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ASCO Rapid Recommendations Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options., Competing Interests: Nadine M. TungResearch Funding: AstraZenecaNo other potential conflicts of interest were reported.

Purpose: The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007, provide standardized definitions of adjuvant breast cancer clinical trial end points. Given the evolution of breast cancer clinical trials and improvements in outcomes, a panel of experts reviewed the STEEP criteria to determine whether modifications are needed., Methods: We conducted systematic searches of ClinicalTrials.gov for adjuvant systemic and local-regional therapy trials for breast cancer to investigate if the primary end points reported met STEEP criteria. On the basis of common STEEP deviations, we performed a series of simulations to evaluate the effect of excluding non-breast cancer deaths and new nonbreast primary cancers from the invasive disease-free survival end point., Results: Among 11 phase III breast cancer trials with primary efficacy end points, three had primary end points that followed STEEP criteria, four used STEEP definitions but not the corresponding end point names, and four used end points that were not included in the original STEEP manuscript. Simulation modeling demonstrated that inclusion of second nonbreast primary cancer can increase the probability of incorrect inferences, can decrease power to detect clinically relevant efficacy effects, and may mask differences in recurrence rates, especially when recurrence rates are low., Conclusion: We recommend an additional end point, invasive breast cancer-free survival, which includes all invasive disease-free survival events except second nonbreast primary cancers. This end point should be considered for trials in which the toxicities of agents are well-known and where the risk of second primary cancer is small. Additionally, we provide end point recommendations for local therapy trials, low-risk populations, noninferiority trials, and trials incorporating patient-reported outcomes., Competing Interests: Sara M. TolaneyConsulting or Advisory Role: Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, AstraZeneca, Puma Biotechnology, Genentech, Eisai, Sanofi, Celldex, Bristol Myers Squibb, Paxman, Seattle Genetics, Odonate Therapeutics, AbbVie, Silverback Therapeutics, G1 Therapeutics, OncoPep, Kyowa Hakko Kirin, Samsung Bioepis, CytomX Therapeutics, Daiichi Sankyo, Athenex, Immunomedics/Gilead, Mersana, CertaraResearch Funding: Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Immunomedics, Odonate Therapeutics, Sanofi, Seattle GeneticsTravel, Accommodations, Expenses: AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Eisai, NanoString Technologies, Puma Biotechnology, Celldex Elizabeth Garrett-MayerConsulting or Advisory Role: Deciphera, Tyme Julia WhiteResearch Funding: Intraop Medical Judith M. BlissResearch Funding: AstraZeneca, Merck Sharp & Dohme, Puma Biotechnology, Pfizer, Roche, GlaxoSmithKline/Novartis, Lilly, Janssen-Cilag, Clovis OncologyTravel, Accommodations, Expenses: Pfizer Eileen RakovitchHonoraria: AstraZenecaResearch Funding: Genomic Health International Patricia A. SpearsConsulting or Advisory Role: Pfizer Elizabeth FrankHonoraria: AstraZenecaTravel, Accommodations, Expenses: Roche Nadine M. TungResearch Funding: AstraZeneca Anthony D. EliasStock and Other Ownership Interests: AbbVie, Merck, Gilead Sciences, Allergan, Pfizer, Abbott Laboratories, Amgen, Bristol Myers Squibb, United Health Group, Align Oncology, Illumina, Exact Sciences, Lilly, Agilent, Cigna, Alexion Pharmaceuticals, BiogenerixConsulting or Advisory Role: Ayala PharmaceuticalsResearch Funding: Medivation, Astellas Pharma, Genentech, Deciphera, Xencor, Infinity Pharmaceuticals, Karyopharm Therapeutics, TopAlliance BioSciences Inc, Fosun Orinove, BioAtlaUncompensated Relationships: Seiyax David CameronConsulting or Advisory Role: Lilly, Novartis, Research Triangle Institute Health Solutions, Daiichi Sankyo, Prima BioMed, Merck Sharp & Dohme, Zymeworks, Eisai, Puma Biotechnology, Pfizer, Oncolytics, Roche, Samsung Bioepis, Seattle Genetics, Synthon, Clarity PharmaceuticalsResearch Funding: Roche, Novartis, AstraZenecaTravel, Accommodations, Expenses: Novartis Neelima DenduluriEmployment: AstraZenecaResearch Funding: Amgen, Novartis, Genentech, Lilly, Pfizer, Daiichi Sankyo, ImmunomedicsTravel, Accommodations, Expenses: Seattle Genetics Angelo DiLeoHonoraria: Roche, Novartis, Pfizer, AstraZeneca, Eisai, Lilly, Celgene, AmgenConsulting or Advisory Role: Roche, Novartis, Pfizer, AstraZeneca, Lilly, Celgene, Puma Biotechnology, Ipsen, Genentech, Amgen, Seattle Genetics, Genomic Health, Athenex, Daiichi SankyoTravel, Accommodations, Expenses: Roche, Pfizer, Celgene, Novartis Eric P. WinerHonoraria: Genentech/Roche, Genomic HealthConsulting or Advisory Role: Leap Therapeutics, Seattle Genetics, Jounce Therapeutics, GlaxoSmithKline, Carrick Therapeutics, Lilly, G1 Therapeutics, Syros Pharmaceuticals, Genentech/Roche, Gilead Sciences, ZymeworksResearch Funding: Genentech, AstraZenecaOther Relationship: InfiniteMDNo other potential conflicts of interest were reported.

