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Purpose: In KATHERINE, adjuvant T-DM1 reduced risk of disease recurrence or death by 50% compared with trastuzumab in patients with residual invasive breast cancer after neoadjuvant therapy (NAT) comprised of HER2-targeted therapy and chemotherapy. This analysis aimed to identify biomarkers of response and differences in biomarker expression before and after NAT. Experimental Design: Exploratory analyses investigated the relationship between invasive disease-free survival (IDFS) and HER2 protein expression/gene amplification, PIK3CA hotspot mutations, and gene expression of HER2, PD-L1, CD8, predefined immune signatures, and Prediction Analysis of Microarray 50 intrinsic molecular subtypes, classified by Absolute Intrinsic Molecular Subtyping. HER2 expression on paired pre- and post-NAT samples was examined. Results: T-DM1 appeared to improve IDFS versus trastuzumab across most biomarker subgroups, except the HER2 focal expression subgroup. High versus low HER2 gene expression in residual disease was associated with worse outcomes with trastuzumab [HR, 2.02; 95% confidence interval (CI), 1.32–3.11], but IDFS with T-DM1 was independent of HER2 expression level (HR, 1.01; 95% CI, 0.56–1.83). Low PD-L1 gene expression in residual disease was associated with worse outcomes with trastuzumab (HR, 0.66; 95% CI, 0.44–1.00), but not T-DM1 (HR, 1.05; 95% CI, 0.59–1.87). PIK3CA mutations were not prognostic. Increased variability in HER2 expression was observed in post-NAT versus paired pre-NAT samples. Conclusions: T-DM1 appears to overcome HER2 resistance. T-DM1 benefit does not appear dependent on immune activation, but these results do not rule out an influence of the tumor immune microenvironment on the degree of response.

PURPOSE: There is a lack of level I evidence to guide radiotherapy recommendations for patients receiving neoadjuvant chemotherapy for breast cancer. We utilized four neoadjuvant chemotherapy trials to determine which patients benefit from regional nodal irradiation (RNI). MATERIALS AND METHODS: We obtained data from NSABP B-18, B-27, B-40, and B-41 clinical trials. B-40 and B-41 allowed RNI at physician’s discretion. We evaluated local-regional recurrence (LRR), distant recurrence (DR), disease-free survival (DFS), and overall survival (OS). Kaplan-Meier, Peto-Peto, Chi-squared, Fisher exact, and Wilcoxon rank-sum tests were used for survival estimates and comparison. RESULTS: Median follow-up for B-18, B-27, B-40, and B-41 was 13.7, 9.7, 4.5, and 5.1 years, respectively, including 742, 2254, 1154, and 504 patients for analysis. On multivariable analysis, factors significantly associated with RNI included tumor size, ypN status, and tumor subtype; Hispanic patients were less likely to receive RNI. Patients with ypN+HER2+ disease who received RNI had improved OS. B-40 patients with ypN+HR+ disease had improved LRR. On multivariable analysis for the B-40 and B-41 study population, RNI was not associated with significantly improved OS, DFS, DR, or LRR. CONCLUSION: RNI was associated with a clinical benefit for patients with ypN+HER2+ and ypN+HR+ disease. RNI was not significantly associated with a clinically beneficial outcome for the entire cohort. Prospective phase III clinical trials are needed to establish guidelines for patients who should receive RNI following neoadjuvant treatment, and action is necessary to eliminate the disparity in care delivery shown for Hispanic women.

Background NSABP B-42 evaluated extended letrozole therapy (ELT) in postmenopausal breast cancer patients who were disease-free after 5 years of aromatase inhibitor-based (AI) therapy. Seven-year results demonstrated a non-statistically significant trend in disease-free survival (DFS) in favor of ELT. We present 10-year outcome results. Methods In this double-blind, phase 3 trial, patients with stage I-IIIA hormone receptor-positive breast cancer, disease-free after 5 years of an AI or tamoxifen followed by an AI, were randomized to 5 years of letrozole or placebo. Primary endpoint was DFS, defined as time from randomization to breast cancer recurrence, second primary malignancy, or death. All statistical tests are two-sided. Results Between 09/06 and 01/10, 3,966 patients were randomized (letrozole: 1,983; placebo: 1,983). Median follow-up time for 3,923 patients included in efficacy analyses was 10.3 years. There was statistically significant improvement in DFS in favor of letrozole compared to placebo (Hazard Ratio [HR]=0.85; 95%CI 0.74-0.96, p-value = 0.01, 10-year DFS: placebo = 72.6%, letrozole = 75.9%, absolute difference 3.3%). There was no difference in the effect of letrozole on overall survival (OS) (HR = 0.97, 95%CI 0.82-1.15, p-value = 0.74). Letrozole significantly reduced breast cancer-free interval (BCFI) events (HR = 0.75, 95%CI 0.62-0.91, p-value = 0.003, absolute difference in cumulative incidence: 2.7%) and distant recurrences (DR) (HR = 0.72, 95%CI 0.55-0.92, p-value = 0.01, absolute difference: 1.8%). The rates of osteoporotic fractures and arterial thrombotic events did not differ between treatment groups. Conclusions The beneficial effect of ELT on DFS persisted at 10 years. Letrozole also significantly improved BCFI and DR without improving OS. Careful assessment of potential risks and benefits is necessary for selecting appropriate candidates for ELT. Clinical Trials registration NCT00382070

HER2, PD-L1, and Five-Gene Signature Quartile Analysis. IDFS by HER2 gene expression quartile (A) in the trastuzumab arm; and (B) in the T-DM1 arm; (C) treatment effect on IDFS by HER2 gene expression quartile; (D) effect of HER2 gene expression quartile on IDFS; IDFS by PD-L1 gene expression quartile (E) in the trastuzumab arm; and (F) in the T-DM1 arm; (G) treatment effect on IDFS by PD-L1 gene expression quartile; (H) effect of PD-L1 gene expression quartile on IDFS; IDFS by five-gene signature (i.e., PD-L1/granzymeB/CD8/IFNγ/CXCL9) gene expression quartile (I) in the trastuzumab arm; and (J) in the T-DM1 arm; (K) treatment effect on IDFS by five-gene signature gene expression quartile; (L) effect of five-gene signature gene expression quartile expression on IDFS. Each expression quartile (quartile 2, quartile 3, and quartile 4) is compared to the lowest quartile (quartile 1). The analyses are unstratified and adjusted using a Cox regression model that includes percent tumor in marked area, clinical stage at presentation, hormone receptor status, type of preoperative HER2-directed therapy, and pathologic nodal status. HER2, human epidermal growth factor receptor 2; IDFS, invasive disease-free survival; IFNγ, interferon gamma; Q, quartile; T-DM1, trastuzumab emtansine.

Prognostic value for IDFS by treatment arm of biomarker gene expression levels (>median vs. ≤median and continuous) in post-NAT surgical RNA-evaluable tissue samples. Analysis is adjusted for tumor content. One sample could not be included because there was insufficient information on tumor content.

