occurred in 19% with anthracycline, vs. none with the doublet.

The toxicity profile of the anthracycline regimen was comparable to those in previous reports.

Ninety-two percent of the docetaxel/carboplatin group completed all six cycles; 72% of women in the anthracycline arm completed 10 or more doses of paclitaxel, and 85% completed all 4 carboplatin doses.

Mean costs of treatment, patient transportation, and lost productivity were $36,720 in the anthracycline arm, vs. $33,148 with the doublet.

The two arms were well balanced with respect to patient characteristics. The median age was 51 years, 30% of patients had axillary lymph node–positive disease, and 16% had ER/PgR expression of 1% to 10%. Of the study population, 17% carried deleterious BRCA1/2 mutations. Women were enrolled from July 2015 to May 2018. Median follow-up was 38 months.

Of the study population, 17% had stage I disease, so NeoSTOP included a lower-risk population than some neoadjuvant trials. However, there was no significant change in pathologic complete response rates in the two arms after exclusion of women with stage I disease (doublet, 50%; anthracycline, 54%).

The study was funded by the University of Kansas Cancer Center, the Breast Cancer Research Foundation, and the National Institute of General Medical Sciences. The investigators disclosed no relevant financial relationships.

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

For patients with triple-negative breast cancer (TNBC), neoadjuvant carboplatin plus docetaxel yields the same pathologic complete response and survival rates as a standard anthracycline-based neoadjuvant regimen – carboplatin and paclitaxel followed by doxorubicin/cyclophosphamide – but with less toxicity, higher completion rates, and at lower cost.

The results come from a phase 2 trial that involved 100 women. The study was published online in February in Clinical Cancer Research.

The doublet provides a safe, effective alternative for patients who are not candidates for treatment with anthracyclines and should be explored further for neoadjuvant deescalation, according to investigators led by Priyanka Sharma, MD, TNBC specialist and professor at the University of Kansas Medical Center, Westwood.

The trial wasn’t powered to demonstrate noninferiority, so it “probably does not provide enough evidence to state that [taxane/platinum] should replace other regimens,” Dr. Sharma said in an interview.

A proper noninferiority trial would require more than 2,500 participants, she said, adding that such a trial is unlikely, because companies are focused on immunotherapies for neoadjuvant TNBC.

“Our study does, however, provide a very effective alternative for patients and providers who want to use or prefer an anthracycline-sparing neoadjuvant chemotherapy regimen. We are very encouraged” by the findings, Dr. Sharma said.

This is “a provocative study that should make us pause and reevaluate our current approach. Further study of this approach in early-stage TNBC is warranted,” Melinda L. Telli, MD, associate professor of medicine and director of the breast cancer program at Stanford (Calif.) University, said when asked for comment.

Avoiding the risks associated with anthracycline “is great. I would be particularly enthusiastic using this regimen in patients with known increased risk of cardiac toxicity,” said Amy Tiersten, MD, a breast cancer specialist and professor at Mount Sinai Hospital, New York.

Anthracycline-based regimens are the standard of care for neoadjuvant TNBC. They typically include a taxane with or without carboplatin plus an anthracycline/cyclophosphamide combination. The regimen is highly active, but there is a small but serious risk for cardiomyopathy and leukemia with anthracycline/cyclophosphamide. In the current trial, one woman in the anthracycline arm died of secondary acute myeloid leukemia.

Given its tolerability and effectiveness, a taxane/carboplatin doublet might serve as a good backbone for the addition of novel immunotherapies in trials. Dr. Sharma is the principal investigator in one such trial, a phase 2 trial of carboplatin/docetaxel plus pembrolizumab for stage I–III TNBC.
 

Study details

The Neoadjuvant Study of Two Platinum Regimens in Stage I–III Triple Negative Breast Cancer (NeoSTOP) involved 100 women with stage I–III TNBC.

In the experimental arm, 52 women received carboplatin AUC 6 plus docetaxel 75 mg/m² every 21 days for six cycles.

In the standard-of-care anthracycline arm, 48 women received carboplatin AUC 6 every 21 days for four cycles plus paclitaxel 80 mg/m² weekly for 12 weeks, followed by doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² every 2 weeks for four cycles.

Docetaxel and paclitaxel in the two regimens are interchangeable because they have shown equal efficacy in adjuvant trials, Dr. Sharma said.

At surgery, 54% of women in both arms had a breast/axilla pathologic complete response – the primary endpoint – and 67% in both arms had a residual cancer burden of 0-1. Event-free and overall survival (about 55% at 3 years for both) were similar with the two regimens.

Grade 3/4 adverse events were more common in the anthracycline arm. They included neutropenia, which occurred in 60% of women in the anthracycline arm, vs. 8% with the doublet; and febrile neutropenia, which occurred in 19% with anthracycline, vs. none with the doublet.

The toxicity profile of the anthracycline regimen was comparable to those in previous reports.

Ninety-two percent of the docetaxel/carboplatin group completed all six cycles; 72% of women in the anthracycline arm completed 10 or more doses of paclitaxel, and 85% completed all 4 carboplatin doses.

Mean costs of treatment, patient transportation, and lost productivity were $36,720 in the anthracycline arm, vs. $33,148 with the doublet.

The two arms were well balanced with respect to patient characteristics. The median age was 51 years, 30% of patients had axillary lymph node–positive disease, and 16% had ER/PgR expression of 1% to 10%. Of the study population, 17% carried deleterious BRCA1/2 mutations. Women were enrolled from July 2015 to May 2018. Median follow-up was 38 months.

Of the study population, 17% had stage I disease, so NeoSTOP included a lower-risk population than some neoadjuvant trials. However, there was no significant change in pathologic complete response rates in the two arms after exclusion of women with stage I disease (doublet, 50%; anthracycline, 54%).

The study was funded by the University of Kansas Cancer Center, the Breast Cancer Research Foundation, and the National Institute of General Medical Sciences. The investigators disclosed no relevant financial relationships.

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

For patients with triple-negative breast cancer (TNBC), neoadjuvant carboplatin plus docetaxel yields the same pathologic complete response and survival rates as a standard anthracycline-based neoadjuvant regimen – carboplatin and paclitaxel followed by doxorubicin/cyclophosphamide – but with less toxicity, higher completion rates, and at lower cost.

The results come from a phase 2 trial that involved 100 women. The study was published online in February in Clinical Cancer Research.

The doublet provides a safe, effective alternative for patients who are not candidates for treatment with anthracyclines and should be explored further for neoadjuvant deescalation, according to investigators led by Priyanka Sharma, MD, TNBC specialist and professor at the University of Kansas Medical Center, Westwood.

