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Bromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in a subset of sarcomas and leukemias. Here, we used novel small molecule inhibitors and degraders along with RNA interference to assess the dependency on BRD9 in the context of diverse hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) model systems. Following depletion of BRD9 protein, AML cells undergo terminal differentiation, whereas apoptosis was more prominent in ALL and MM. RNA-seq analysis of acute leukemia and MM cells revealed both unique and common signaling pathways affected by BRD9 degradation, with common pathways including those associated with regulation of inflammation, cell adhesion, DNA repair and cell cycle progression. Degradation of BRD9 potentiated the effects of several chemotherapeutic agents and targeted therapies against AML, ALL, and MM. Our findings support further development of therapeutic targeting of BRD9, alone or combined with other agents, as a novel strategy for acute leukemias and MM., (© 2022. The Author(s).)

Approximately 50% of patients with metastatic HER2-positive (HER2+) breast cancer develop brain metastases (BCBMs). We report that the tumor suppressor p16 INK4A is deficient in the majority of HER2+ BCBMs. p16 INK4A -deficiency as measured by protein immunohistochemistry predicted response to combined tucatinib and abemaciclib in orthotopic patient-derived xenografts (PDXs) of HER2 + BCBMs. Our findings establish the rationale for a biomarker-driven clinical trial of combined CDK4/6- and HER2-targeted agents for patients with HER2 + BCBM., (© 2022. The Author(s).)

Bromodomain and extra-terminal (BET) proteins can drive carcinogenesis and therapy resistance. RO6870810 (RO) is a novel, small-molecule BET inhibitor. We conducted a study in 32 patients with relapsed/refractory acute myeloid leukemia and hypomethylating agent-refractory myelodysplastic syndrome (NCT02308761). Pharmacodynamic assessments showed decreases in CD11b in peripheral blood mononuclear cells at RO concentrations above 120 ng/mL. Treatment emergent adverse events were generally mild and the most frequent were fatigue, injection site reactions, diarrhea, decreased appetite and nausea. There were no treatment-related deaths. Potential drug-related dose limiting toxicities included decreased appetite, congestive cardiac failure, hypertension, fatigue, increased conjugated bilirubin and increased gamma glutamyltransferase. One AML patient achieved complete remission after withdrawal from study. Eleven AML patients experienced SD. For AML, the median OS was 72.0 days. For MDS, two patients experienced SD. Further development of RO as monotherapy was discontinued due to lack of efficacy, but combinations with other agents are under consideration.

Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708., (© 2021 by The American Society of Hematology.)

The 21-gene Recurrence Score (RS) assay has been validated as both a prognostic and predictive tool in node-negative (pN0), estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer. A large body of evidence supports the clinical utility of the RS in the node positive (pN+) population as well. Retrospective analyses of archived tissue from multiple clinical trials have found the RS to be prognostic in both endocrine therapy (ET)-treated and chemotherapy-treated patient with pN+ disease. Distribution of RS results in pN+ patients have also been consistent with those of pN0 populations. Data from the SWOG 8814 trial and large population-based registries further support the prognostic and potential predictive value of the RS. Specifically, patients with 1 to 3 positive nodes and RS less than 18 derived negligible benefit from adjuvant chemotherapy in these studies. In the prospective West German Study Group PlanB and ADAPT trials, pN+ patients with RS less than 11 and RS 25 or less, respectively, who were treated with ET alone experienced excellent outcomes. Finally, 5-year results of the RxPONDER clinical trial randomizing patients with 1 to 3 positive nodes and RS 25 or less to ET alone vs ET plus chemotherapy confirmed an absence of chemotherapy benefit in postmenopausal patients. Clinical practice guidelines support use of the RS in the pN+, ER+/HER2- population, and many institutions have adopted the RS to guide clinical decisionmaking, resulting in a net reduction of adjuvant chemotherapy use. This review highlights the existing data supporting the prognostic and predictive ability of the RS in pN+ disease, current practice patterns related to RS use in this population, and emerging applications.