Purpose:In KATHERINE, adjuvant T-DM1 reduced risk of disease recurrence or death by 50% compared with trastuzumab in patients with residual invasive breast cancer after neoadjuvant therapy (NAT) comprised of HER2-targeted therapy and chemotherapy. This analysis aimed to identify biomarkers of response and differences in biomarker expression before and after NAT.Materials and Methods:Exploratory analyses investigated the relationship between invasive disease-free survival (IDFS) and HER2 protein expression/gene amplification, PIK3CA hotspot mutations, and gene expression of HER2, PD-L1, CD8, predefined immune signatures, and Prediction Analysis of Microarray 50 intrinsic molecular subtypes, classified by Absolute Intrinsic Molecular Subtyping. HER2 expression on paired pre- and post-NAT samples was examined.Results:T-DM1 appeared to improve IDFS versus trastuzumab across most biomarker subgroups, except the HER2 focal expression subgroup. High versus low HER2 gene expression in residual disease was associated with worse outcomes with trastuzumab [HR, 2.02; 95% confidence interval (CI), 1.32–3.11], but IDFS with T-DM1 was independent of HER2 expression level (HR, 1.01; 95% CI, 0.56–1.83). Low PD-L1 gene expression in residual disease was associated with worse outcomes with trastuzumab (HR, 0.66; 95% CI, 0.44–1.00), but not T-DM1 (HR, 1.05; 95% CI, 0.59–1.87). PIK3CA mutations were not prognostic. Increased variability in HER2 expression was observed in post-NAT versus paired pre-NAT samples.Conclusions:T-DM1 appears to overcome HER2 resistance. T-DM1 benefit does not appear dependent on immune activation, but these results do not rule out an influence of the tumor immune microenvironment on the degree of response.

Purpose:In NSABP B-41, pathologic complete response (pCR) was associated with prolonged survival among women with HER2-positive operable breast cancer treated with neoadjuvant chemotherapy and lapatinib, trastuzumab, or the combination. We used a large human breast cancer gene expression panel to select candidate prognostic biomarkers for pCR among women treated with trastuzumab in NSABP B-41.Patients and Methods:Eligible patients had a baseline preadjuvant treatment core biopsy sample, known pCR status, and no withdrawal of consent. We analyzed extracted RNA using the human nCounter Breast Cancer 360 gene expression panel. Gene counts were normalized to housekeeping genes and transformed into logarithmic scale with base 2. To screen for candidate genes and metagene signatures prognostic of pCR, we used univariate logistic regression. Variable selection was done by multivariable logistic regression with lasso regularization.Results:Analyses of data from 130 patients revealed that a composite of gene expression from 19 genes and one gene signature appeared to predict pCR in women with HER2-positive early-stage breast cancer undergoing neoadjuvant chemotherapy with trastuzumab-containing regimens. The identified genes are involved in important pathways such as epithelial–mesenchymal transition, adhesion and migration, estrogen receptor signaling, DNA damage and repair, apoptosis, and proliferation. The AUC from a 10-fold cross-validation on predicting pCR, with these 20 genomic markers in a logistic regression model, was 0.73.Conclusions:The expression level of ERBB2, ESR1, and a few other genomic markers was highly predictive of pCR after trastuzumab-containing regimens. These findings need to be validated and calibrated in future studies.

Tables S1-S6 and Figures S1-S5

Roughly 50% of newly diagnosed breast cancer is stage 1, the majority being ER/PR positive, HER2- negative. Genomic assays such as Oncotype DX® have identified patients with reduced distant metastasis and lack of chemotherapy benefit, allowing patients to avoid excess toxicity. These genomic assays have been shown to be prognostic for local-regional recurrence (LRR). The de-escalation of therapy is of interest to patients, providers, and payers. Low risk, as identified by both the use of Oncotype and Mammaprint® is associated with low LRR after lumpectomy and breast radiotherapy. TRIAL DESIGN: In the DEBRA trial, we hypothesized that breast-conserving surgery (BCS) alone is non-inferior to BCS plus radiotherapy for in-breast cancer control and breast preservation in women intending appropriate endocrine therapy for stage 1 (ER and/or PR-positive, HER2-negative, and Oncotype DX Recurrence Score [RS] low) breast cancer. Stratification is by age (1-2 cm), and RS 18, making them ineligible for the study. An extra step in the accrual process will require us to register 1,714 patients to ensure our final randomized cohort is 1,670 patients. Accrual: Screen 1,714 to randomize 1,670 into the study. Contact information: Protocol: CTSU member website: https://www.ctsu.org. NRG Oncology Pgh Clinical Coordinating Dpt: 1-800-477-7227 or ccd@nsabp.org. Support: U10CA180868, U10CA180822. NCT04852887. Citation Format: Julia White, Stewart J Anderson, Eleanor ER Harris, Eleftherios P Mamounas, Daniel G Stover, Patricia A Ganz, Reshma Jagsi, Reena S Cecchini, Carmen Bergom, Valerie Theberge, Mahmoud El-Tamer, Rich C Zellars, Dean A Shumway, Guang-Pei Chen, Thomas B Julian, Norman Wolmark. Evaluating de-escalation of breast radiation (DEBRA) following lumpectomy for breast conservative treatment of stage 1, hr+, HER2-, RS ≤18 breast cancer: NRG-BR007 a phase III trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-18-04.

Over the last decade, rates of risk-reducing prophylactic mastectomy (PM) have risen dramatically. A topic of debate regarding the procedure is whether to use sentinel lymph node biopsy (SLNB) at the time of PM and what factors might predict for such need. In order to assess the rate of identifying presence of occult invasive breast cancer in the PM specimen, we performed a retrospective review of the pathology findings from a single-surgeon case-series of PM.Patients undergoing PM between January 2013 and June 2019 at Orlando Health Cancer Institute were identified for a retrospective chart review. Demographic, clinical, and histopathological data from the surgical procedure were collected and analyzed for the incidence of occult invasive breast cancer in the PM specimen.A total of 146 consecutive patients with PM were identified; 120 (82.2%) underwent contralateral PM (CPM) and 26 (17.8%) underwent bilateral PM (BPM). Final pathology of the 172 PM specimens identified 4 (3.3%) with lobular carcinoma in situ, 3 (2.5%) with atypical ductal hyperplasia, and 2 (1.7%) with atypical lobular hyperplasia and 2 (1.7%) with intraductal papilloma. No invasive malignancy was detected in any of the 172 PM specimens.The absence of occult invasive carcinoma in 172 consecutive PM specimens suggests a limited clinical utility in routinely performing SLNB in this setting. This study also suggests that use of preoperative breast MRI imaging could offer a potential non-invasive tool to detect occult malignancy and select patients who can safely undergo omission of SLNB at the time of PM.

Background In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. Patients and methods KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). Results The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR = 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. Conclusions T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.