The trial wasn’t powered to demonstrate noninferiority, so it “probably does not provide enough evidence to state that [taxane/platinum] should replace other regimens,” Dr. Sharma said in an interview.

A proper noninferiority trial would require more than 2,500 participants, she said, adding that such a trial is unlikely, because companies are focused on immunotherapies for neoadjuvant TNBC.

“Our study does, however, provide a very effective alternative for patients and providers who want to use or prefer an anthracycline-sparing neoadjuvant chemotherapy regimen. We are very encouraged” by the findings, Dr. Sharma said.

This is “a provocative study that should make us pause and reevaluate our current approach. Further study of this approach in early-stage TNBC is warranted,” Melinda L. Telli, MD, associate professor of medicine and director of the breast cancer program at Stanford (Calif.) University, said when asked for comment.

Avoiding the risks associated with anthracycline “is great. I would be particularly enthusiastic using this regimen in patients with known increased risk of cardiac toxicity,” said Amy Tiersten, MD, a breast cancer specialist and professor at Mount Sinai Hospital, New York.

Anthracycline-based regimens are the standard of care for neoadjuvant TNBC. They typically include a taxane with or without carboplatin plus an anthracycline/cyclophosphamide combination. The regimen is highly active, but there is a small but serious risk for cardiomyopathy and leukemia with anthracycline/cyclophosphamide. In the current trial, one woman in the anthracycline arm died of secondary acute myeloid leukemia.

Given its tolerability and effectiveness, a taxane/carboplatin doublet might serve as a good backbone for the addition of novel immunotherapies in trials. Dr. Sharma is the principal investigator in one such trial, a phase 2 trial of carboplatin/docetaxel plus pembrolizumab for stage I–III TNBC.
 

Study details

The Neoadjuvant Study of Two Platinum Regimens in Stage I–III Triple Negative Breast Cancer (NeoSTOP) involved 100 women with stage I–III TNBC.

In the experimental arm, 52 women received carboplatin AUC 6 plus docetaxel 75 mg/m² every 21 days for six cycles.

In the standard-of-care anthracycline arm, 48 women received carboplatin AUC 6 every 21 days for four cycles plus paclitaxel 80 mg/m² weekly for 12 weeks, followed by doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² every 2 weeks for four cycles.

Docetaxel and paclitaxel in the two regimens are interchangeable because they have shown equal efficacy in adjuvant trials, Dr. Sharma said.

At surgery, 54% of women in both arms had a breast/axilla pathologic complete response – the primary endpoint – and 67% in both arms had a residual cancer burden of 0-1. Event-free and overall survival (about 55% at 3 years for both) were similar with the two regimens.

Grade 3/4 adverse events were more common in the anthracycline arm. They included neutropenia, which occurred in 60% of women in the anthracycline arm, vs. 8% with the doublet; and febrile neutropenia, which occurred in 19% with anthracycline, vs. none with the doublet.

The toxicity profile of the anthracycline regimen was comparable to those in previous reports.

Ninety-two percent of the docetaxel/carboplatin group completed all six cycles; 72% of women in the anthracycline arm completed 10 or more doses of paclitaxel, and 85% completed all 4 carboplatin doses.

Mean costs of treatment, patient transportation, and lost productivity were $36,720 in the anthracycline arm, vs. $33,148 with the doublet.

The two arms were well balanced with respect to patient characteristics. The median age was 51 years, 30% of patients had axillary lymph node–positive disease, and 16% had ER/PgR expression of 1% to 10%. Of the study population, 17% carried deleterious BRCA1/2 mutations. Women were enrolled from July 2015 to May 2018. Median follow-up was 38 months.

Of the study population, 17% had stage I disease, so NeoSTOP included a lower-risk population than some neoadjuvant trials. However, there was no significant change in pathologic complete response rates in the two arms after exclusion of women with stage I disease (doublet, 50%; anthracycline, 54%).

The study was funded by the University of Kansas Cancer Center, the Breast Cancer Research Foundation, and the National Institute of General Medical Sciences. The investigators disclosed no relevant financial relationships.

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

In the United States, breast cancer mortality rates dropped every year for women across all age groups between 1989 and 2010, but after that, the trend stalled for those younger than 40 years.

“It’s clear that mortality rates in women under 40 are no longer decreasing,” lead author R. Edward Hendrick, PhD, clinical professor from the department of radiology at the University of Colorado at Denver, Aurora, stated in a press release. “I estimate that, in 2-3 years, the mortality rate will be increasing significantly in these women.”

These findings were published online Feb. 9, 2021, in Radiology.

The authors speculate that the findings may be related to recommendations for mammography screening.

For their study, the authors analyzed National Center for Health Statistics data for 1969-2017 and delay-adjusted invasive breast cancer incidence rates from the Surveillance, Epidemiology, and End Results program.

They found that breast cancer mortality rates decreased significantly by 1.5%-3.4% per year for all age groups from 1989 to 2010, and by 1.2%-2.2% per year after 2010 for those aged 40-79 years. However, the rates increased after 2010 by a nonsignificant 2.8% per year for women aged 20-29 years and 0.3% per year for those aged 30-39 years.

Distant-stage breast cancer incidence rates increased by more than 4% per year after the year 2000 in women aged 20-39 years.

“Our hope is that these findings focus more attention and research on breast cancer in younger women and what is behind this rapid increase in late-stage cancers,” Dr. Hendrick stated in the press release.

He and his colleagues speculate that the contrast between the upward trend in women aged younger than 40 years and the downward trend in older women highlights the value of mammography and may reflect the benefits of regular screening, which is not currently recommended for women younger than 40 who are not at high risk for breast cancer.

However, other groups, including the American College of Radiology and the Society for Breast Imaging, support starting annual mammograms at age 40 years.

An expert who was approached for comment noted that the incidence of breast cancer increases with age.

It is more common in women as they age, so screening recommendations do not include women aged younger than 40 years unless they are at very high risk for breast cancer, noted Joann G. Elmore, MD, MPH, professor of medicine at the University of California, Los Angeles.

“The majority of deaths due to breast cancer are in women over age 40. The breast cancer mortality rates per 100,000 as shown [in this study] are about 3 patients/100,000 for the under 40 age group, about 30/100,000 in the 40-69 age group, and about 80/100,000 in the 70 and above age group,” she pointed out.

Dr. Elmore was a coauthor of an editorial regarding the 2019 evidence-based guidance statement from the American College of Physicians . That guidance, which was endorsed by the U.S. Preventive Services Task Force, recommended screening every other year for average-risk women aged 50-74 years, as reported by this news organization.

In their editorial, Dr. Elmore and coauthor Christoph Lee, MD, of the University of Washington, Seattle, applauded the ACP’s approach but stressed that the guidance is not a perfect product and does not “clearly illuminate the full path ahead for every woman.”