An important challenge in the field of cancer is finding the balance between delivering effective treatments and avoiding adverse effects and financial toxicity caused by innovative, yet expensive, drugs. To address this, several treatment de-escalation trials have been conducted, but only a few of these have provided clear answers. A few trials had poor accrual or had design flaws that led to conflicting results. Members of the Breast International Group (BIG) and North American Breast Cancer Group (NABCG) believe the way forward is to understand the lessons from these trials and listen more carefully to what truly matters to our patients. We reviewed several adjuvant trials of different cancer types and developed a road map for improving the design and implementation of future de-escalation trials. The road map incorporates patients' insights obtained through focused group discussions across the BIG-NABCG networks. Considerations for the development of de-escalation trials for systemic adjuvant treatment, including noninferiority trial design, choice of end points, and prioritization of a patient's perspectives, are presented in this consensus article.

Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive (HR + ) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2 , and FGFR2 , and loss of estrogen receptor expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA , or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations-in AKT1, RAS , and AURKA -have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients. SIGNIFICANCE: We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR + metastatic breast cancer. This article is highlighted in the In This Issue feature, p. 1079 ., (©2020 American Association for Cancer Research.)

Importance: Breast cancer will be diagnosed in 12% of women in the United States over the course of their lifetimes and more than 250 000 new cases of breast cancer were diagnosed in the United States in 2017. This review focuses on current approaches and evolving strategies for local and systemic therapy of breast cancer., Observations: Breast cancer is categorized into 3 major subtypes based on the presence or absence of molecular markers for estrogen or progesterone receptors and human epidermal growth factor 2 (ERBB2; formerly HER2): hormone receptor positive/ERBB2 negative (70% of patients), ERBB2 positive (15%-20%), and triple-negative (tumors lacking all 3 standard molecular markers; 15%). More than 90% of breast cancers are not metastatic at the time of diagnosis. For people presenting without metastatic disease, therapeutic goals are tumor eradication and preventing recurrence. Triple-negative breast cancer is more likely to recur than the other 2 subtypes, with 85% 5-year breast cancer-specific survival for stage I triple-negative tumors vs 94% to 99% for hormone receptor positive and ERBB2 positive. Systemic therapy for nonmetastatic breast cancer is determined by subtype: patients with hormone receptor-positive tumors receive endocrine therapy, and a minority receive chemotherapy as well; patients with ERBB2-positive tumors receive ERBB2-targeted antibody or small-molecule inhibitor therapy combined with chemotherapy; and patients with triple-negative tumors receive chemotherapy alone. Local therapy for all patients with nonmetastatic breast cancer consists of surgical resection, with consideration of postoperative radiation if lumpectomy is performed. Increasingly, some systemic therapy is delivered before surgery. Tailoring postoperative treatment based on preoperative treatment response is under investigation. Metastatic breast cancer is treated according to subtype, with goals of prolonging life and palliating symptoms. Median overall survival for metastatic triple-negative breast cancer is approximately 1 year vs approximately 5 years for the other 2 subtypes., Conclusions and Relevance: Breast cancer consists of 3 major tumor subtypes categorized according to estrogen or progesterone receptor expression and ERBB2 gene amplification. The 3 subtypes have distinct risk profiles and treatment strategies. Optimal therapy for each patient depends on tumor subtype, anatomic cancer stage, and patient preferences.

Purpose To update evidence-based guideline recommendations for practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer to 2018. Methods An Expert Panel conducted a targeted systematic literature review (for both systemic treatment and CNS metastases) and identified 622 articles. Outcomes of interest included overall survival, progression-free survival, and adverse events. Results Of the 622 publications identified and reviewed, no additional evidence was identified that would warrant a change to the 2014 recommendations. Recommendations HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. Trastuzumab, pertuzumab, and taxane for first-line treatment and trastuzumab emtansine for second-line treatment are recommended. In the third-line setting, clinicians should offer other HER2-targeted therapy combinations or trastuzumab emtansine (if not previously administered) and may offer pertuzumab if the patient has not previously received it. Optimal duration of chemotherapy is at least 4 to 6 months or until maximum response, depending on toxicity and in the absence of progression. HER2-targeted therapy can continue until time of progression or unacceptable toxicities. For patients with HER2-positive and estrogen receptor-positive/progesterone receptor-positive breast cancer, clinicians may recommend either standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy or endocrine therapy alone. Additional information is available at www.asco.org/breast-cancer-guidelines .