Purpose: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline (g) BRCA1 / 2 mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s) BRCA1 / 2 mutations or g/s mutations in homologous recombination (HR)-related genes other than BRCA1/ 2., Methods: Eligible patients had MBC with measurable disease and germline mutations in non- BRCA1 / 2 HR-related genes (cohort 1) or somatic mutations in these genes or BRCA1 / 2 (cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS)., Results: Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in PALB2, s BRCA1 / 2 , ATM, or CHEK2 . In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with g PALB2 (ORR, 82%) and s BRCA1 / 2 (ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable [NA]) for g PALB2 and 6.3 months (90% CI, 4.4 months to NA) for s BRCA1 / 2 mutation carriers. No responses were observed with ATM or CHEK2 mutations alone., Conclusion: PARP inhibition is an effective treatment for patients with MBC and g PALB2 or s BRCA1 / 2 mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond g BRCA1 / 2 mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.

Purpose: To develop recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes., Methods: The American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an Expert Panel to develop recommendations based on a systematic review of the literature and a formal consensus process., Results: Fifty-eight articles met eligibility criteria and formed the evidentiary basis for the local therapy recommendations; six randomized controlled trials of systemic therapy met eligibility criteria., Recommendations: Patients with newly diagnosed BC and BRCA1 / 2 mutations may be considered for breast-conserving therapy (BCT), with local control of the index cancer similar to that of noncarriers. The significant risk of a contralateral BC (CBC), especially in young women, and the higher risk of new cancers in the ipsilateral breast warrant discussion of bilateral mastectomy. Patients with mutations in moderate-risk genes should be offered BCT. For women with mutations in BRCA1 / 2 or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or CBC events from radiation exposure in BRCA1 / 2 carriers. Radiation therapy should not be withheld in ATM carriers. For patients with germline TP53 mutations, mastectomy is advised; radiation therapy is contraindicated except in those with significant risk of locoregional recurrence. Platinum agents are recommended versus taxanes to treat advanced BC in BRCA carriers. In the adjuvant/neoadjuvant setting, data do not support the routine addition of platinum to anthracycline- and taxane-based chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in BRCA1 / 2 carriers. Data are insufficient to recommend PARP inhibitor use in the early setting or in moderate-penetrance carriers. Additional information available at www.asco.org/breast-cancer-guidelines.