Background: Pertuzumab, a monoclonal antibody targeting subdomain II of HER2 and blocking dimerization, was approved by the FDA in 2013 as neoadjuvant therapy in combination with trastuzumab + chemotherapy for HER2+ locally advanced or early-stage breast cancer patients (pts). TCHP (Docetaxel/Carboplatin/Trastuzumab/Pertuzumab) is a popular, non-anthracycline neoadjuvant therapy. In the TRYPHAENA trial, pathologic complete response (pCR) rate was 63.6% with 6 cycles of neoadjuvant TCHP (47.5% in ER+/PR+ and 81.1% in ER-/PR- tumors). We previously reported (SABCS 2015) our institutional experience with neoadjuvant TCHP in 75 pts with operable/locally advanced HER2+ breast cancer (10/2013 - 12/2015). Now we report our updated experience of 230 pts (10/2013 - 12/2019) with neoadjuvant chemotherapy + dual anti-HER2 therapy. Patients & Methods: Medical record search identified HER2+ pts (T1c-T3/N0-3 or Tany/N1-3) treated with neoadjuvant chemotherapy + dual anti-HER2 therapy from 10/2013 to 12/2019. Collected information included pt and tumor characteristics at diagnosis, details of neoadjuvant therapy, clinical, radiologic, & pathologic assessment of tumor response, type of breast and axillary nodal surgery, and long-term disease outcomes. Results: 230 pts (229 female, 1 male) met the inclusion criteria; median age: 52 yrs (range 25-79); Clinical stage: I (2%), II (78%) , III (20%); ER+ and/or PR+ 70% ; ER-/PR- 30%. 228 pts received TCHP and 2 pts AC then THP. 170 pts (74%) received 6 cycles of TCHP without dose reduction; 49 pts (21%) received 6 cycles, but with dose reduction (most commonly due to diarrhea, nausea, neutropenia, and anemia); 11 pts (5%) received < 6 cycles (7 of those also needed dose reduction). Mean left ventricular ejection fraction was 62.0% pre-treatment, and 60.9% post-treatment. Of the 230 pts who underwent breast surgery (1 had no breast primary at presentation), 86 pts (38%) had breast conserving surgery, 19 (8%) unilateral mastectomy, and 124 (54%) bilateral mastectomy. Axillary assessment was by SLNB in 75% and ALND in 25% (with/without SLNB). Among 138 pts with cN0 and axillary assessment, 124 had SLNB (4 had + nodes), 14 had ALND (11 had + nodes). Among 91 pts with cN1-3, 47 had SLNB (1 had + nodes) and 44 had ALND (27 had + nodes). Overall pCR rate (ypT0/Tis, ypN0) was 59%. pCR rate was 50% for ER+ and/or PR+, and 79% for ER-/PR-. pCR by Stage: I (50%), II (60%), III (55%). At median follow-up of 2.9 years, 221 pts (96%) were alive with no evidence of disease; 8 pts (3.5%) have experienced recurrence (6 distant, 1 locoregional, 1 unknown site), and 1 pt died after developing AML as the only event. The table below presents details on the 8 pts who suffered recurrence: 4 had clinical stage II disease, and 4 clinical stage III. All pts had hormone receptor + tumors at diagnosis. 7 of 8 pts (88%) with recurrence did not have pCR at surgery. Most common sites of distant metastases as first event were liver and bone. Of the 8 pts with recurrence, 6 are alive with disease (median follow-up 2.8 years). There was 1 death due to disease progression, and 1 pt was lost to follow-up. Conclusions: Our updated results continue to demonstrate the clinical safety and efficacy of neoadjuvant therapy with TCHP for operable/locally advanced HER2+ breast cancer. Our pCR rates are similar to those observed in the TRYPHAENA trial. Longer follow-up is required to evaluate the long-term clinical outcomes with this regimen. Recurrence DataPatient NumberAge at DiagnosisDate of DiagnosisHormone Receptor at DiagnosisClinical Stage at DiagnosisType of Breast SurgerypCRPathologic Stage at SurgeryDate of RecurrenceTime to Metastases (Years)Site of Recurrence16511/19/14PositivecT2N1 (IIB)Left MastectomyYesypT0N0 (0)4/6/172.4Liver, Bone2366/15/15PositivecT2N0 (IIA)Bilateral MastectomyNoypT3N0 (IIB)3/19/182.8Liver3546/29/15PositivecT2N3 (IIIC)Left MastectomyNoypT1bN1a (IIA)10/2/194.3Bone4577/1/15PositivecT2N3 (IIIC)Left LumpectomyNoypT1cN1a (IIA)2/4/193.6Bone, Soft Tissue5568/20/15PositivecT2N0 (IIA)Left LumpectomyNoypT1aN0 (IA)6/28/182.8Lymph Node6264/29/16PositivecT4N0 (IIIB)Bilateral MastectomyNoypT2N1 (IIB)12/13/171.6Liver7539/27/16PositivecT3N3 (IIIC)Bilateral MastectomyNoypT3N3 (IIIC)Not KnownNot KnownNot Known8319/3/17PositivecT2N1 (IIB)Bilateral MastectomyNo (clinical progression)ypT3N2a (IIIC)6/25/180.8Lungs Citation Format: Nirja Shah, Nikita Shah, Said Baidas, Ana Cuesta-Fernandez, Marc Demers, Maria Demori, Tomas Dvorak, Rachel Eisenberg, Terrence Gross, Danielle Henry, Michael Kahky, Patrick Kelly, Swathy Kolli, Regan Rostorfer, Jeffrey Smith, Cameron Swanick, Eleftherios Mamounas. Clinical outcomes with neoadjuvant chemotherapy plus dual anti-HER2 therapy in patients with operable/locally advanced breast cancer: Single institution experience [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-42.

Summary Background Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. Methods PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II–III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1–21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). Findings Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9–29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2–90·6) for palbociclib plus endocrine therapy and 88·5% (85·8–90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76–1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3–4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. Interpretation At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. Funding Pfizer.

Background: Trastuzumab targets the extracellular domain of the HER2 protein. Adding trastuzumab to chemotherapy for patients with early-stage, HER2-positive breast cancer reduces the risk of recurrence and death, but is associated with cardiac toxicity. We investigated the long-term benefits and risks of adjuvant trastuzumab on breast cancer recurrence and cause-specific mortality. Methods: We did a collaborative meta-analysis of individual patient data from randomised trials assessing chemotherapy plus trastuzumab versus the same chemotherapy alone. Randomised trials that enrolled women with node-negative or node-positive, operable breast cancer were included. We collected individual patient-level data on baseline characteristics, dates and sites of first distant breast cancer recurrence and any previous local recurrence or second primary cancer, and the date and underlying cause of death. Primary outcomes were breast cancer recurrence, breast cancer mortality, death without recurrence, and all-cause mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, oestrogen receptor (ER) status, and trial yielded first-event rate ratios (RRs). Findings: Seven randomised trials met the inclusion criteria, and included 13 864 patients enrolled between February, 2000, and December, 2005. Mean scheduled treatment duration was 14·4 months and median follow-up was 10·7 years (IQR 9·5 to 11·9). The risks of breast cancer recurrence (RR 0·66, 95% CI 0·62 to 0·71; p Interpretation: Adding trastuzumab to chemotherapy for early-stage, HER2-positive breast cancer reduces recurrence of, and mortality from, breast cancer by a third, with worthwhile proportional reductions irrespective of recorded patient and tumour characteristics.

Background: For women with early-stage oestrogen receptor (ER)-positive breast cancer, adjuvant tamoxifen reduces 15-year breast cancer mortality by a third. Aromatase inhibitors are more effective than tamoxifen in postmenopausal women but are ineffective in premenopausal women when used without ovarian suppression. We aimed to investigate whether premenopausal women treated with ovarian suppression benefit from aromatase inhibitors. Methods: We did a meta-analysis of individual patient data from randomised trials comparing aromatase inhibitors (anastrozole, exemestane, or letrozole) versus tamoxifen for 3 or 5 years in premenopausal women with ER-positive breast cancer receiving ovarian suppression (goserelin or triptorelin) or ablation. We collected data on baseline characteristics, dates and sites of any breast cancer recurrence or second primary cancer, and dates and causes of death. Primary outcomes were breast cancer recurrence (distant, locoregional, or contralateral), breast cancer mortality, death without recurrence, and all-cause mortality. As distant recurrence invariably results in death from breast cancer several years after the occurrence, whereas locoregional recurrence and new contralateral breast cancer are not usually fatal, the distant recurrence analysis is shown separately. Standard intention-to-treat log-rank analyses estimated first-event rate ratios (RR) and their confidence intervals (CIs). Findings: We obtained data from all four identified trials (ABCSG XII, SOFT, TEXT, and HOBOE trials), which included 7030 women with ER-positive tumours enrolled between June 17, 1999, and Aug 4, 2015. Median follow-up was 8·0 years (IQR 6·1–9·3). The rate of breast cancer recurrence was lower for women allocated to an aromatase inhibitor than for women assigned to tamoxifen (RR 0·79, 95% CI 0·69–0·90, p=0·0005). The main benefit was seen in years 0–4 (RR 0·68, 99% CI 0·55–0·85; p Interpretation: Using an aromatase inhibitor rather than tamoxifen in premenopausal women receiving ovarian suppression reduces the risk of breast cancer recurrence. Longer follow-up is needed to assess any impact on breast cancer mortality.

