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Background: The primary aim of this randomized neoadjuvant trial in operable, HER2-positive breast cancer, was to determine the efficacy on pathologic complete response (pCR) of substituting lapatinib (L) for trastuzumab (T) or adding L to T, in combination with weekly paclitaxel (WP) following AC. Results on pCR were previously reported. Here, we report data on planned secondary endpoints, recurrence-free interval (RFI) post-surgery, and overall survival (OS)., Methods: All patients received standard AC q3 weeks × 4 cycles followed by WP (80 mg/m 2 ) on days 1, 8, and 15, q28 days × 4 cycles. Concurrently with WP, patients received either T (4 mg/kg load, then 2 mg/kg) weekly until surgery, L (1250 mg) daily until surgery, or weekly T plus L (750 mg) daily until surgery. Following surgery, all patients received T to complete 52 weeks of HER2-targeted therapy. 522 of 529 randomized patients had follow-up. Median follow-up was 5.1 years., Results: RFI at 4.5 years was 87.2%, 79.4% (p = 0.34; HR = 1.37; 95% CI 0.80, 2.34), and 89.4% (p = 0.37; HR = 0.70; 0.37, 1.32) for arms T, L, and TL, respectively. The corresponding five-year OS was 94.8%, 89.1% (p = 0.34; HR = 1.46; 0.68, 3.11), and 95.8% (p = 0.25; HR = 0.58; 0.22, 1.51), respectively. Patients with pCR had a much better prognosis, especially in the ER-negative cohort: RFI (HR = 0.23, p < 0.001) and OS (HR = 0.28, p < 0.001)., Conclusions: Although pCR, RFI, and OS were numerically better with the dual combination and less with L, the differences were not statistically significant. However, achievement of pCR again correlated with improved outcomes, especially remarkable in the ER-negative subset., Clinical Trials Registration: NCT00486668., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Results from adjuvant trials evaluating 6 cycles of epirubicin-based chemotherapy regimens suggested these programs may be more effective than 4 cycles of doxorubicin-based chemotherapy., Method: NSABP B-36 was a phase III clinical trial originally designed as a 2 × 2 factorial study comparing 6 cycles of 5-FU, epirubicin, and cyclophosphamide (FEC-100) to 4 cycles of conventional doxorubicin and cyclophosphamide (AC) with celecoxib or placebo. Shortly after activation, concerns regarding increased cardiovascular risks among selective COX-2 inhibitors resulted in a decision to remove the celecoxib/placebo from the trial. Women with histologically node-negative invasive breast cancer who had undergone primary surgery with a lumpectomy or total mastectomy were eligible. Primary endpoint was disease-free survival (DFS)., Results: Between May 2004 and July 2008, 2722 patients were enrolled. Administration of FEC-100 did not result in improvement in DFS compared to AC (HR 1.09; 95% CI 0.92-1.29, p value = 0.31). The effect of FEC-100 compared to AC on DFS was significantly different for receptor-positive (HR 1.32, 95% CI 1.05-1.66) compared to receptor-negative patients (HR 0.86, 95% CI 0.66-1.11) (treatment-by-receptor status interaction p value = 0.02). There was no statistically significant difference in the effect of treatment on overall survival (OS) with FEC-100 compared to AC (HR 1.06; 95% CI 0.84-1.35, p value = 0.61). Overall, Grade 3 and 4 adverse events were more frequent in the FEC-100 group., Conclusion: The results of B-36 do not support use of six-cycle anthracycline-based regimens in node-negative breast cancer. Prolongation of anthracycline-based therapy with FEC-100 does not improve DFS or OS, relative to AC for 4 cycles, and was associated with expected increases in toxicity. A statistically significant interaction between treatment and hormone receptor status favoring AC in hormone-receptor-positive breast cancers is consistent with the hypothesis that optimal duration of chemotherapy may be four cycles in these patients. Late cardiac events and deaths prior to recurrence or second cancer were infrequent on both arms, but slightly higher with FEC-100., Trial Registration: ClinicalTrials.gov: NCT00087178., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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, are 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 the 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.