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity caused by several chemotherapeutic agents. Currently, CIPN is managed by empirical dose modifications at the discretion of the treating physician. The goal of this research is to quantitate the dose-CIPN relationship to inform the optimal strategies for dose modification. Data were obtained from the Cancer and Leukemia Group B (CALGB) 40502 trial, a randomized phase III trial of paclitaxel vs. nab-paclitaxel vs. ixabepilone as first-line chemotherapy for locally recurrent or metastatic breast cancer. CIPN was measured using a subset of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group Neurotoxicity (FACT-GOG-NTX) scale. A kinetic-pharmacodynamic (K-PD) model was utilized to quantitate the dose-CIPN relationship simultaneously for the three drugs. Indirect response models with linear and S max drug effects were evaluated. The model was evaluated by comparing the predicted proportion of patients with CIPN (score ≥8 or score ≥12) to the observed proportion. An indirect response model with linear drug effect was able to describe the longitudinal CIPN data reasonably well. The proportion of patients that were falsely predicted to have CIPN or were falsely predicted not to have CIPN was 20% or less at any cycle. The model will be utilized to identify an early time point that can predict CIPN at later time points. This strategy will be utilized to inform dose adjustments to prospectively manage CIPN. Clinicaltrials.gov ID: NCT00785291.

Purpose: To provide further insight into the role of proliferation and other cellular processes in chemosensitivity and resistance, we evaluated the association of a diverse set of gene expression signatures with response to neoadjuvant chemotherapy (NAC) in breast cancer., Experimental Design: Expression data from primary breast cancer biopsies for 1,419 patients in 17 studies prior to NAC were identified and aggregated using common normalization procedures. Clinicopathologic characteristics, including response to NAC, were collected. Scores for 125 previously published breast cancer-related gene expression signatures were calculated for each tumor., Results: Within each receptor-based subgroup or PAM50 subtype, breast tumors with high proliferation signature scores were significantly more likely to achieve pathologic complete response to NAC. To distinguish "proliferation-associated" from "proliferation-independent" signatures, we used correlation and linear modeling approaches. Most signatures associated with response to NAC were proliferation associated: 90.5% (38/42) in ER + /HER2 - and 63.3% (38/60) in triple-negative breast cancer (TNBC). Proliferation-independent signatures predictive of response to NAC in ER + /HER2 - breast cancer were related to immune activity, while those in TNBC comprised a diverse set of signatures, including immune, DNA damage, signaling pathways (PI3K, AKT, Ras, and EGFR), and "stemness" phenotypes., Conclusions: Proliferation differences account for the vast majority of predictive capacity of gene expression signatures in neoadjuvant chemosensitivity for ER + /HER2 - breast cancers and, to a lesser extent, TNBCs. Immune activation signatures are proliferation-independent predictors of pathologic complete response in ER + /HER2 - breast cancers. In TNBCs, significant proliferation-independent signatures include gene sets that represent a diverse set of cellular processes. Clin Cancer Res; 22(24); 6039-50. ©2016 AACR., Competing Interests: The authors have no conflicts of interest to report., (©2016 American Association for Cancer Research.)