Expression of human epidermal growth factor receptor 2 (HER2) in breast cancer defines a subset of patients (∼15%-20%) who are candidates for anti-HER2 therapies, most notably, trastuzumab, pertuzumab, antibody drug conjugates (eg, T-DM1), and tyrosine kinase inhibitor (TKI) drugs (eg, lapatinib and neratinib), all of which have dramatically changed the prognosis for this aggressive subtype of breast cancer. A roundtable meeting of the Breast Cancer Therapy Expert Group (BCTEG) was convened in March 2018 in an effort to discuss and clarify, from the perspective of the practicing community oncologist, recent developments in the diagnosis and treatment of HER2-positive (HER2+) breast cancer. Members of the group selected 4 key topics for discussion prior to the meeting, including diagnosis of HER2+ disease, and its treatment in the neoadjuvant, adjuvant, and metastatic settings. Approved testing methods, such as immunohistochemistry and fluorescence in situ hybridization, are used to demonstrate overexpression and/or amplification of HER2 in breast tumors, and established clinical guidelines are used to appropriately define treatment plans for patients with HER2+ disease. The panel acknowledges a range of treatment options now available for treatment of HER2+ breast cancer in the neoadjuvant, adjuvant, and advanced/metastatic settings, although it is noted that many controversies remain, including the optimal sequence of therapies, the most appropriate treatment(s) for subsets of patients with HER2+ disease (eg, hormone receptor-negative or -positive/HER2+), and uncertainties surrounding the diagnosis and definition of HER2+ disease. The current report summarizes the discussion of the BCTEG panel on this topic.

Background/Objective: Sentinel lymph node biopsy (SLNB) is not routine in DCIS. Guidelines suggest SLNB when there is high risk for underlying invasion (large size, high grade, symptomatic lesion) ...

Background The phase 3 KATHERINE trial demonstrated significantly improved invasive disease–free survival with adjuvant trastuzumab emtansine (T‐DM1) versus trastuzumab in patients with HER2‐positive early breast cancer and residual invasive disease after neoadjuvant chemotherapy plus HER2‐targeted therapy. Methods Patients who received taxane‐ and trastuzumab‐containing neoadjuvant therapy (with/without anthracyclines) and had residual invasive disease (breast and/or axillary nodes) at surgery were randomly assigned to 14 cycles of adjuvant T‐DM1 (3.6 mg/kg intravenously every 3 weeks) or trastuzumab (6 mg/kg intravenously every 3 weeks). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ‐C30) and breast cancer module (QLQ‐BR23) were completed at screening, at day 1 of cycles 5 and 11, within 30 days after study drug completion, and at 6‐ and 12‐month follow‐up visits. Results Of patients who were randomly assigned to T‐DM1 (n = 743) and trastuzumab (n = 743), 612 (82%) and 640 (86%), respectively, had valid baseline and ≥1 postbaseline assessments. No clinically meaningful changes (≥10 points) from baseline in mean QLQ‐C30 and QLQ‐BR23 scores occurred in either arm. More patients receiving T‐DM1 reported clinically meaningful deterioration at any assessment point in role functioning (49% vs 41%), appetite loss (38% vs 28%), constipation (47% vs 38%), fatigue (66% vs 60%), nausea/vomiting (39% vs 30%), and systemic therapy side effects (49% vs 36%). These differences were no longer apparent at the 6‐month follow‐up assessment, except for role functioning (23% vs 16%). Conclusion These data suggest that health‐related quality of life was generally maintained in both study arms over the course of treatment., Patient‐reported outcomes are reported from the randomized, phase 3 KATHERINE trial, which demonstrated significantly improved invasive disease–free survival with adjuvant T‐DM1 compared with trastuzumab in patients who had residual invasive disease following neoadjuvant chemotherapy plus HER2‐targeted therapy. Patients who are treated with T‐DM1 have a greater incidence of any grade and grade ≥3 adverse events compared with trastuzumab‐treated patients; however, these adverse events appear to have a minimal impact on patient‐reported quality of life.

Background: Patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy (NACT) + HER2-targeted therapy have a higher risk of recurrence and death than those with pathologic complete response. In the phase III KATHERINE study, adjuvant T-DM1 reduced the risk of recurrence or death by 50% vs H in this population. Data from KATHERINE subgroups are reported here, including patients treated with non-anthracycline (AC) vs AC based NACT, patients with small tumors (cT1cN0) who typically do not receive neoadjuvant treatment, and patients with particularly higher-risk tumors defined by nodal involvement and hormone-receptor status. Methods: Eligible patients had HER2-positive early breast cancer, received taxane- and H-containing neoadjuvant therapy ± AC followed by surgery, and had residual invasive disease in the breast and/or axillary nodes. Patients received 14 cycles of adjuvant T-DM1 (3.6 mg/kg IV q3w) or H (6 mg/kg IV q3w) and endocrine and/or radiation therapy per local standards. The primary endpoint was invasive disease-free survival (IDFS), defined as time from randomization to the first occurrence of ipsilateral locoregional or contralateral invasive breast cancer recurrence, distant recurrence, or death from any cause. In this exploratory analysis, efficacy subpopulations were derived from the intent-to-treat population and safety data were reported for patients who received ≥1 dose of study treatment. Results: In the non-AC v AC based NACT analysis (N=1486), some patient characteristics were imbalanced. For non-AC/AC based NACT, respectively, these included: region (North America; 60.6% v 11.0%), race (Asian; 12.8% v 7.4%), ECOG PS 1 (28.0% v 15.7%); neoadjuvant HER2-based therapy (H + pertuzumab; 46.6% v 9.8%), and neoadjuvant carboplatin/cisplatin (78.7 v 2.3%). Benefit was observed with T-DM1 regardless of neoadjuvant AC use (Table). The all-grade incidence of selected AEs with T-DM1 including hepatotoxicity, peripheral neuropathy, hemorrhage, IRR/hypersensitivity, and cardiac dysfunction was similar between non-AC and AC NACT groups. There was a small increase in the non-AC group in all-grade thrombocytopenia (32.5% v 27.4%) and pulmonary toxicity (6.7% vs 1.7%). There was an increased incidence of grade ≥3 AEs (39.9% vs 21.7%) in the non-AC vs the AC group with T-DM1 which was likely driven by an increase in thrombocytopenia (10.4% v 4.3%) and peripheral sensory neuropathy (4.3% vs 0.5%). However, the percentage of patients with AEs leading to T-DM1 withdrawal in the non-AC vs AC groups (19.6% v 17.5%) was similar, as was the percentage with AEs leading to T-DM1 dose reduction (14.1% v 11.6%). In patients with cT1N0 tumors (n=77), baseline characteristics were well-balanced for H v T-DM1. There were only 6 IDFS events in this subgroup overall; none were observed with T-DM1 (Table). In the analysis of particularly higher-risk tumors, all subgroups showed a benefit with T-DM1; the number of patients was small in some subgroups (Table). Conclusions: T-DM1 provides clinical benefit regardless of prior non-AC vs AC based NACT, and in subgroups with small or particularly higher-risk tumors. There was an increased incidence of grade ≥3 AEs with T-DM1 in the non-AC vs the AC group but these did not result in increased treatment discontinuation and were likely driven by the imbalance in prior therapy. Table 1. Risk of IDFS event in patients treated with non-AC versus AC based NACT, patients with small tumors, and patients with particularly higher-risk tumors.Unstratified hazard ratio of IDFS (95% confidence interval [CI])Patients treated with non-AC vs AC based NACT (N=1,486)Non-AC-based NACT: H (n=179) vs T-DM1 (n=164)0.43 (0.22–0.82)AC-based NACT: H (n=564) vs T-DM1 (n=579)0.51 (0.38–0.67)Patients with small (cT1cN0) tumors (N=77)H (n=32) vs T-DM1 (n=45)6 events with H; 0 events with T-DM1(hazard ratio not applicable due to zero events in T-DM1 arm)Tumor subgroups defined by nodal and HR status (N=957)Inoperable; any HR or ypN statusH (n=190)T-DM1 (n=185)3-year IDFS event-free rate, % (95% CI)60.2 (52.7–67.8)76.0 (70.0–82.4)Unstratified hazard ratio (95% CI)0.54 (0.37–0.80)Operable; ypN positive and HR negativeH (n=52)T-DM1 (n=58)3-year IDFS event-free rate, % (95% CI)69.5 (56.1–82.9)76.0 (64.5–87.5)Unstratified hazard ratio (95% CI)0.72 (0.35–1.50)Operable; ypN positive and HR positiveH (n=167)T-DM1 (n=168)3-year IDFS event-free rate, % (95% CI)77.2 (70.2–84.1)91.4 (86.6–96.2)Unstratified hazard ratio (95% CI)0.43 (0.25–0.75)Operable; ypN0 and HR negativeH (n=68)T-DM1 (n=69)3-year IDFS event-free rate, % (95% CI)77.2 (66.5–87.9)91.1 (84.3–97.9)Unstratified hazard ratio (95% CI)0.43 (0.17–1.06) Citation Format: Max S Mano, Sibylle Loibl, Eleftherios P. Mamounas, Gunter von Minckwitz, Chiun-Sheng Huang, Michael Untch, Norman Wolmark, Irene L. Wapnir, Youngsen Yang, Alison K. Conlin, Sherko Kümmel, Mahasti Saghatchian, Michael P. DiGiovanna, Claudia Strunk, Martina Zimovjanova, Chunyan Song, Haying Liu, David Tesarowski, Steven Blotner, Lisa H. Lam, Melanie Smitt, Charles E. Geyer Jr. Adjuvant trastuzumab emtansine (T-DM1) vs trastuzumab (H) in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: KATHERINE subgroup analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-14-01.