Purpose: This multicenter phase II trial evaluated lurbinectedin (PM01183), a selective inhibitor of active transcription of protein-coding genes, in patients with metastatic breast cancer. A unicenter translational substudy assessed potential mechanisms of lurbinectedin resistance., Patients and Methods: Two arms were evaluated according to germline BRCA1/2 status: BRCA1/2 mutated (arm A; n = 54) and unselected ( BRCA1/2 wild-type or unknown status; arm B; n = 35). Lurbinectedin starting dose was a 7-mg flat dose and later, 3.5 mg/m 2 in arm A. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST). The translational substudy of resistance mechanisms included exome sequencing (n = 13) and in vivo experiments with patient-derived xenografts (n = 11) from BRCA1/2-mutated tumors., Results: ORR was 41% (95% CI, 28% to 55%) in arm A and 9% (95% CI, 2% to 24%) in arm B. In arm A, median progression-free survival was 4.6 months (95% CI, 3.0 to 6.0 months), and median overall survival was 20.0 months (95% CI, 11.8 to 26.6 months). Patients with BRCA2 mutations showed an ORR of 61%, median progression-free survival of 5.9 months, and median overall survival of 26.6 months. The safety profile improved with lurbinectedin dose adjustment to body surface area. The most common nonhematologic adverse events seen at 3.5 mg/m 2 were nausea (74%; grade 3, 5%) and fatigue (74%; grade 3, 21%). Neutropenia was the most common severe hematologic adverse event (grade 3, 47%; grade 4, 10%). Exome sequencing showed mutations in genes related to the nucleotide excision repair pathway in four of seven tumors at primary or acquired resistance and in one patient with short-term stable disease. In vivo, sensitivity to cisplatin and lurbinectedin was evidenced in lurbinectedin-resistant (one of two) and cisplatin-resistant (two of three) patient-derived xenografts., Conclusion: Lurbinectedin showed noteworthy activity in patients with BRCA1/2 mutations. Response and survival was notable in those with BRCA2 mutations. Additional clinical development in this subset of patients with metastatic breast cancer is warranted.

PURPOSE Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer share features suggesting common pathogenesis, we conducted a neoadjuvant trial of cisplatin in TNBC and explored specific biomarkers to identify predictors of response. PATIENTS AND METHODS Twenty-eight women with stage II or III breast cancers lacking estrogen and progesterone receptors and HER2/Neu (TNBC) were enrolled and treated with four cycles of cisplatin at 75 mg/m(2) every 21 days. After definitive surgery, patients received standard adjuvant chemotherapy and radiation therapy per their treating physicians. Clinical and pathologic treatment response were assessed, and pretreatment tumor samples were evaluated for selected biomarkers. Results Six (22%) of 28 patients achieved pathologic complete responses, including both patients with BRCA1 germline mutations;18 (64%) patients had a clinical complete or partial response. Fourteen (50%) patients showed good pathologic responses (Miller-Payne score of 3, 4, or 5), 10 had minor responses (Miller-Payne score of 1 or 2), and four (14%) progressed. All TNBCs clustered with reference basal-like tumors by hierarchical clustering. Factors associated with good cisplatin response include young age (P = .001), low BRCA1 mRNA expression (P = .03), BRCA1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03). CONCLUSION Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive. Other biomarkers show promise in predicting cisplatin response.

Purpose: To explore the health-related and psychological factors that influence decision making about tamoxifen (Nolvadex; AstraZeneca, Waltham, MA) chemoprevention in women at increased risk for developing breast cancer., Methods: This study involves the assessment of 129 women eligible to take tamoxifen following cancer-risk counseling. Treatment decision and decision satisfaction were measured at 2 and 4 months following counseling. Health-related factors included physician recommendation, personal and family-related health history, and concern about side effects. Psychological factors included breast cancer-related anxiety, risk perception, and depression., Results: At 2 months' follow-up, 44% of participants declined tamoxifen treatment. This number increased to 49% at 4 months. Personal and family health history were not related to the decision, but history of abnormal biopsy did predict tamoxifen use. Physician recommendation was highly correlated with treatment decision. Concern about side effects was related to the decision to decline treatment. Breast cancer-related anxiety and heightened risk perception were associated with the decision to take tamoxifen. However, anxiety and psychological distress were also negatively related to treatment satisfaction., Conclusion: Decision-making about tamoxifen is complex, and many eligible women decline treatment or remain undecided. Findings call for further educational follow-up with high-risk women after they undergo initial counseling. Factors related to misperceptions of risk and side effects, as well as psychological distress, may be particularly important targets for intervention.