Breast cancer screening guidelines continue to evolve, they said, concluding that “physicians are left to use their best judgment based on available research and expert recommendations.”

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

In the United States, breast cancer mortality rates dropped every year for women across all age groups between 1989 and 2010, but after that, the trend stalled for those younger than 40 years.

“It’s clear that mortality rates in women under 40 are no longer decreasing,” lead author R. Edward Hendrick, PhD, clinical professor from the department of radiology at the University of Colorado at Denver, Aurora, stated in a press release. “I estimate that, in 2-3 years, the mortality rate will be increasing significantly in these women.”

These findings were published online Feb. 9, 2021, in Radiology.

The authors speculate that the findings may be related to recommendations for mammography screening.

For their study, the authors analyzed National Center for Health Statistics data for 1969-2017 and delay-adjusted invasive breast cancer incidence rates from the Surveillance, Epidemiology, and End Results program.

They found that breast cancer mortality rates decreased significantly by 1.5%-3.4% per year for all age groups from 1989 to 2010, and by 1.2%-2.2% per year after 2010 for those aged 40-79 years. However, the rates increased after 2010 by a nonsignificant 2.8% per year for women aged 20-29 years and 0.3% per year for those aged 30-39 years.

Distant-stage breast cancer incidence rates increased by more than 4% per year after the year 2000 in women aged 20-39 years.

“Our hope is that these findings focus more attention and research on breast cancer in younger women and what is behind this rapid increase in late-stage cancers,” Dr. Hendrick stated in the press release.

He and his colleagues speculate that the contrast between the upward trend in women aged younger than 40 years and the downward trend in older women highlights the value of mammography and may reflect the benefits of regular screening, which is not currently recommended for women younger than 40 who are not at high risk for breast cancer.

However, other groups, including the American College of Radiology and the Society for Breast Imaging, support starting annual mammograms at age 40 years.

An expert who was approached for comment noted that the incidence of breast cancer increases with age.

It is more common in women as they age, so screening recommendations do not include women aged younger than 40 years unless they are at very high risk for breast cancer, noted Joann G. Elmore, MD, MPH, professor of medicine at the University of California, Los Angeles.

“The majority of deaths due to breast cancer are in women over age 40. The breast cancer mortality rates per 100,000 as shown [in this study] are about 3 patients/100,000 for the under 40 age group, about 30/100,000 in the 40-69 age group, and about 80/100,000 in the 70 and above age group,” she pointed out.

Dr. Elmore was a coauthor of an editorial regarding the 2019 evidence-based guidance statement from the American College of Physicians . That guidance, which was endorsed by the U.S. Preventive Services Task Force, recommended screening every other year for average-risk women aged 50-74 years, as reported by this news organization.

In their editorial, Dr. Elmore and coauthor Christoph Lee, MD, of the University of Washington, Seattle, applauded the ACP’s approach but stressed that the guidance is not a perfect product and does not “clearly illuminate the full path ahead for every woman.”

Breast cancer screening guidelines continue to evolve, they said, concluding that “physicians are left to use their best judgment based on available research and expert recommendations.”

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

In the United States, breast cancer mortality rates dropped every year for women across all age groups between 1989 and 2010, but after that, the trend stalled for those younger than 40 years.

“It’s clear that mortality rates in women under 40 are no longer decreasing,” lead author R. Edward Hendrick, PhD, clinical professor from the department of radiology at the University of Colorado at Denver, Aurora, stated in a press release. “I estimate that, in 2-3 years, the mortality rate will be increasing significantly in these women.”

These findings were published online Feb. 9, 2021, in Radiology.

The authors speculate that the findings may be related to recommendations for mammography screening.

For their study, the authors analyzed National Center for Health Statistics data for 1969-2017 and delay-adjusted invasive breast cancer incidence rates from the Surveillance, Epidemiology, and End Results program.

They found that breast cancer mortality rates decreased significantly by 1.5%-3.4% per year for all age groups from 1989 to 2010, and by 1.2%-2.2% per year after 2010 for those aged 40-79 years. However, the rates increased after 2010 by a nonsignificant 2.8% per year for women aged 20-29 years and 0.3% per year for those aged 30-39 years.

Distant-stage breast cancer incidence rates increased by more than 4% per year after the year 2000 in women aged 20-39 years.

“Our hope is that these findings focus more attention and research on breast cancer in younger women and what is behind this rapid increase in late-stage cancers,” Dr. Hendrick stated in the press release.

He and his colleagues speculate that the contrast between the upward trend in women aged younger than 40 years and the downward trend in older women highlights the value of mammography and may reflect the benefits of regular screening, which is not currently recommended for women younger than 40 who are not at high risk for breast cancer.

However, other groups, including the American College of Radiology and the Society for Breast Imaging, support starting annual mammograms at age 40 years.

An expert who was approached for comment noted that the incidence of breast cancer increases with age.

It is more common in women as they age, so screening recommendations do not include women aged younger than 40 years unless they are at very high risk for breast cancer, noted Joann G. Elmore, MD, MPH, professor of medicine at the University of California, Los Angeles.

“The majority of deaths due to breast cancer are in women over age 40. The breast cancer mortality rates per 100,000 as shown [in this study] are about 3 patients/100,000 for the under 40 age group, about 30/100,000 in the 40-69 age group, and about 80/100,000 in the 70 and above age group,” she pointed out.

Dr. Elmore was a coauthor of an editorial regarding the 2019 evidence-based guidance statement from the American College of Physicians . That guidance, which was endorsed by the U.S. Preventive Services Task Force, recommended screening every other year for average-risk women aged 50-74 years, as reported by this news organization.

In their editorial, Dr. Elmore and coauthor Christoph Lee, MD, of the University of Washington, Seattle, applauded the ACP’s approach but stressed that the guidance is not a perfect product and does not “clearly illuminate the full path ahead for every woman.”

Breast cancer screening guidelines continue to evolve, they said, concluding that “physicians are left to use their best judgment based on available research and expert recommendations.”

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

A large, retrospective study shows how germline genetic testing has evolved over time in women with breast or ovarian cancer and reveals a path forward for testing these patients.

Investigators found racial and ethnic disparities in genetic testing as well as “persistent underuse” of testing in patients with ovarian cancer.

The team also discovered that most pathogenic variant (PV) results were in 20 genes associated with breast and/or ovarian cancer, and testing other genes largely revealed variants of uncertain significance (VUS).

Allison W. Kurian, MD, of Stanford (Calif.) University, and colleagues recounted these findings in the Journal of Clinical Oncology.