Purpose: Cabozantinib (XL184), a multi-targeted oral tyrosine kinase inhibitor with activity against MET, VEGFR2, AXL, and other tyrosine kinases, was assessed in a cohort of metastatic breast cancer (MBC) patients in a phase II randomized discontinuation trial (RDT)., Methods: Patients received 100 mg cabozantinib daily during a 12-week lead-in stage. Those with stable disease per modified Response Evaluation Criteria in Solid Tumors version 1.0 at 12 weeks were randomized to either continue cabozantinib or receive placebo. Primary endpoints were objective response rate (ORR) during the 12-week lead-in stage and progression-free survival (PFS) after randomization. Patients were also followed for overall survival (OS)., Results: Forty-five patients with MBC and a median of three prior lines of chemotherapy for metastatic disease were enrolled. The ORR during the lead-in stage was 13.6 % (95 % confidence interval [CI] 6-25.7 %), and the disease control rate at week 12 was 46.7 % (95 % CI 31.7-61.6 %). Per the initial RDT study design, patients with stable disease at week 12 were randomized to cabozantinib or placebo. Following a Study Oversight Committee recommendation, randomization was suspended. Patients in the lead-in stage continued on open-label cabozantinib. Patients in the randomization stage were subsequently unblinded. The overall median PFS for all MBC patients was 4.3 months. Median OS was 11.4 months (95 % CI 10.5-16.5 months). The most common grade 3/4 adverse events in the lead-in stage were palmar-plantar erythrodysesthesia (13 %) and fatigue (11 %). One death from respiratory failure was reported as drug-related during the lead-in stage., Conclusions: In heavily pretreated MBC patients, cabozantinib monotherapy demonstrated clinical activity including objective response and disease control., Competing Interests: SMT has received support for clinical research from Exelixis. HN has received support for clinical research from Exelixis. I-GR has no conflicts to report. PS has received institutional research support from Exelixis, and received travel support and honoraria for participation in educational and advisory functions from Exelixis and SOBI. AA has no conflicts to report. CAY has no conflicts to report. ADL was an employee and stockholder of Exelixis. BO was an employee and stockholder of Exelixis. GIS has received support for clinical research from Exelixis. EPW has received support for clinical research from Exelixis.

Purpose: To investigate whether anti-vascular endothelial growth factor therapy with bevacizumab prolongs progression-free survival (PFS) when added to first-line letrozole as treatment of hormone receptor-positive metastatic breast cancer (MBC)., Patients and Methods: Women with hormone receptor-positive MBC were randomly assigned 1:1 in a multicenter, open-label, phase III trial of letrozole (2.5 mg orally per day) with or without bevacizumab (15 mg/kg intravenously once every 3 weeks) within strata defined by measurable disease and disease-free interval. This trial had 90% power to detect a 50% improvement in median PFS from 6 to 9 months. Using a one-sided α = .025, a target sample size of 352 patients was planned., Results: From May 2008 to November 2011, 350 women were recruited; 343 received treatment and were observed for efficacy and safety. Median age was 58 years (range, 25 to 87 years). Sixty-two percent had measurable disease, and 45% had de novo MBC. At a median follow-up of 39 months, the addition of bevacizumab resulted in a significant reduction in the hazard of progression (hazard ratio, 0.75; 95% CI, 0.59 to 0.96; P = .016) and a prolongation in median PFS from 15.6 months with letrozole to 20.2 months with letrozole plus bevacizumab. There was no significant difference in overall survival (hazard ratio, 0.87; 95% CI, 0.65 to 1.18; P = .188), with median overall survival of 43.9 months with letrozole versus 47.2 months with letrozole plus bevacizumab. The largest increases in incidence of grade 3 to 4 treatment-related toxicities with the addition of bevacizumab were hypertension (24% v 2%) and proteinuria (11% v 0%)., Conclusion: The addition of bevacizumab to letrozole improved PFS in hormone receptor-positive MBC, but this benefit was associated with a markedly increased risk of grade 3 to 4 toxicities. Research on predictive markers will be required to clarify the role of bevacizumab in this setting., Competing Interests: Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. contributions are found at the end of this article., (© 2016 by American Society of Clinical Oncology.)

Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.