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 < 0.001). In multivariate analysis among patients receiving trastuzumab-containing regimens (with clinical factors and HER2E subtype as factors), HER2E subtype was most strongly associated with pCR [OR 8.41 (95% CI 2.52-28.1) p < 0.001]. Patients with HER2E tumors did not benefit more from dual HER2-targeted therapy versus trastuzumab. The pCR rate was higher among HER2E tumors versus other subtypes in both estrogen receptor-positive and -negative tumors (p ≤ 0.001). Higher ESR1 gene expression was associated with lower pCR rate. No association was observed between subtype and long-term outcomes., Conclusion: Patients with HER2E tumors were most likely to attain pCR versus other subtypes. HER2E subtype represents a favorable marker for predicting HER2-targeting benefit, particularly with trastuzumab-based therapies.

Background: The 21-gene recurrence score (RS) predicts outcome and benefit from adjuvant chemotherapy benefit in breast cancer patients treated with adjuvant endocrine therapy. In the NSABP B-28 study, we evaluated the 21-gene RS for its prognostic impact and its ability to predict benefit from paclitaxel (P) in node-positive, estrogen receptor-positive (ER+) breast cancer patients treated with adjuvant chemotherapy plus tamoxifen., Methods: The B-28 trial compared doxorubicin/cyclophosphamide (AC) with AC followed by P in 3060 patients. Tamoxifen for 5 years was also given to patients > 50 years and those < 50 years with ER+ and/or progesterone receptor-positive (PR+) tumors. The present study includes 1065 ER-positive, tamoxifen-treated patients with RS assessment. Median follow-up time was 11.2 years., Results: In univariate analyses, RS was a significant predictor of outcome. In multivariate analyses, RS remained a significant independent predictor of outcome beyond clinico-pathologic factors, age, and type of surgery (p < 0.001). In the study population (n = 1065), the disease-free survival (DFS) hazard ratio (HR) with adding P to AC was 0.87 (95% CI 0.72-1.05; p = 0.14). RS was not a significant predictor of P benefit: for DFS, HRs for adding P to AC in RS low, intermediate, and high subgroups were 1.01 (95% CI 0.69-1.47; p = 0.99), 0.84 (95% CI 0.62-1.14; p = 0.26), and 0.81 (95% CI 0.60-1.10; p = 0.21), respectively (interaction p = 0.64). Similar findings were observed for the other study endpoints., Conclusions: RS maintains significant prognostic impact in ER-positive, node-positive patients treated with adjuvant chemotherapy plus tamoxifen. However, RS did not significantly predict benefit from adding paclitaxel to AC chemotherapy. (Trial Registration: PDQ: NSABP-B-28).

Neoadjuvant chemotherapy has the advantage of converting unresectable breast tumors to resectable tumors and allowing more conservative surgery in some mastectomy candidates. Chemotherapy agents, including taxanes, which are recommended in the adjuvant setting, are also considered in the neoadjuvant setting. Here, we review studies of nab-paclitaxel as a neoadjuvant treatment for patients with breast cancer. PubMed and conference or congress proceedings were searched for clinical studies of nab-paclitaxel in the neoadjuvant treatment of breast cancer. We also searched ClinicalTrials.gov for ongoing trials of nab-paclitaxel as a neoadjuvant agent in breast cancer. Twenty studies of nab-paclitaxel in the neoadjuvant setting were identified. In addition to reviewing key efficacy and safety data, we discuss how each trial assessed response, focusing on pathologic complete response and residual cancer burden scoring. Safety profiles are also reviewed. nab-Paclitaxel demonstrated antitumor activity and an acceptable safety profile in the neoadjuvant treatment of breast cancer. Ongoing and future trials will further evaluate preoperative nab-paclitaxel in breast cancer, including in combination with many novel immunological targeted therapies.