Because of improvements in sequencing technology, competition among commercial purveyors, and declining cost, genetic testing has been increasingly available to clinicians for patient management and cancer prevention (JAMA. 2015 Sep 8;314[10]:997-8). Although germline testing can guide therapy for several solid tumors, there is little research about how often and how well it is used in practice.

For their study, Dr. Kurian and colleagues used a SEER Genetic Testing Linkage Demonstration Project in a population-based assessment of testing for cancer risk. The investigators analyzed 7-year trends in testing among all women diagnosed with breast or ovarian cancer in Georgia or California from 2013 to 2017, reviewing testing patterns and result interpretation from 2012 to 2019.

Before analyzing the data, the investigators made the following hypotheses:

• Multigene panels (MGP) would entirely replace testing for BRCA1/2 only.
• Testing underutilization in patients with ovarian cancer would improve over time.
• More patients would be tested at lower levels of pretest risk for PVs.
• Sociodemographic differences in testing trends would not be observed.
• Detection of PVs and VUS would increase.
• Racial and ethnic disparities in rates of VUS would diminish.

Study conduct

The investigators examined genetic tests performed from 2012 through the beginning of 2019 at major commercial laboratories and linked that information with data in the SEER registries in Georgia and California on all breast and ovarian cancer patients diagnosed between 2013 and 2017. There were few criteria for exclusion.

Genetic testing results were categorized as identifying a PV or likely PV, VUS, or benign or likely benign mutation by American College of Medical Genetics criteria. When a patient had genetic testing on more than one occasion, the most recent test was used.

If a PV was identified, the types of PVs were grouped according to the level of evidence that supported pathogenicity into the following categories:

• BRCA1 or BRCA2 mutations.
• PVs in other genes designated by the National Comprehensive Cancer Network as associated with breast or ovarian cancer (e.g., ATM, BARD1, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PALB2, MS2, PTEN, RAD51C, RAD51D, STK11, and TP53).
• PVs in other actionable genes (e.g., APC, BMPR1A, MEN1, MUTYH, NF2, RB1, RET, SDHAF2, SDHB, SDHC, SDHD, SMAD4, TSC1, TSC2, and VHL).
• Any other tested genes.

The investigators also tabulated instances in which genetic testing identified a VUS in any gene but no PV. If a VUS was identified originally and was reclassified more recently into the “PV/likely PV” or “benign/likely benign” categories, only the resolved categorization was recorded.

The authors evaluated clinical and sociodemographic correlates of testing trends for breast and ovarian cancer, assessing the relationship between race, age, and geographic site in receipt of any test or type of test.

Among laboratories, the investigators examined trends in the number of genes tested, associations with sociodemographic factors, categories of test results, and whether trends differed by race or ethnicity.
 

Findings, by hypothesis

Hypothesis #1: MGP will entirely replace testing for BRCA1/2 only.

About 25% of tested patients with breast cancer diagnosed in early 2013 received MGP, compared with more than 80% of those diagnosed in late 2017.

The trend for ovarian cancer was similar. About 40% of patients diagnosed in early 2013 received MGP, compared with more than 90% diagnosed in late 2017. These trends were similar in California and Georgia.

From 2012 to 2019, there was a consistent upward trend in gene number for patients with breast cancer (mean, 19) or ovarian cancer (mean, 21), from approximately 10 genes to 35 genes.
 

Hypothesis #2: Underutilization of testing in patients with ovarian cancer will improve.

Among the 187,535 patients with breast cancer and the 14,689 patients with ovarian cancer diagnosed in Georgia or California from 2013 through 2017, on average, testing rates increased 2% per year.

In all, 25.2% of breast cancer patients and 34.3% of ovarian cancer patients had genetic testing on one (87.3%) or more (12.7%) occasions.

Prior research suggested that, in 2013 and 2014, 31% of women with ovarian cancer had genetic testing (JAMA Oncol. 2018 Aug 1;4[8]:1066-72/ J Clin Oncol. 2019 May 20;37[15]:1305-15).

The investigators therefore concluded that underutilization of genetic testing in ovarian cancer did not improve substantially during the 7-year interval analyzed.
 

Hypothesis #3: More patients will be tested at lower levels of pretest risk.

These data were more difficult to abstract from the SEER database, but older patients were more likely to be tested in later years.

In patients older than 60 years of age (who accounted for more than 50% of both cancer cohorts), testing rates increased from 11.1% to 14.9% for breast cancer and 25.3% to 31.4% for ovarian cancer. By contrast, patients younger than 45 years of age were less than 15% of the sample and had lower testing rates over time.

There were no substantial changes in testing rates by other clinical variables. Therefore, in concert with the age-related testing trends, it is likely that women were tested for genetic mutations at increasingly lower levels of pretest risk.
 

Hypothesis #4: Sociodemographic differences in testing trends will not be observed.

Among patients with breast cancer, approximately 31% of those who had genetic testing were uninsured, 31% had Medicaid, and 26% had private insurance, Medicare, or other insurance.

For patients with ovarian cancer, approximately 28% were uninsured, 27% had Medicaid, and 39% had private insurance, Medicare, or other insurance.

The authors had previously found that less testing was associated with Black race, greater poverty, and less insurance coverage (J Clin Oncol. 2019 May 20;37[15]:1305-15). However, they noted no changes in testing rates by sociodemographic variables over time.
 

Hypothesis #5: Detection of both PVs and VUS will increase.

The proportion of tested breast cancer patients with PVs in BRCA1/2 decreased from 7.5% to 5.0% (P < .001), whereas PV yield for the two other clinically salient categories (breast or ovarian and other actionable genes) increased.

The proportion of PVs in any breast or ovarian gene increased from 1.3% to 4.6%, and the proportion in any other actionable gene increased from 0.3% to 1.3%.

For breast cancer patients, VUS-only rates increased from 8.5% in early 2013 to 22.4% in late 2017.

For ovarian cancer patients, the yield of PVs in BRCA1/2 decreased from 15.7% to 12.4% (P < .001), whereas the PV yield for breast or ovarian genes increased from 3.9% to 4.3%, and the yield for other actionable genes increased from 0.3% to 2.0%.

In ovarian cancer patients, the PV or VUS-only result rate increased from 30.8% in early 2013 to 43.0% in late 2017, entirely due to the increase in VUS-only rates. VUS were identified in 8.1% of patients diagnosed in early 2013 and increased to 28.3% in patients diagnosed in late 2017.
 

Hypothesis #6: Racial or ethnic disparities in rates of VUS will diminish.

Among patients with breast cancer, racial or ethnic differences in PV rates were small and did not change over time. For patients with ovarian cancer, PV rates across racial or ethnic groups diminished over time.

However, for both breast and ovarian cancer patients, there were large differences in VUS-only rates by race and ethnicity that persisted during the interval studied.