Cytotoxic chemotherapy remains the systemic therapy of choice for triple-negative breast cancer (TNBC), a poor-prognosis subtype of breast cancer. Growing data focusing on TNBC provides an opportunity to assess if we can tailor adjuvant chemotherapy based on patient and tumor characteristics. The standard of care for moderate-to-high risk TNBC remains a sequential anthracycline-taxane combination, with the potential for shorter and less toxic regimens in stage I disease. Platinums are promising in the neoadjuvant and metastatic settings but we await long-term outcome data before incorporation into standard regimens in the adjuvant setting. Specific subgroups within TNBC, such as BRCA mutation carriers, require special attention, and the role of platinums in these patients warrants further consideration. There is hope that in the future, further subdividing TNBC by gene expression profile, mutation, immune infiltrate, and others will reveal novel susceptibilities., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: MET expression and activation appear to be important for initiation and progression of triple-negative breast cancer. Tivantinib (ARQ 197) is an orally administered agent that targets MET, although recent preclinical data suggests the agent may have mechanisms of action that are independent of MET signaling. We conducted a phase 2 study of tivantinib monotherapy in patients with metastatic triple-negative breast cancer., Methods: Patients with metastatic triple-negative breast cancer who had received 1 to 3 prior lines of chemotherapy in the metastatic setting were enrolled into this two-stage, single arm phase 2 study. Treatment consisted of twice daily oral dosing of tivantinib (360 mg po bid) during a 21-day cycle. Patients underwent restaging scans at 6 weeks, and then every 9 weeks. Tumor biomarkers that might predict response to tivantinib were explored., Results: 22 patients were enrolled. The overall response rate was 5 % (95 % CI 0-25 %) and the 6-month progression-free survival (PFS) was 5 % (95 % CI 0-25 %), with one patient achieving a partial response (PR). Toxicity was minimal with only 5 grade ≥3 adverse events (one grade 3 anemia, one grade 3 fatigue, and 3 patients with grade 3/4 neutropenia)., Conclusion: This study represents the first evaluation of tivantinib for the treatment of metastatic triple-negative breast cancer. These results suggest that single agent tivantinib is well tolerated, but did not meet prespecified statistical targets for efficacy.

Purpose: The identification of patients with metastatic triple-negative breast cancer (mTNBC) who are expected to benefit from platinum-based chemotherapy is of interest. We conducted a single-arm phase II clinical trial of single-agent platinum for mTNBC with biomarker correlates., Patients and Methods: Patients with mTNBC received first- or second-line cisplatin (75 mg/m(2)) or carboplatin (area under the concentration-time curve 6) by physician's choice once every 3 weeks. Coprimary end points were objective response rate (RR) and response prediction by p63/p73 gene expression. Secondary and exploratory end points included toxicity assessment, RR in cisplatin versus carboplatin, and RR in molecularly defined subgroups, including BRCA1/2 mutation carriers., Results: Patients (N = 86; 69 as first-line therapy) received cisplatin (n = 43) or carboplatin (n = 43). RR was 25.6% (95% CI, 16.8% to 36%) and was numerically higher with cisplatin (32.6%) than with carboplatin (18.7%). RR was 54.5% in patients with germline BRCA1/2 mutations (n = 11). In patients without BRCA1/2 mutations (n = 66), exploratory analyses showed that a BRCA-like genomic instability signature (n = 32) discriminated responding and nonresponding tumors (mean homologous recombination deficiency-loss of heterozygosity/homologous recombination deficiency-large-scale state transitions [HRD-LOH/HRD-LST] scores were 12.68 and 5.11, respectively), whereas predefined analysis by p63/p73 expression status (n = 61), p53 and PIK3CA mutation status (n = 53), or PAM50 gene expression subtype (n = 55) did not. Five of the six long-term responders alive at a median of 4.5 years lacked germline BRCA1/2 mutations, and two of them had increased tumor HRD-LOH/HRD-LST scores., Conclusion: Platinum agents are active in mTNBC, especially in patients with germline BRCA1/2 mutations. A measure of tumor DNA repair function may identify patients without mutations who could benefit from platinum therapy agents. Prospective controlled confirmatory trials are warranted., (© 2015 by American Society of Clinical Oncology.)