Background The Adjuvant Zoledronic Acid (ZA) study in early breast cancer (AZURE) showed correlation between a non-amplified MAF gene in the primary tumor and benefit from adjuvant zoledronic acid (ZA). Adverse ZA outcomes occurred in MAF-amplified patients. NSABP B-34 is a validation study. Methods A retrospective analysis of MAF gene status in NSABP B-34 was performed. Eligible patients were randomly assigned to standard adjuvant systemic treatment plus 3-years oral clodronate (1600mg/daily) or placebo. Tumors were tested for MAF gene amplification, and analyzed for their relationship to clodronate for disease-free survival (DFS) and overall survival (OS) in MAF non-amplified patients. All statistical tests were 2-sided. Results . MAF status was assessed in 2,533 available primary tumor samples from 3,311 patients. Of these, 37 withdrew consent; in 77 samples no tumor was found; 536 assays did not meet quality standards, leaving 1,883 (77.8%) evaluable for MAF assay by fluorescence in situ hybridization (947 from placebo, and 936 from clodronate arms). At 5 years, in MAF non-amplified patients receiving clodronate, DFS improved by 30% (hazard ratio =0.70, 95% confidence interval = 0.51-0.94, P=0.02). OS improved at 5 years (hazard ratio =0.59, 95% confidence interval = 0.37–0.93, P=0.02) remaining statistically significant for clodronate throughout study follow-up. Conversely, adjuvant clodronate in women with MAF-amplified tumors was not associated with benefit, but possible harm in some subgroups. Association between MAF status and menopausal status was not seen. Conclusions Non-amplified MAF showed statistically significant benefits (DFS and OS) with oral clodronate, supporting validation of the AZURE study.

Background: TNBC is associated with higher percentages of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC), and women with a pCR have a favorable prognosis. However, previous studies have found that women with residual disease have a substantially higher risk of recurrence than women with other subtypes of breast cancer. Additionally, other recent studies have found that therapeutic blockade of PD-L1 binding by atezolizumab has resulted in relevant anti-tumor efficacy. Design This is a phase III, double blind, placebo-control trial evaluating neoadjuvant atezolizumab with NAC followed by adjuvant atezolizumab in TNBC. Pts are stratified by region (North America; Europe), tumor size (1.1-3.0cm; >3.0cm), AC/EC schedule (q2w; q3w), nodal status (positive; negative), and PD-L1 status (positive; negative or indeterminate) then randomized 1:1 to receive atezolizumab/placebo 1200 mg IV every 3 wks concurrently with both sequential regimens of weekly paclitaxel 80 mg/m2 IV for 12 doses with every 3-wk carboplatin AUC of 5 IV for 4 doses followed by AC/EC every 2-3 wks (per investigator discretion) for 4 cycles. Following surgery, pts resume atezolizumab/placebo 1200 mg IV every 3 wks as adjuvant therapy for 6 months. Radiotherapy based on local standards is co-administered with atezolizumab/placebo. Eligibility criteria Centrally-confirmed ER-neg, PR-neg, HER2-neg invasive breast cancer by ASCO/CAP guidelines. Primary tumor must be stage T2 or T3 if cN0 or cN1 with negative biopsy or T1c, T2, or T3 if cN1 with positive biopsy or cN2 or cN3. LVEF >55% and no significant cardiac history. Statistical methods Co-primary endpoints are event-free survival (EFS) and pCR breast/nodes. Secondary endpoints include pCR breast, overall survival, distant disease-free survival, safety and toxicity. Trial is an academic collaboration between NSABP and GBG with support from Genentech/Roche. As of 7-8-19, 279/1,520 pts have been randomized. NCT03281954 Support: Genentech/Roche. Citation Format: Charles E Geyer Jr., Sibylle Loibl, Priya Rastogi, Sabine Seiler, Joseph P Costantino, Valentina Nekljudova, Patricia Cortazar, Peter C Lucas, Carsten Denkert, Eleftherios P Mamounas, Christian Jackish, Norman Wolmark. A randomized double-blind phase III clinical trial of neoadjuvant chemotherapy (NAC) with atezolizumab or placebo in patients (pts) with triple negative breast cancer (TNBC) followed by adjuvant atezolizumab or placebo: NSABP B-59/GBG 96-GeparDouze [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-04-08.

Purpose NSABP B-41, a phase three randomized trial, evaluated neoadjuvant lapatinib, trastuzumab, or the combination with chemotherapy in patients with HER2-positive operable breast cancer. Though no significant difference in pathologic complete response (pCR) was found among the three arms, pCR was associated with prolonged survival. We analyzed tumor intrinsic subtypes with Prediction Analysis of Microarray 50 in a subset of B-41 patients to determine their value in predicting HER2-targeting benefit. Methods Pearson’s Chi square test and logistic regression were used to compare pCR in the breast and nodes (ypT0/Tis ypN0). Kaplan–Meier estimates and Cox models were used to compare event-free and overall survival among subtypes. Results Intrinsic subtypes were determined in 271 baseline core biopsy samples. The pCR rate among patients with HER2-enriched (HER2E) subtype was greater compared to other subtypes combined (120/197, 60.9% versus 19/74, 25.7%; p

Important results are emerging from clinical trials showing that surgery followed by chemotherapy might not be the optimal strategy to maximise a patient's chance of survival from triple-negative or HER2-positive breast cancers. Administering chemotherapy before surgery provides an opportunity to directly observe the efficacy of a particular chemotherapy regimen. Patients who have extensive residual invasive cancer after neoadjuvant chemotherapy are at a high risk of recurrence for metastatic disease, which, in turn, make these patients ideal candidates for clinical trials. Two important clinical trials, CREATE-X (UMIN000000843) and KATHERINE (NCT01772472), have shown improved disease-free survival with postoperative capecitabine and ado-trastuzumab emtansine in patients with either triple-negative or HER2-positive breast cancer who had residual disease after neoadjuvant chemotherapy. The opportunity for residual-disease guided therapy, as observed in these trials, is lost when patients undergo surgery first. In this Personal View, we discuss the clinical implications of the CREATE-X and KATHERINE trials and place them into context with other developments in the adjuvant setting of early-stage breast cancer. We suggest that neoadjuvant systemic therapy should be considered as the new standard of care for HER2-positive and oestrogen receptor negative breast cancer, even for patients who present with operable (T1 or T2) disease.