In 2017, for patients with breast cancer, VUS-only rates were substantially higher in Asian (42.4%), Black (36.6%), and Hispanic (27.7%) patients than in non-Hispanic White patients (24.5%, P < .001).

Similar trends were noted for patients with ovarian cancer. VUS-only rates were substantially higher in Asian (47.8%), Black (46.0%), and Hispanic (36.8%) patients than in non-Hispanic White patients (24.6%, P < .001).

Multivariable logistic regressions were performed separately for tested patients with breast cancer and ovarian cancer, and the results showed no significant interaction between race or ethnicity and date. Therefore, there was no significant change in racial or ethnic differences in VUS-only results across the study period.
 

Where these findings leave clinicians in 2021

Among the patients studied, there was:

• Marked expansion in the number of genes sequenced.
• A likely modest trend toward testing patients with lower pretest risk of a PV.
• No sociodemographic differences in testing trends.
• A small increase in PV rates and a substantial increase in VUS-only rates.
• Near-complete replacement of selective testing by MGP.

For patients with breast cancer, the proportion of all PVs that were in BRCA1/2 fell substantially. Adoption of MGP testing doubled the probability of detecting a PV in other tested genes. Most of the increase was in genes with an established breast or ovarian cancer association, with fewer PVs found in other actionable genes and very few PVs in other tested genes.

Contrary to their hypothesis, the authors observed a sustained undertesting of patients with ovarian cancer. Only 34.3% performed versus nearly 100% recommended, with little change since 2014.

This finding is surprising – and tremendously disappointing – since the prevalence of BRCA1/2 PVs is higher in ovarian cancer than in other cancers (Gynecol Oncol. 2017 Nov;147[2]:375-380), and germline-targeted therapy with PARP inhibitors has been approved for use since 2014.

Furthermore, insurance carriers provide coverage for genetic testing in most patients with carcinoma of the ovary, fallopian tube, and/or peritoneum.
 

Action plans: Less could be more

During the period analyzed, the increase in VUS-only results dramatically outpaced the increase in PVs.

Since there is a substantially larger volume of clinical genetic testing in non-Hispanic White patients with breast or ovarian cancer, the spectrum of normal variation is less well-defined in other racial or ethnic groups.

The study showed a widening of the “racial-ethnic VUS gap,” with Black and Asian patients having nearly twofold more VUS, although they were not tested for more genes than non-Hispanic White patients.

This is problematic on several levels. Identification of a VUS is challenging for communicating results to and recommending cascade testing for family members.

There is worrisome information regarding overtreatment or counseling of VUS patients about their results. For example, the PROMPT registry showed that 10%-15% of women with PV/VUS in genes not associated with a high risk of ovarian cancer underwent oophorectomy without a clear indication for the procedure.

Although population-based testing might augment the available data on the spectrum of normal variation in racial and ethnic minorities, it would likely exacerbate the proliferation of VUS over PVs.

It is essential to accelerate ongoing approaches to VUS reclassification.

In addition, the authors suggest that it may be time to reverse the trend in increasing the number of genes tested in MGPs. Their rationale is that, in Georgia and California, most PVs among patients with breast and ovarian cancer were identified in 20 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PMS2, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53).

If the Georgia and California data are representative of a more generalized pattern, a panel of 20 breast cancer– and/or ovarian cancer–associated genes may be ideal for maximizing the yield of clinically relevant PVs and minimizing VUS results for all patients.

Finally, defining the patient, clinician, and health care system factors that impede widespread genetic testing for ovarian cancer patients must be prioritized. As the authors suggest, quality improvement efforts should focus on getting a lot closer to testing rates of 100% for patients with ovarian cancer and building the database that will help sort VUS in minority patients into their proper context of pathogenicity, rather than adding more genes per test.

This research was supported by the National Cancer Institute, the Centers for Disease Control and Prevention, and the California Department of Public Health. The authors disclosed relationships with Myriad Genetics, Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, Genentech, Genomic Health, Roche/Genentech, Oncoquest, Tesaro, and Karyopharm Therapeutics.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

A large, retrospective study shows how germline genetic testing has evolved over time in women with breast or ovarian cancer and reveals a path forward for testing these patients.

Investigators found racial and ethnic disparities in genetic testing as well as “persistent underuse” of testing in patients with ovarian cancer.

The team also discovered that most pathogenic variant (PV) results were in 20 genes associated with breast and/or ovarian cancer, and testing other genes largely revealed variants of uncertain significance (VUS).

Allison W. Kurian, MD, of Stanford (Calif.) University, and colleagues recounted these findings in the Journal of Clinical Oncology.

Because of improvements in sequencing technology, competition among commercial purveyors, and declining cost, genetic testing has been increasingly available to clinicians for patient management and cancer prevention (JAMA. 2015 Sep 8;314[10]:997-8). Although germline testing can guide therapy for several solid tumors, there is little research about how often and how well it is used in practice.

For their study, Dr. Kurian and colleagues used a SEER Genetic Testing Linkage Demonstration Project in a population-based assessment of testing for cancer risk. The investigators analyzed 7-year trends in testing among all women diagnosed with breast or ovarian cancer in Georgia or California from 2013 to 2017, reviewing testing patterns and result interpretation from 2012 to 2019.

Before analyzing the data, the investigators made the following hypotheses:

• Multigene panels (MGP) would entirely replace testing for BRCA1/2 only.
• Testing underutilization in patients with ovarian cancer would improve over time.
• More patients would be tested at lower levels of pretest risk for PVs.
• Sociodemographic differences in testing trends would not be observed.
• Detection of PVs and VUS would increase.
• Racial and ethnic disparities in rates of VUS would diminish.

Study conduct

The investigators examined genetic tests performed from 2012 through the beginning of 2019 at major commercial laboratories and linked that information with data in the SEER registries in Georgia and California on all breast and ovarian cancer patients diagnosed between 2013 and 2017. There were few criteria for exclusion.

Genetic testing results were categorized as identifying a PV or likely PV, VUS, or benign or likely benign mutation by American College of Medical Genetics criteria. When a patient had genetic testing on more than one occasion, the most recent test was used.

If a PV was identified, the types of PVs were grouped according to the level of evidence that supported pathogenicity into the following categories:

• BRCA1 or BRCA2 mutations.
• PVs in other genes designated by the National Comprehensive Cancer Network as associated with breast or ovarian cancer (e.g., ATM, BARD1, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PALB2, MS2, PTEN, RAD51C, RAD51D, STK11, and TP53).
• PVs in other actionable genes (e.g., APC, BMPR1A, MEN1, MUTYH, NF2, RB1, RET, SDHAF2, SDHB, SDHC, SDHD, SMAD4, TSC1, TSC2, and VHL).
• Any other tested genes.