Purpose: Increased circulating tumor cells (CTCs; five or more CTCs per 7.5 mL of whole blood) are associated with poor prognosis in metastatic breast cancer (MBC). A randomized trial of patients with persistent increase in CTCs tested whether changing chemotherapy after one cycle of first-line chemotherapy would improve the primary outcome of overall survival (OS)., Patients and Methods: Patients with MBC who did not have increased CTCs at baseline remained on initial therapy until progression (arm A). Patients with initially increased CTCs that decreased after 21 days of therapy remained on initial therapy (arm B). Patients with persistently increased CTCs after 21 days of therapy were randomly assigned to continue initial therapy (arm C1) or change to an alternative chemotherapy (arm C2)., Results: Of 595 eligible and evaluable patients, 276 (46%) did not have increased CTCs (arm A). Of those with initially increased CTCs, 31 (10%) were not retested, 165 were assigned to arm B, and 123 were randomly assigned to arm C1 or C2. No difference in median OS was observed between arm C1 and C2 (10.7 and 12.5 months, respectively; P = .98). CTCs were strongly prognostic. Median OS for arms A, B, and C (C1 and C2 combined) were 35 months, 23 months, and 13 months, respectively (P < .001)., Conclusion: This study confirms the prognostic significance of CTCs in patients with MBC receiving first-line chemotherapy. For patients with persistently increased CTCs after 21 days of first-line chemotherapy, early switching to an alternate cytotoxic therapy was not effective in prolonging OS. For this population, there is a need for more effective treatment than standard chemotherapy., (© 2014 by American Society of Clinical Oncology.)

Purpose: We evaluated associations among comorbidity, toxicity, time to relapse (TTR), and overall survival (OS) in older women with early-stage breast cancer receiving adjuvant chemotherapy., Methods: Cancer and Leukemia Group B 49907 (Alliance) randomly assigned women ≥ 65 years old with stages I-III breast cancer to standard adjuvant chemotherapy or capecitabine. We reviewed data from 329 women who participated in the quality of life companion study CALGB 70103 and completed the Physical Health Subscale of the Older American Resources and Services Questionnaire. This questionnaire captures data on 14 comorbid conditions and the degree to which each interferes with daily activities. A comorbidity burden score was computed by multiplying the total number of conditions by each condition's level of interference with function. Outcomes were grade 3 to 5 toxicity, TTR, and OS. Logistic regression was used to evaluate associations between comorbidity and toxicity, and Cox proportional hazards models for TTR and survival., Results: Number of comorbidities ranged from 0 to 10 (median 2); the comorbidity burden score ranged from 0 to 25 (median 3). The most common conditions were arthritis (58%) and hypertension (55%). Comorbidity was associated with shorter OS, but not with toxicity or TTR. The hazard of death increased by 18% for each comorbidity (hazard ratio [HR] = 1.18, 95% CI = 1.06 to 1.33) after adjusting for age, tumor size, treatment, node and receptor status. Comorbidity burden score was similarly associated with OS (HR = 1.08; 95% CI, 1.03 to 1.14)., Conclusions: Among older women enrolled onto a clinical trial, comorbidity was associated with shorter OS, but not toxicity or relapse., (Copyright © 2014 by American Society of Clinical Oncology.)

PURPOSE: Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor-positive breast cancer has not been confirmed. PATIENTS AND METHODS: In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer-free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival. RESULTS: Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial. CONCLUSION: At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor-positive breast cancer.

PURPOSE: Predictive biomarkers to identify patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who may benefit from targeted therapy alone are required. We hypothesized that early measurements of tumor maximum standardized uptake value corrected for lean body mass (SULmax) on 18F-labeled fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) would predict pathologic complete response (pCR) to pertuzumab and trastuzumab (PT). PATIENTS AND METHODS: Patients with stage II or III, estrogen receptor-negative, HER2-positive breast cancer received four cycles of neoadjuvant PT. 18F-labeled fluorodeoxyglucose positron emission tomography-computed tomography was performed at baseline and 15 days after PT initiation (C1D15). Eighty evaluable patients were required to test the null hypothesis that the area under the curve of percent change in SULmax by C1D15 predicting pCR is ≤ 0.65, with a one-sided type I error rate of 10%. RESULTS: Eighty-eight women were enrolled (83 evaluable), and 85% (75 of 88) completed all four cycles of PT. pCR after PT alone was 22%. Receiver operator characteristic analysis of percent change in SULmax by C1D15 yielded an area under the curve of 0.72 (80% CI, 0.64 to 0.80; one-sided P = .12), which did not reject the null hypothesis. However, between patients who obtained pCR and who did not, a significant difference in median percent reduction in SULmax by C1D15 was observed (63.8% v 41.8%; P = .004) and SULmax reduction ≥ 40% was more prevalent (83% v 52%; P = .03; positive predictive value, 31%). Participants not obtaining a 40% reduction in SULmax by C1D15 were unlikely to obtain pCR (negative predictive value, 91%). CONCLUSION: Although the primary objective was not met, early changes in SULmax predict response to PT in estrogen receptor-negative and HER2-positive breast cancer. Once optimized, this quantitative imaging strategy may facilitate tailoring of therapy in this setting.