Metaplastic breast carcinoma (MBC) is a rare subtype of invasive breast cancer consisting of various combinations of malignant epithelial and mesenchymal cells. Its aggressive growth pattern combined with its histological heterogeneity account for MBC's characteristic resistance to systemic therapies, which subsequently leads to increased risk of recurrence and breast cancer mortality compared with other invasive mammary carcinomas. The aim of this review is to discuss the current therapeutic approaches, both in loco-regional as well as in systemic management of MBC. With the accumulation of knowledge from histopathologic assessment and the increasing identification of underlying molecular aberrations, emerging, novel targeted therapies will enable physicians to implement a more individualized and efficacious therapeutic strategy, leading hopefully to an improvement in the poor prognosis of MBC.

Background Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p Interpretation Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes.

The increased use of neoadjuvant chemotherapy (NCT) has enabled higher rates of breast-conserving surgery (BCS) as well as provided prognostic information for women with breast cancer. High pathological complete response (pCR) rates question the requirement for surgery, with its attendant morbidity. In order to avoid surgery, the ability to predict pCR prior to it must be very high. Trimodality imaging alone is inadequate to predict pCR prior to surgery. We hypothesize that performing core-needle biopsy (bx) of the tumor bed in addition to trimodality imaging in patients (pts) having had a clinical complete response (cCR) will increase the ability to predict pCR. Utilizing predetermined imaging response criteria of complete or near-complete response coupled with a stereotactic core-needle bx of the tumor bed, BR005 aims to determine the predictive value of imaging followed by tumor bed bx for pCR and demonstrate its reproducibility across a multi-institutional setting. Methods: 175 pts with operable focal or multifocal (T1-T3), stage II/IIIA invasive ductal carcinoma (all receptor subtypes) will be entered. Pts must have completed a minimum of 8 wks of standard NCT and achieved a complete or near-complete radiologic tumor response on breast imaging with mammogram, ultrasound, and MRI, and undergo BCS. Following cCR and prior to surgery, pts will undergo a stereotactic-vacuum-assisted breast bx with clip placement. The primary endpoint is the proportion of pts with post-NCT neg image-directed bx who have a pCR. Residual cancer burden scores and core bx pathology will be collected along with trimodality imaging data. Evaluation after 135 pts will allow for the possibility of early termination of the study. Results will provide the first step toward a paradigm change in the treatment of breast cancer, enabling a study to assess the criteria for successful avoidance of surgery in pts with high response rates to NCT. Accrual as of 6-15-18: 39 (22.3%). Support: U10CA180868, -180822, UG1CA189867. Citation Format: Basik M, Costantino JP, De Los Santos JF, Umphrey HR, Julian TB, Mamounas EP, White JR, Lucas PC, Wagner JL, Tjoe JA, Thompson AM, Wolmark N. Phase II trial assessing accuracy of tumor bed biopsies in predicting pathologic response in patients with clinical/radiological complete response after neoadjuvant chemotherapy in order to explore the feasibility of breast-conserving surgery without surgery: NRG Oncology BR005 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-09-01.

Introduction: The 21-gene Breast Recurrence Score® (RS) in the randomized NSABP B-20, SWOG S8814, and TAILORx studies predicted chemotherapy (CT) benefit for pts with N0 and N+ disease. Endocrine therapy was not inferior to chemoendocrine therapy in 6,711 randomized TAILORx pts with RS 11-25 and N0 disease. We characterized BCSM for the TAILORx-defined RS groups (0-10, 11-15, 16-20, 21-25, and 26-100) in the large population-based SEER study of pts treated based on RS results. Methods: RS results were provided electronically to SEER registries per their linkage methods (Petkov npj Breast Cancer 2016). Eligible pts were diagnosed Jan 2004 - Dec 2014 with N0 and N+(N1mic, 1-3 positive nodes[N1]), HR+, HER2-negative BC, and had no prior malignancy or multiple tumors, with follow-up information through Dec 2015. BCSM estimates by reported CT use yes vs. no/unknown were computed, and must be interpreted cautiously given lack of randomization. Results: There were 80,605 pts with RS results; 70,087 with N0 disease, 4,336 with N1mic, and 6,182 with N1. Median follow-up was 49 months, with 20,151 pts followed >76 months. 1,020 pts had experienced breast cancer death. There was a significant positive association between higher RS results and increased BCSM (p Table N0; CT Use No (N=55726)N0; CT Use Yes (N=14361)N1; CT Use No (N=3810)N1; CT Use Yes (N=2372)RS 0-10n139823891005283 9-y BCSM1.4% (1.0%, 2.1%)2.1% (0.7%, 5.9%)2.2% (1.0%, 4.8%)1.4% (0.4%, 4.6%)RS 11-15n1675810661193453 9-y BCSM2.0% (1.5%, 2.6%)2.7% (1.3%, 5.4%)1.5% (0.8%, 3.1%)4.4% (1.4%, 13.6%)RS 16-20n144842719992587 9-y BCSM2.2% (1.7%, 2.8%)1.9% (1.1%, 3.0%)3.8% (1.6%, 8.5%)4.2% (1.6%, 10.9%)RS 21-25n67043544397431 9-y BCSM3.9% (3.0%, 5.0%)3.4% (2.6%, 4.6%)7.1% (4.1%, 12.1%)5.7% (2.9%, 11.2%)RS 26-100n37986643223618 9-y BCSM8.8% (7.4%, 10.4%)7.0% (5.9%, 8.4%)15.2% (8.7%, 25.9%)10.8% (7.2%, 16.2%) Conclusion: In both N0 and N+ disease (up to 3 positive nodes), low RS results identify more than 70% of BC patients with excellent long-term outcomes and no apparent CT benefit, and high RS results (26-100) identifies an important minority of patients where CT reduces BCSM. Real-world evidence from SEER reconfirms that the 21-gene assay is prognostic and strongly suggests it is predictive of CT benefit, irrespective of nodal status. Citation Format: Hortobagyi GN, Shak S, Sledge, Jr. GW, Winer EP, Albain KS, Mamounas EP, Jakubowski DM, Petkov VI, Wolmark N. Breast cancer-specific mortality (BCSM) in patients (pts) with node-negative (N0) and node-positive (N+) breast cancer (BC) guided by the 21-gene assay: A SEER-genomic population-based study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-11-02.

Background: Patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy have a high risk of recurrence and death. The current standard of care is continuation of the same HER2-targeted therapy in the adjuvant setting for one year. T-DM1 has shown activity and a favorable benefit-risk profile in metastatic patients with disease progression after prior chemotherapy plus HER2-targeted therapy. Thus, T-DM1 may also be active in patients with residual invasive disease after neoadjuvant HER2-targeted therapy. Methods: KATHERINE (NCT01772472/BO27938/NSABP B-50-I/GBG 77) is a phase III, open-label, global study of patients with centrally confirmed HER2-positive (IHC3+ or ISH+) primary breast cancer (T1–4, N0–3, M0) who received neoadjuvant chemotherapy plus HER2-targeted therapy, which had to include a taxane and trastuzumab, followed by surgery, with pathologically documented residual invasive disease in the breast and/or axillary lymph nodes. Within 12 weeks of surgery, patients were randomized 1:1 to T-DM1 (3.6 mg/kg IV q3w) or trastuzumab (6 mg/kg IV q3w), for 14 cycles. Randomization was stratified by clinical stage at presentation, hormone receptor status, single versus dual neoadjuvant HER2-targeted therapy, and pathological nodal status after neoadjuvant therapy. Patients received radiotherapy and/or endocrine therapy per local standards. The primary endpoint is invasive disease-free survival (IDFS). A single interim analysis (IA) was planned after approximately 67% of the IDFS events required for the primary analysis had occurred, with an efficacy stopping boundary of HR?0.732 or p Results:After review of the pre-specified IA, the IDMC recommended full analysis and disclosure of the results. With 256 IDFS events reported, administration of T-DM1 significantly improved IDFS compared with trastuzumab (unstratified HR=0.50; 95% CI: 0.39 to 0.64; p Conclusions: Adjuvant T-DM1 substantially improved IDFS in patients with HER2-positive early breast cancer with residual disease after completion of neoadjuvant therapy. Citation Format: Geyer, Jr. CE, Huang C-S, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Fischer HH, Redondo A, Jackisch C, Jacot W, Conlin AK, Schneeweiss A, Wapnir IL, Fasching PA, DiGiovanna MP, Wuelfing P, Arce-Salinas C, Crown JP, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, von Minckwitz G. Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: Primary results from KATHERINE [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS1-10.