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.

NSABP B-43 is the first prospective, randomized phase III multi-institution clinical trial targeting high-risk, HER2-positive DCIS. It compares whole breast irradiation alone with WBI given concurrently with trastuzumab in women with HER2-positive DCIS treated by lumpectomy. The primary aim is to determine if trastuzumab plus radiation will reduce in-breast tumor recurrence. HER2-positive DCIS was previously estimated at >50 %, occurring primarily in ER-negative, comedo-type DCIS of high nuclear grade. There has been no documented centralized multi-institutional HER2 analysis of DCIS. NSABP B-43 provides a unique opportunity to evaluate this in a large cohort of DCIS patients. Patients undergoing lumpectomy for DCIS without evidence of an invasive component are eligible. A central review of each patient's pure DCIS lesion is carried out by immunohistochemistry analysis. If the lesion is 2+, FISH analysis is performed. Patients whose tumors are HER2 3+ or FISH-positive are randomly assigned to receive two doses of trastuzumab during WBI or WBI alone. NSABP B-43 opened 11/9/08. As of 7/31/2013, 5,861 patients have had specimens received centrally, and 5,645 of those had analyzable blocks; 1,969 (34.9 %) were HER2 positive. A total of 1,428 patients have been accrued, 1,137 (79.6 %) of whom have follow-up information. The average follow-up time for the 1,137 patients is 23.3 months. No grade 4 or 5 toxicity has been observed. In NSABP B-43 the HER2-positive rate for pure DCIS among patients undergoing breast-preserving surgery is 34.9 %, lower than the previously reported rate. No trastuzumab-related safety signals have been observed. Interest in this trial has been robust.

The Oncotype DX Recurrence Score (RS) is a validated genomic predictor of outcome and response to adjuvant chemotherapy in ER-positive breast cancer. Adjuvant! was developed using SEER registry data and results from the Early Breast Cancer Clinical Trialists' overview analyses to estimate outcome and benefit from adjuvant hormonal therapy and chemotherapy. In this report we compare the prognostic and predictive utility of these two tools in node-negative, ER-positive breast cancer. RS and Adjuvant! results were available from 668 tamoxifen-treated NSABP B-14 patients, 227 tamoxifen-treated NSABP B-20 patients, and 424 chemotherapy plus tamoxifen-treated B-20 patients. Adjuvant! results were also available from 1952 B-20 patients. The primary endpoint was distant recurrence-free interval (DRFI). Cox proportional hazards models were used to compare the prognostic and predictive utility of RS and Adjuvant!. Both RS (P < 0.001) and Adjuvant! (P = 0.002) provided strong independent prognostic information in tamoxifen-treated patients. Combining RS and individual clinicopathologic characteristics provided greater prognostic discrimination than combining RS and the composite Adjuvant!. In the B-20 cohort with RS results (n = 651), RS was significantly predictive of chemotherapy benefit (interaction P = 0.031 for DRFI, P = 0.011 for overall survival [OS], P = 0.082 for disease-free survival [DFS]), but Adjuvant! was not (interaction P = 0.99, P = 0.311, and P = 0.357, respectively). However, in the larger B-20 sub-cohort (n = 1952), Adjuvant! was significantly predictive of chemotherapy benefit for OS (interaction P = 0.009) but not for DRFI (P = 0.219) or DFS (P = 0.099). Prognostic estimates can be optimized by combining RS and clinicopathologic information instead of simply combining RS and Adjuvant!. RS should be used for estimating relative chemotherapy benefit.