The investigators also tabulated instances in which genetic testing identified a VUS in any gene but no PV. If a VUS was identified originally and was reclassified more recently into the “PV/likely PV” or “benign/likely benign” categories, only the resolved categorization was recorded.

The authors evaluated clinical and sociodemographic correlates of testing trends for breast and ovarian cancer, assessing the relationship between race, age, and geographic site in receipt of any test or type of test.

Among laboratories, the investigators examined trends in the number of genes tested, associations with sociodemographic factors, categories of test results, and whether trends differed by race or ethnicity.
 

Findings, by hypothesis

Hypothesis #1: MGP will entirely replace testing for BRCA1/2 only.

About 25% of tested patients with breast cancer diagnosed in early 2013 received MGP, compared with more than 80% of those diagnosed in late 2017.

The trend for ovarian cancer was similar. About 40% of patients diagnosed in early 2013 received MGP, compared with more than 90% diagnosed in late 2017. These trends were similar in California and Georgia.

From 2012 to 2019, there was a consistent upward trend in gene number for patients with breast cancer (mean, 19) or ovarian cancer (mean, 21), from approximately 10 genes to 35 genes.
 

Hypothesis #2: Underutilization of testing in patients with ovarian cancer will improve.

Among the 187,535 patients with breast cancer and the 14,689 patients with ovarian cancer diagnosed in Georgia or California from 2013 through 2017, on average, testing rates increased 2% per year.

In all, 25.2% of breast cancer patients and 34.3% of ovarian cancer patients had genetic testing on one (87.3%) or more (12.7%) occasions.

Prior research suggested that, in 2013 and 2014, 31% of women with ovarian cancer had genetic testing (JAMA Oncol. 2018 Aug 1;4[8]:1066-72/ J Clin Oncol. 2019 May 20;37[15]:1305-15).

The investigators therefore concluded that underutilization of genetic testing in ovarian cancer did not improve substantially during the 7-year interval analyzed.
 

Hypothesis #3: More patients will be tested at lower levels of pretest risk.

These data were more difficult to abstract from the SEER database, but older patients were more likely to be tested in later years.

In patients older than 60 years of age (who accounted for more than 50% of both cancer cohorts), testing rates increased from 11.1% to 14.9% for breast cancer and 25.3% to 31.4% for ovarian cancer. By contrast, patients younger than 45 years of age were less than 15% of the sample and had lower testing rates over time.

There were no substantial changes in testing rates by other clinical variables. Therefore, in concert with the age-related testing trends, it is likely that women were tested for genetic mutations at increasingly lower levels of pretest risk.
 

Hypothesis #4: Sociodemographic differences in testing trends will not be observed.

Among patients with breast cancer, approximately 31% of those who had genetic testing were uninsured, 31% had Medicaid, and 26% had private insurance, Medicare, or other insurance.

For patients with ovarian cancer, approximately 28% were uninsured, 27% had Medicaid, and 39% had private insurance, Medicare, or other insurance.

The authors had previously found that less testing was associated with Black race, greater poverty, and less insurance coverage (J Clin Oncol. 2019 May 20;37[15]:1305-15). However, they noted no changes in testing rates by sociodemographic variables over time.
 

Hypothesis #5: Detection of both PVs and VUS will increase.

The proportion of tested breast cancer patients with PVs in BRCA1/2 decreased from 7.5% to 5.0% (P < .001), whereas PV yield for the two other clinically salient categories (breast or ovarian and other actionable genes) increased.

The proportion of PVs in any breast or ovarian gene increased from 1.3% to 4.6%, and the proportion in any other actionable gene increased from 0.3% to 1.3%.

For breast cancer patients, VUS-only rates increased from 8.5% in early 2013 to 22.4% in late 2017.

For ovarian cancer patients, the yield of PVs in BRCA1/2 decreased from 15.7% to 12.4% (P < .001), whereas the PV yield for breast or ovarian genes increased from 3.9% to 4.3%, and the yield for other actionable genes increased from 0.3% to 2.0%.

In ovarian cancer patients, the PV or VUS-only result rate increased from 30.8% in early 2013 to 43.0% in late 2017, entirely due to the increase in VUS-only rates. VUS were identified in 8.1% of patients diagnosed in early 2013 and increased to 28.3% in patients diagnosed in late 2017.
 

Hypothesis #6: Racial or ethnic disparities in rates of VUS will diminish.

Among patients with breast cancer, racial or ethnic differences in PV rates were small and did not change over time. For patients with ovarian cancer, PV rates across racial or ethnic groups diminished over time.

However, for both breast and ovarian cancer patients, there were large differences in VUS-only rates by race and ethnicity that persisted during the interval studied.

In 2017, for patients with breast cancer, VUS-only rates were substantially higher in Asian (42.4%), Black (36.6%), and Hispanic (27.7%) patients than in non-Hispanic White patients (24.5%, P < .001).

Similar trends were noted for patients with ovarian cancer. VUS-only rates were substantially higher in Asian (47.8%), Black (46.0%), and Hispanic (36.8%) patients than in non-Hispanic White patients (24.6%, P < .001).

Multivariable logistic regressions were performed separately for tested patients with breast cancer and ovarian cancer, and the results showed no significant interaction between race or ethnicity and date. Therefore, there was no significant change in racial or ethnic differences in VUS-only results across the study period.
 

Where these findings leave clinicians in 2021

Among the patients studied, there was:

• Marked expansion in the number of genes sequenced.
• A likely modest trend toward testing patients with lower pretest risk of a PV.
• No sociodemographic differences in testing trends.
• A small increase in PV rates and a substantial increase in VUS-only rates.
• Near-complete replacement of selective testing by MGP.

For patients with breast cancer, the proportion of all PVs that were in BRCA1/2 fell substantially. Adoption of MGP testing doubled the probability of detecting a PV in other tested genes. Most of the increase was in genes with an established breast or ovarian cancer association, with fewer PVs found in other actionable genes and very few PVs in other tested genes.

Contrary to their hypothesis, the authors observed a sustained undertesting of patients with ovarian cancer. Only 34.3% performed versus nearly 100% recommended, with little change since 2014.

This finding is surprising – and tremendously disappointing – since the prevalence of BRCA1/2 PVs is higher in ovarian cancer than in other cancers (Gynecol Oncol. 2017 Nov;147[2]:375-380), and germline-targeted therapy with PARP inhibitors has been approved for use since 2014.

Furthermore, insurance carriers provide coverage for genetic testing in most patients with carcinoma of the ovary, fallopian tube, and/or peritoneum.
 

Action plans: Less could be more

During the period analyzed, the increase in VUS-only results dramatically outpaced the increase in PVs.