TPS613 Background: Approximately 50% of newly diagnosed breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX® have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy, freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after BCS and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that BCS alone is non-inferior to BCS plus RT for in-breast recurrence and breast preservation in women intending endocrine therapy (ET) for stage 1 breast cancer (ER &/or PR positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (1-2cm), & (RS 18, making them ineligible for the study. In the accrual process, pts will be required to register (1,714 pts) to ensure that our final randomized cohort is 1,670 pts. Current accrual (2-2-2022) is 52 screened and 45 randomized. Support: U10CA180868, -180822, NCT04852887. Clinical trial information: NCT04852887.

1007 Background: Prospective and retrospective studies of patients (pts) with oligometastatic (OM) disease have supported that metastases (mets) directed treatment (MDT) with SBRT or SR in addition to standard of care systemic therapy (SOC ST) can improve progression-free (PFS) and overall survival (OS) compared with SOC ST alone. However, randomized evidence in oligometastatic breast cancer (OMBC) are lacking. NRG-BR002, a randomized Phase IIR/III trial, sought to determine the efficacy of SOC ST + MDT (SBRT or SR) as first line treatment of OMBC. Methods: OMBC pts with ≤ 4 extracranial mets on standard imaging with controlled primary disease were eligible if on first line SOC ST for ≤ 12 months without progression. Pts were randomized (1:1) to ARM 1 – SOC ST (mainly chemotherapy, endocrine therapy, anti-HER2) or ARM 2 – SOC ST with MDT of all mets. Stratification included mets number (1 vs > 1), ER/PR and Her2 status, and chemotherapy use. Phase IIR targeted sample size was 128 total/116 eligible pts, for 92% power and 1-sided significance level = 0.15 to determine if adding MDT shows a signal for improved PFS (hazard ratio [HR] = 0.55, corresponding to median PFS (mPFS) from 10.5 to 19 months), in order to continue to the full phase III trial for OS. PFS and OS were estimated by Kaplan-Meier and arms compared with log-rank. Results: 125 of the 129 pts randomized were eligible (ARM 1 = 65, ARM 2 = 60). Key characteristics included median age 54, 79% ER+ or PR+/HER2-, 13% HER2+, 8% triple negative. 60% had 1 metastasis and 20% presented synchronously with primary disease. Following randomization, systemic therapy was delivered to 95% in ARM 1 and 93% in ARM 2; ablation: SBRT 93%, SR 2%, and 5% none. The median follow-up was 30 mo. The mPFS (70% CI) in ARM 1 was 23 mo (18, 29) and 19.5 mo (17, 36) in ARM 2; 24 and 36-mo PFS (70% CI) for ARM 1 were 45.7% (38.9, 52.5) and 32.8% (26.0, 39.5) compared with 46.8 (39.2, 54.3) and 38.1 (29.7, 46.6) in ARM 2; HR (70% CI): 0.92 (0.71, 1.17); and 1-sided log-rank p = 0.36. As PFS did not show signal, OS reporting is included: median OS was not reached in either arm; 36-mo OS (95% CI) in ARM 1 71.8% (58.9, 84.7) and ARM 2 68.9% (55.1, 82.6; 2-sided log-rank p = 0.54). Analysis of first failure showed new mets outside index area (Arm 1) /RT field (Arm 2) developed similarly in both arms at 40%. There were fewer new mets inside treated/index area for Arm 2 6.7% vs ARM 1 29.2%, respectively. There were no grade 5 treatment-related adverse events (AEs), 1 grade 4 AE in ARM 1, and 9.7% and 5.3% grade 3 AEs in ARMS 1 and 2, respectively. Circulating tumor cell counts (0 vs ≥1) at baseline were similar in both arms and were not prognostic HR (95% CI): 1.04 (0.54, 2.02). Conclusions: The addition of MDT to SOC ST did not show signal for improved PFS, nor OS difference in patients with OMBC. The trial will not proceed to the Phase III component. Clinical trial information: NCT02364557.

The NSABP B-20 prospective-retrospective study of the 21-gene Oncotype DX Breast Cancer Recurrence Score® test predicted benefit from addition of chemotherapy to tamoxifen in node-negative, estrogen-receptor positive breast cancer when recurrence score (RS) was ≥31. HER2 is a component of the RS algorithm with a positive coefficient and contributes to higher RS values. Accrual to B-20 occurred prior to routine testing for HER2, so questions have arisen regarding assay performance if HER2-positive patients were identified and excluded. We report an exploratory reanalysis of the B-20, 21-gene study following exclusion of such patients. Patients were considered HER2 positive if quantitative RT-PCR for HER2 was ≥11.5 units, and excluded from re-analyses performed using the original cutoffs: 25. The endpoint remained distant recurrence-free interval (DRFI) as in the original study. Distribution was estimated via the Kaplan–Meier method and compared via log-rank test. Multivariate Cox proportional hazards models estimated chemotherapy benefit in each group. In the RS 25 cohort (HR = 0.28; 95% CI: 0.12–0.64). No benefit from chemotherapy was evident in the other RS groups. Following exclusion of HER2-positive patients based on RT-PCR expression, substantial benefit of chemotherapy remained for RS ≥ 31 as originally employed, and with RS > 25 employed in TAILORx., Genetics: multigene panel predicts chemo benefit regardless of HER2 status A commonly used genetic test helps to predict whether patients with estrogen-receptor positive, node-negative breast cancer stand to gain from chemotherapy. Charles Geyer from NRG Oncology/NSABP and Virginia Commonwealth University and colleagues reanalyzed data from a decades-old study that helped establish a 21-gene panel as a tool for determining whether to add chemotherapy to endocrine therapy for women with estrogen-receptor positive, node-negative breast cancer. The researchers excluded patients with HER2-positive disease because HER2 gene expression is part of the diagnostic test and questions have persisted regarding the performance of the assay, if HER2-positive patients were excluded. This new analysis demonstrated that although chemotherapy did not extend disease-free survival overall among the cohort of patients with HER2-negative disease, it still proved beneficial for those with high recurrence scores on the genetic test. The findings thus validate the clinical utility of the test for patients with estrogen-receptor positive, HER2-negative, node negative breast cancers.