Imaging and local therapy are important modalities for detection and management of localized breast cancer. Improvements in screening and local therapy have contributed to reduced breast cancer-associated morbidity and mortality. The Coalition of Cancer Cooperative Groups (CCCG) convened the Scientific Leadership Council (SLC) in breast cancer, an expert panel, to identify priorities for future research and current trials with greatest practice-changing potential. Panelists formed a consensus on research priorities for breast imaging and locoregional therapy, and also identified six trials judged to be of high priority. Current high priority trials included trials determining: (1) the role of accelerated partial breast versus whole-breast radiation (B39), (2) the feasibility, safety, and local and systemic control of small localized breast cancers treated with tumor ablation (Z1072), (3) the role of removal of the primary cancer in selected patients with metastatic disease (E2108), and (4) the clinical and biological effects of pre-operative anti-HER2-directed and ER-directed therapies in localized or locally advanced breast cancer (B41, Z1031, Z1041). Ongoing and future trials will further refine optimal locoregional management, and additional research is required to develop improved screening methods and identify high risk populations most likely to benefit from targeted screening.

Background: For patients with axillary lymph node-negative breast cancer, benefits from adjuvant therapy are smaller than in node-positive disease and thus more selective use is warranted, prompting development of risk profiling to identify those most likely to benefit. Examination of the magnitude and changes in the hazard of failure over time in node-negative breast cancer may also be informative in this regard., Methods: Among 9,444 participants from five randomized trials (accrual 1982-1998) investigating chemotherapy and tamoxifen for node-negative breast cancer, we estimated recurrence hazards over time by tumor estrogen receptor (ER) status and adjuvant treatment., Results: In patients treated by surgery only, we observed the previously noted larger hazard peak followed by a rapid decrease in ER-negative patients and smaller but more persistent hazard in ER-positive patients. After approximately 48 months, the ER-positive hazard is greater. For adjuvant treatment, while tamoxifen decreases the early hazard in ER-positive patients to that of the chemotherapy-treated ER-negative group, in later follow-up (beyond 5 years) the hazard for ER-positive patients again exceeds that of ER-negative patients. Adding chemotherapy to tamoxifen in ER-positive patients results in large early hazard reduction, but in later follow-up the hazard converges with those of patients treated by surgery only or tamoxifen., Conclusions: Recurrence hazards over time reveal changes in risk that may have biologic and therapeutic strategy relevance. In ER-negative tumors, a large early chemotherapy benefit is followed by a consistently low recurrence hazard over time. In ER-positive patients, the chemotherapy benefit appears concentrated mostly in earlier follow-up, and a greater recurrence risk remains.

The NSABP B-30 trial addresses whether amenorrhea after adjuvant chemotherapy increases survival. Preliminary to the trial outcome analysis, we examined the incidence of amenorrhea and its relationship to symptoms and quality of life (QOL) in the standard-care arm of this adjuvant breast cancer trial. Premenopausal women treated on the doxorubicin-and-cyclophosphamide-followed-by-docetaxel arm were included. Questionnaires assessing menstrual history, QOL, and symptoms were administered at baseline, day 1 of cycle 4 (or 9 weeks from start of chemotherapy for those who stopped chemotherapy early), and at 6, 12, and 24 months. Seven hundred and eight patients were evaluable for the analysis, with median potential follow-up of 57.5 months. Of these, 321 patients also participated in the QOL substudy. Of the 708 patients, 83% reported > or =1 episode of amenorrhea for > or =6 months. The estimated rate of resumption of menses at 24 months was 45.3% for women <40 years, 10.9% for women 40-50, and 3.2% for women >50 years. Those treated with tamoxifen were more likely to become amenorrheic (p = 0.003). Menstrual status was not significantly associated with QOL or symptoms. Prolonged amenorrhea is associated with a regimen that contains doxorubicin, cyclophosphamide, and docetaxel, and is age dependent and impacted by tamoxifen use. Vasomotor symptoms are common in this patient population but are not associated with menstrual status. These results can be used to inform premenopausal women about the risk and time course of amenorrhea associated with this common adjuvant therapy regimen, along with the effects on symptoms and QOL.