Since there is a substantially larger volume of clinical genetic testing in non-Hispanic White patients with breast or ovarian cancer, the spectrum of normal variation is less well-defined in other racial or ethnic groups.

The study showed a widening of the “racial-ethnic VUS gap,” with Black and Asian patients having nearly twofold more VUS, although they were not tested for more genes than non-Hispanic White patients.

This is problematic on several levels. Identification of a VUS is challenging for communicating results to and recommending cascade testing for family members.

There is worrisome information regarding overtreatment or counseling of VUS patients about their results. For example, the PROMPT registry showed that 10%-15% of women with PV/VUS in genes not associated with a high risk of ovarian cancer underwent oophorectomy without a clear indication for the procedure.

Although population-based testing might augment the available data on the spectrum of normal variation in racial and ethnic minorities, it would likely exacerbate the proliferation of VUS over PVs.

It is essential to accelerate ongoing approaches to VUS reclassification.

In addition, the authors suggest that it may be time to reverse the trend in increasing the number of genes tested in MGPs. Their rationale is that, in Georgia and California, most PVs among patients with breast and ovarian cancer were identified in 20 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PMS2, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53).

If the Georgia and California data are representative of a more generalized pattern, a panel of 20 breast cancer– and/or ovarian cancer–associated genes may be ideal for maximizing the yield of clinically relevant PVs and minimizing VUS results for all patients.

Finally, defining the patient, clinician, and health care system factors that impede widespread genetic testing for ovarian cancer patients must be prioritized. As the authors suggest, quality improvement efforts should focus on getting a lot closer to testing rates of 100% for patients with ovarian cancer and building the database that will help sort VUS in minority patients into their proper context of pathogenicity, rather than adding more genes per test.

This research was supported by the National Cancer Institute, the Centers for Disease Control and Prevention, and the California Department of Public Health. The authors disclosed relationships with Myriad Genetics, Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, Genentech, Genomic Health, Roche/Genentech, Oncoquest, Tesaro, and Karyopharm Therapeutics.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

A large, retrospective study shows how germline genetic testing has evolved over time in women with breast or ovarian cancer and reveals a path forward for testing these patients.

Investigators found racial and ethnic disparities in genetic testing as well as “persistent underuse” of testing in patients with ovarian cancer.

The team also discovered that most pathogenic variant (PV) results were in 20 genes associated with breast and/or ovarian cancer, and testing other genes largely revealed variants of uncertain significance (VUS).

Allison W. Kurian, MD, of Stanford (Calif.) University, and colleagues recounted these findings in the Journal of Clinical Oncology.

Because of improvements in sequencing technology, competition among commercial purveyors, and declining cost, genetic testing has been increasingly available to clinicians for patient management and cancer prevention (JAMA. 2015 Sep 8;314[10]:997-8). Although germline testing can guide therapy for several solid tumors, there is little research about how often and how well it is used in practice.

For their study, Dr. Kurian and colleagues used a SEER Genetic Testing Linkage Demonstration Project in a population-based assessment of testing for cancer risk. The investigators analyzed 7-year trends in testing among all women diagnosed with breast or ovarian cancer in Georgia or California from 2013 to 2017, reviewing testing patterns and result interpretation from 2012 to 2019.

Before analyzing the data, the investigators made the following hypotheses:

• Multigene panels (MGP) would entirely replace testing for BRCA1/2 only.
• Testing underutilization in patients with ovarian cancer would improve over time.
• More patients would be tested at lower levels of pretest risk for PVs.
• Sociodemographic differences in testing trends would not be observed.
• Detection of PVs and VUS would increase.
• Racial and ethnic disparities in rates of VUS would diminish.

Study conduct

The investigators examined genetic tests performed from 2012 through the beginning of 2019 at major commercial laboratories and linked that information with data in the SEER registries in Georgia and California on all breast and ovarian cancer patients diagnosed between 2013 and 2017. There were few criteria for exclusion.

Genetic testing results were categorized as identifying a PV or likely PV, VUS, or benign or likely benign mutation by American College of Medical Genetics criteria. When a patient had genetic testing on more than one occasion, the most recent test was used.

If a PV was identified, the types of PVs were grouped according to the level of evidence that supported pathogenicity into the following categories:

• BRCA1 or BRCA2 mutations.
• PVs in other genes designated by the National Comprehensive Cancer Network as associated with breast or ovarian cancer (e.g., ATM, BARD1, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PALB2, MS2, PTEN, RAD51C, RAD51D, STK11, and TP53).
• PVs in other actionable genes (e.g., APC, BMPR1A, MEN1, MUTYH, NF2, RB1, RET, SDHAF2, SDHB, SDHC, SDHD, SMAD4, TSC1, TSC2, and VHL).
• Any other tested genes.

The investigators also tabulated instances in which genetic testing identified a VUS in any gene but no PV. If a VUS was identified originally and was reclassified more recently into the “PV/likely PV” or “benign/likely benign” categories, only the resolved categorization was recorded.

The authors evaluated clinical and sociodemographic correlates of testing trends for breast and ovarian cancer, assessing the relationship between race, age, and geographic site in receipt of any test or type of test.

Among laboratories, the investigators examined trends in the number of genes tested, associations with sociodemographic factors, categories of test results, and whether trends differed by race or ethnicity.
 

Findings, by hypothesis

Hypothesis #1: MGP will entirely replace testing for BRCA1/2 only.

About 25% of tested patients with breast cancer diagnosed in early 2013 received MGP, compared with more than 80% of those diagnosed in late 2017.

The trend for ovarian cancer was similar. About 40% of patients diagnosed in early 2013 received MGP, compared with more than 90% diagnosed in late 2017. These trends were similar in California and Georgia.

From 2012 to 2019, there was a consistent upward trend in gene number for patients with breast cancer (mean, 19) or ovarian cancer (mean, 21), from approximately 10 genes to 35 genes.
 

Hypothesis #2: Underutilization of testing in patients with ovarian cancer will improve.

Among the 187,535 patients with breast cancer and the 14,689 patients with ovarian cancer diagnosed in Georgia or California from 2013 through 2017, on average, testing rates increased 2% per year.

In all, 25.2% of breast cancer patients and 34.3% of ovarian cancer patients had genetic testing on one (87.3%) or more (12.7%) occasions.

Prior research suggested that, in 2013 and 2014, 31% of women with ovarian cancer had genetic testing (JAMA Oncol. 2018 Aug 1;4[8]:1066-72/ J Clin Oncol. 2019 May 20;37[15]:1305-15).

The investigators therefore concluded that underutilization of genetic testing in ovarian cancer did not improve substantially during the 7-year interval analyzed.
 