PURPOSE Preclinical studies report that trastuzumab (T) can boost radiotherapy (RT) effectiveness. The primary aim of the B-43 trial was to assess the efficacy of RT alone vs concurrent RT plus T in preventing recurrence of ipsilateral breast cancer (IBTR) in women with ductal carcinoma in situ (DCIS). PATIENTS AND METHODS Eligibility: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, DCIS resected by lumpectomy, known estrogen receptor (ER) and/or progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) status by centralized testing. Whole-breast RT was given concurrently with T. Stratification was by menopausal status, adjuvant endocrine therapy plan, and nuclear grade. Definitive intent-to-treat primary analysis was to be conducted when either 163 IBTR events occurred or all accrued patients were on study ≥ 5 years. RESULTS There were 2,014 participants who were randomly assigned. Median follow-up time as of December 31, 2019, was 79.2 months. At primary definitive analysis, 114 IBTR events occurred: RT arm, 63 and RT plus T arm, 51 (hazard ratio [HR], 0.81; 95% CI, 0.56 to 1.17; P value = .26). There were 34 who were invasive: RT arm, 18 and RT plus T arm, 20 (HR, 1.11; 95% CI, 0.59 to 2.10; P value = .71). Seventy-six were DCIS: RT arm, 45 and RT plus T arm, 31 (HR, 0.68; 95% CI, 0.43 to 1.08; P value = .11). Annual IBTR event rates were: RT arm, 0.99%/y and RT plus T arm, 0.79%/y. The study did not reach the 163 protocol-specified events, so the definitive analysis was triggered by all patients having been on study for ≥ 5 years. CONCLUSION Addition of T to RT did not achieve the objective of 36% reduction in IBTR rate but did achieve a modest but statistically nonsignificant reduction of 19%. Nonetheless, this trial had negative results. Further exploration of RT plus T is needed in HER2-positive DCIS before its routine delivery in patients with DCIS resected by lumpectomy.

PURPOSE: Accrual to clinical trials that challenge well-established treatment paradigms represents a unique challenge. Physician opinions on investigation of a novel approach to breast cancer treatment, in which patients with complete response to neoadjuvant chemotherapy are offered omission of lumpectomy, is unknown. NRG-CC006 sought to describe physician attitudes toward a novel approach to breast cancer treatment. METHODS: We recruited 18 participants in the fields of surgery, medical oncology, and radiation oncology to participate in semi-structured telephone interviews. Main outcomes are qualitative themes associated with omission of surgery. RESULTS: Of 18 interview participants, specialty and gender were evenly represented across surgery, medical oncology, and radiation oncology. Qualitative themes included general attitudes toward treatment de-escalation, stakeholder considerations, and trial/protocol considerations. The vast majority of participants expressed interest in investigation of omission of surgery, with all participants endorsing need for further investigation into treatment de-escalation. Stakeholder considerations in opening such a trial emphasized need for multidisciplinary involvement, and particularly, the unique role of surgeons as gatekeepers in breast cancer treatment. Finally, participants endorsed a need for further foundational studies to develop ways to predict complete pathologic response to chemotherapy without surgical intervention. CONCLUSIONS: Physicians expressed interest in investigating a novel approach to breast cancer treatment that would omit surgery in complete responders to neoadjuvant chemotherapy. Multidisciplinary input, and specifically surgeon engagement, will be key to the success of future investigations. Ongoing work to develop approaches to predict pathologic complete response accurately is needed to achieve the promise of this idea. CLINTRIALS #: BR005: NCT03188393 June 13, 2017

Our objective was to validate the NSABP 8-gene trastuzumab-benefit signature, developed and initially validated in NRG Oncology/NSABP B-31 in Alliance/NCCTG N9831. The B-31 and N9831 trials demonstrated the benefit of adding trastuzumab to chemotherapy in the adjuvant setting for HER2+ breast cancer patients. NSABP investigators utilized gene expression profiles of N9831 patients (N = 892) to blindly assign patients to large-, moderate-, or no-trastuzumab benefit groups and then NCCTG investigators assessed the degree of trastuzumab benefit using Cox models adjusted for age, nodes, estrogen receptor/progesterone receptor status, tumor size, and grade. Hazard ratios and 2-sided P values for recurrence-free survival of the predicted large- (n = 387), moderate- (n = 401), and no-benefit (n = 104) groups, based on the 8-gene signature were 0.47 (95% CI = 0.31 to 0.73, P < .001), 0.60 (95% CI = 0.39 to 0.92, P = .02), and 1.54 (95% CI = 0.59 to 4.02, P = .38), respectively (Pinteraction = .02), providing validation of the 8-gene signature in an independent study.

Triple-negative breast cancer (TNBC), defined as breast cancer lacking expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), accounts for up to 20% of all breast cancer, and it occurs at a higher frequency in younger, African American, and Hispanic women. Compared to breast cancers that are hormone receptor and/or HER2 positive, TNBC has an aggressive clinical course and worse prognosis. Because TNBC is by definition unresponsive to endocrine therapy (eg, tamoxifen, aromatase inhibitors) and HER2-directed therapies (eg, trastuzumab), chemotherapy continues to play an important role. TNBC constitutes a molecularly heterogeneous group of tumors that can vary in response to treatment, and clinical management can be challenging, particularly for the practicing community oncologist, for whom breast cancer may be only one of many tumor types encountered. In January 2020, the Breast Cancer Therapy Expert Group (BCTEG) convened a roundtable discussion on the topic of advances in the treatment of TNBC. Topics discussed included histopathologic classification/definition of TNBC, neoadjuvant strategies, adjuvant chemotherapy (with special emphasis on management of patients who do not experience a pathologic complete response), and treatment of metastatic disease. Also reviewed was the wide range of emerging pathways and therapies currently under investigation to expand TNBC treatment options, including immunotherapies and poly(ADP-ribose) polymerase (PARP) inhibitors. This article summarizes the BCTEG discussion and highlights the key opinions relating to the treatment of patients with TNBC.

Advancements in clinical practice usually require level one evidence from clinical trials that directly compare new approaches to standard of care. While clinical trials have provided data to guide advances in practices across surgical oncology, all too often accrual to clinical trials is slower than anticipated, and once results are presented and published, adoption in clinical practice is slow. Why and how can surgeons be successfully involved with clinical trials? An expert panel discusses the basic infrastructure of clinical trials, investigator-initiated trials, the National Clinical Trials Network, and opportunities for surgeon involvement. Two national clinical trials, NSABP B-51/RTOG 1304 and PROSPECT N1048, are discussed to highlight the role of the surgical oncologist.

PURPOSE Adjuvant trastuzumab reduces invasive breast cancer (IBC) recurrence and risk for death in patients with HER2-amplified or overexpressing IBC. A subset of patients in the landmark trastuzumab adjuvant trials who originally tested HER2-positive but were HER2-negative by central HER2 testing appeared to possibly benefit from trastuzumab. The objective for the NSABP B-47 trial was to determine whether the addition of trastuzumab to adjuvant chemotherapy (CRx) would improve invasive disease-free survival (IDFS) in patients with HER2-negative breast cancer. PATIENTS AND METHODS A total of 3,270 women with high-risk primary IBC were randomly assigned to CRx with or without 1 year of trastuzumab. Eligibility criteria included immunohistochemistry (IHC) score 1+ or 2+ with fluorescence in situ hybridization ratio (FISH) < 2.0 or, if ratio was not performed, HER2 gene copy number < 4.0. CRx was either docetaxel plus cyclophosphamide or doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks. RESULTS At a median follow-up of 46 months, the addition of trastuzumab to CRx did not improve IDFS (5-year IDFS: 89.8% with CRx plus trastuzumab [CRxT] v 89.2% with CRx alone; hazard ratio [HR], 0.98; 95% CI, 0.76 to 1.25; P = .85). These findings did not differ by level of HER2 IHC expression, lymph node involvement, or hormone-receptor status. For distant recurrence-free interval, 5-year estimates were 92.7% with CRxT compared with 93.6% for CRx alone (HR, 1.10; 95% CI, 0.81 to 1.50; P = .55) and for overall survival (OS) were 94.8% with CRxT and 96.3% in CRx alone (HR, 1.33; 95% CI, 0.90 to 1.95; P = .15). There were no unexpected toxicities from the addition of trastuzumab to CRx. CONCLUSION The addition of trastuzumab to CRx did not improve IDFS, distant recurrence-free interval, or OS in women with non-HER2–overexpressing IBC. Trastuzumab does not benefit women without IHC 3+ or FISH ratio-amplified breast cancer.