PurposePrimary endocrine therapy for ductal carcinoma in situ (DCIS) as a potential alternative to surgery has been understudied. This trial explored the feasibility of a short-term course of letrozole and sought to determine whether treatment results in measurable radiographic and biologic changes in estrogen receptor (ER)-positive DCIS.Patients and methodsA phase II single-arm multicenter cooperative-group trial was conducted in postmenopausal patients diagnosed with ER-positive DCIS without invasion. Patients were treated with letrozole 2.5 mg per day for 6 months before surgery. Breast magnetic resonance imaging (MRI) was obtained at baseline, 3 months, and 6 months. The primary end point was change in 6-month MRI enhancement volume compared with baseline.ResultsOverall, 79 patients were enrolled and 70 completed 6 months of letrozole. Of these, 67 patients had MRI data available for each timepoint. Baseline MRI volumes ranged from 0.004 to 26.3 cm3. Median reductions from baseline MRI volume (1.4 cm3) were 0.6 cm3 (61.0%) at 3 months (P < .001) and 0.8 cm3 (71.7%) at 6 months (P < .001). Consistent reductions were seen in median baseline ER H-score (228; median reduction, 15.0; P = .005), progesterone receptor H-score (15; median reduction, 85.0; P < .001), and Ki67 score (12%; median reduction, 6.3%; P = .007). Of the 59 patients who underwent surgery per study protocol, persistent DCIS remained in 50 patients (85%), invasive cancer was detected in six patients (10%), and no residual DCIS or invasive cancer was seen in nine patients (15%).ConclusionsIn a cohort of postmenopausal women with ER-positive DCIS, preoperative letrozole resulted in significant imaging and biomarker changes. These findings support future trials of extended endocrine therapy as primary nonoperative treatment of some DCIS.

Background: Hairy cell leukemia (HCL) is characterized by the underlying genetic lesion of BRAFV600E and responsiveness to BRAF inhibitors. We assessed the safety and activity of the BRAF inhibitor vemurafenib combined with obinutuzumab in patients with previously untreated HCL. Methods: We conducted a single-arm, multicenter clinical study of vemurafenib plus obinutuzumab. Vemurafenib 960 mg twice daily was administered for four cycles, and obinutuzumab was administered in cycles 2 to 4. The primary end point was complete remission (CR). Secondary end points included assessment of safety, minimal residual disease (MRD), and BRAF allele burden according to digital droplet polymerase chain reaction (ddPCR). Results: Thirty patients were enrolled in the study, and 27 patients completed all four cycles of treatments and achieved CR (90%; 95% confidence interval [CI], 73 to 98). Three patients discontinued the study early because of adverse events and were not evaluable for response. Of the 27 patients who achieved CR, 26 patients (96%; 95% CI, 81 to 99) achieved MRD negativity. BRAFV600E allele was undetectable by ddPCR in all 21 evaluable patients. At a median follow-up of 34.9 months (95% CI, 29.6 to 36.9), no patient experienced disease relapse. The most common vemurafenib-related adverse events were rash and arthralgia. Febrile neutropenia occurred in two patients, and blood or platelet transfusions were required in two patients. Conclusions: Combined time-limited vemurafenib and obinutuzumab achieved CR in more than 90% of patients with previously untreated HCL. In this small study, acquired vemurafenib resistance or dose-limiting toxicity was not observed. Patients were not observed long enough to reveal secondary malignancies. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03410875.) [ABSTRACT FROM AUTHOR]