Hypothesis #3: More patients will be tested at lower levels of pretest risk.

These data were more difficult to abstract from the SEER database, but older patients were more likely to be tested in later years.

In patients older than 60 years of age (who accounted for more than 50% of both cancer cohorts), testing rates increased from 11.1% to 14.9% for breast cancer and 25.3% to 31.4% for ovarian cancer. By contrast, patients younger than 45 years of age were less than 15% of the sample and had lower testing rates over time.

There were no substantial changes in testing rates by other clinical variables. Therefore, in concert with the age-related testing trends, it is likely that women were tested for genetic mutations at increasingly lower levels of pretest risk.
 

Hypothesis #4: Sociodemographic differences in testing trends will not be observed.

Among patients with breast cancer, approximately 31% of those who had genetic testing were uninsured, 31% had Medicaid, and 26% had private insurance, Medicare, or other insurance.

For patients with ovarian cancer, approximately 28% were uninsured, 27% had Medicaid, and 39% had private insurance, Medicare, or other insurance.

The authors had previously found that less testing was associated with Black race, greater poverty, and less insurance coverage (J Clin Oncol. 2019 May 20;37[15]:1305-15). However, they noted no changes in testing rates by sociodemographic variables over time.
 

Hypothesis #5: Detection of both PVs and VUS will increase.

The proportion of tested breast cancer patients with PVs in BRCA1/2 decreased from 7.5% to 5.0% (P < .001), whereas PV yield for the two other clinically salient categories (breast or ovarian and other actionable genes) increased.

The proportion of PVs in any breast or ovarian gene increased from 1.3% to 4.6%, and the proportion in any other actionable gene increased from 0.3% to 1.3%.

For breast cancer patients, VUS-only rates increased from 8.5% in early 2013 to 22.4% in late 2017.

For ovarian cancer patients, the yield of PVs in BRCA1/2 decreased from 15.7% to 12.4% (P < .001), whereas the PV yield for breast or ovarian genes increased from 3.9% to 4.3%, and the yield for other actionable genes increased from 0.3% to 2.0%.

In ovarian cancer patients, the PV or VUS-only result rate increased from 30.8% in early 2013 to 43.0% in late 2017, entirely due to the increase in VUS-only rates. VUS were identified in 8.1% of patients diagnosed in early 2013 and increased to 28.3% in patients diagnosed in late 2017.
 

Hypothesis #6: Racial or ethnic disparities in rates of VUS will diminish.

Among patients with breast cancer, racial or ethnic differences in PV rates were small and did not change over time. For patients with ovarian cancer, PV rates across racial or ethnic groups diminished over time.

However, for both breast and ovarian cancer patients, there were large differences in VUS-only rates by race and ethnicity that persisted during the interval studied.

In 2017, for patients with breast cancer, VUS-only rates were substantially higher in Asian (42.4%), Black (36.6%), and Hispanic (27.7%) patients than in non-Hispanic White patients (24.5%, P < .001).

Similar trends were noted for patients with ovarian cancer. VUS-only rates were substantially higher in Asian (47.8%), Black (46.0%), and Hispanic (36.8%) patients than in non-Hispanic White patients (24.6%, P < .001).

Multivariable logistic regressions were performed separately for tested patients with breast cancer and ovarian cancer, and the results showed no significant interaction between race or ethnicity and date. Therefore, there was no significant change in racial or ethnic differences in VUS-only results across the study period.
 

Where these findings leave clinicians in 2021

Among the patients studied, there was:

• Marked expansion in the number of genes sequenced.
• A likely modest trend toward testing patients with lower pretest risk of a PV.
• No sociodemographic differences in testing trends.
• A small increase in PV rates and a substantial increase in VUS-only rates.
• Near-complete replacement of selective testing by MGP.

For patients with breast cancer, the proportion of all PVs that were in BRCA1/2 fell substantially. Adoption of MGP testing doubled the probability of detecting a PV in other tested genes. Most of the increase was in genes with an established breast or ovarian cancer association, with fewer PVs found in other actionable genes and very few PVs in other tested genes.

Contrary to their hypothesis, the authors observed a sustained undertesting of patients with ovarian cancer. Only 34.3% performed versus nearly 100% recommended, with little change since 2014.

This finding is surprising – and tremendously disappointing – since the prevalence of BRCA1/2 PVs is higher in ovarian cancer than in other cancers (Gynecol Oncol. 2017 Nov;147[2]:375-380), and germline-targeted therapy with PARP inhibitors has been approved for use since 2014.

Furthermore, insurance carriers provide coverage for genetic testing in most patients with carcinoma of the ovary, fallopian tube, and/or peritoneum.
 

Action plans: Less could be more

During the period analyzed, the increase in VUS-only results dramatically outpaced the increase in PVs.

Since there is a substantially larger volume of clinical genetic testing in non-Hispanic White patients with breast or ovarian cancer, the spectrum of normal variation is less well-defined in other racial or ethnic groups.

The study showed a widening of the “racial-ethnic VUS gap,” with Black and Asian patients having nearly twofold more VUS, although they were not tested for more genes than non-Hispanic White patients.

This is problematic on several levels. Identification of a VUS is challenging for communicating results to and recommending cascade testing for family members.

There is worrisome information regarding overtreatment or counseling of VUS patients about their results. For example, the PROMPT registry showed that 10%-15% of women with PV/VUS in genes not associated with a high risk of ovarian cancer underwent oophorectomy without a clear indication for the procedure.

Although population-based testing might augment the available data on the spectrum of normal variation in racial and ethnic minorities, it would likely exacerbate the proliferation of VUS over PVs.

It is essential to accelerate ongoing approaches to VUS reclassification.

In addition, the authors suggest that it may be time to reverse the trend in increasing the number of genes tested in MGPs. Their rationale is that, in Georgia and California, most PVs among patients with breast and ovarian cancer were identified in 20 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PMS2, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53).

If the Georgia and California data are representative of a more generalized pattern, a panel of 20 breast cancer– and/or ovarian cancer–associated genes may be ideal for maximizing the yield of clinically relevant PVs and minimizing VUS results for all patients.

Finally, defining the patient, clinician, and health care system factors that impede widespread genetic testing for ovarian cancer patients must be prioritized. As the authors suggest, quality improvement efforts should focus on getting a lot closer to testing rates of 100% for patients with ovarian cancer and building the database that will help sort VUS in minority patients into their proper context of pathogenicity, rather than adding more genes per test.

This research was supported by the National Cancer Institute, the Centers for Disease Control and Prevention, and the California Department of Public Health. The authors disclosed relationships with Myriad Genetics, Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, Genentech, Genomic Health, Roche/Genentech, Oncoquest, Tesaro, and Karyopharm Therapeutics.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.