Background: Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer.Methods: KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative [CPS <1]) and history of previous neoadjuvant or adjuvant treatment versus de-novo metastatic disease at initial diagnosis. Primary endpoints were overall survival in participants with a PD-L1 combined positive score (CPS) of 10 or more, those with a CPS of 1 or more, and all participants; superiority of pembrolizumab versus chemotherapy was tested in all participants only if shown in those with a CPS of one or more. The primary endpoint was analysed in the intention-to-treat population; safety was analysed in the all-subjects-as-treated population. This Article describes the final analysis of the trial, which is now completed. This trial is registered with ClinicalTrials.gov, number NCT02555657.Findings: From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up was 31·4 months (IQR 27·8-34·4) for the pembrolizumab group and 31·5 months (27·8-34·6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9-16·3) for the pembrolizumab group and 11·6 months (8·3-13·7) for the chemotherapy group (hazard ratio [HR] 0·78 [95% CI 0·57-1·06]; log-rank p=0·057). In participants with a CPS of 1 or more, median overall survival was 10·7 months (9·3-12·5) for the pembrolizumab group and 10·2 months (7·9-12·6) for the chemotherapy group (HR 0·86 [95% CI 0·69-1·06]; log-rank p=0·073). In the overall population, median overall survival was 9·9 months (95% CI 8·3-11·4) for the pembrolizumab group and 10·8 months (9·1-12·6) for the chemotherapy group (HR 0·97 [95% CI 0·82-1·15]). The most common grade 3-4 treatment-related adverse events were anaemia (three [1%] patients in the pembrolizumab group vs ten [3%] in the chemotherapy group), decreased white blood cells (one [<1%] vs 14 [5%]), decreased neutrophil count (one [<1%] vs 29 [10%]), and neutropenia (0 vs 39 [13%]). 61 (20%) patients in the pembrolizumab group and 58 (20%) patients in the chemotherapy group had serious adverse events. Three (<1%) of 601 participants had treatment-related adverse events that led to death (one [<1%] in the pembrolizumab group due to circulatory collapse; two [1%] in the chemotherapy group, one [<1%] due to pancytopenia and sepsis and one [<1%] haemothorax).Interpretation: Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer.Funding: Merck Sharp & Dohme. [ABSTRACT FROM AUTHOR]

Background Newly diagnosed multiple myeloma patients have many available treatment options. While lenalidomide, bortezomib, and dexamethasone (RVD) is the preferred initial treatment for many patients, several other agents may provide similar efficacy with less toxicity and improved ease of administration. Methods We evaluated the safety and efficacy of the all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone with the use of metronomic cyclophosphamide dosing in the treatment of patients with newly diagnosed multiple myeloma. Results The study was stopped prior to planned enrollment due to slow recruitment, with 12 patients available for final analysis. The overall response rate was 58.3% with 2 patients achieving a very good partial response (16.7%) and 5 patients achieving a partial response (41.7%). Median progression-free survival was 16 months, and median overall survival was 43 months. There were no episodes of grade 3 or greater peripheral neuropathy. Grade 3 or greater dermatologic toxicity was experienced in 50% of patients. Conclusion Although limited enrollment prevented full efficacy evaluation, our data do not support further study of metronomic cyclophosphamide in combination with ixazomib and dexamethasone in the treatment of newly diagnosed multiple myeloma. The activity of this regimen in the relapsed/refractory setting requires further study (ClinicalTrials.gov Identifier: NCT02412228). [ABSTRACT FROM AUTHOR]

Background: Published studies have suggested that most patients with early stage breast cancer are willing, for modest survival benefits, to receive 6 months of adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil, an older regimen that is used infrequently today. We examined preferences regarding the survival benefit needed to justify 6 months of a contemporary chemotherapy regimen.Methods: The Eastern Cooperative Oncology Group Protocol 5103 was a phase 3 trial that randomized breast cancer patients to receive standard adjuvant doxorubicin, cyclophosphamide, and paclitaxel with either bevacizumab or placebo. Serial surveys to assess quality of life were administered to patients enrolled between January 1, 2010, and June 8, 2010. Survival benefit needed to justify 6 months of chemotherapy by patients was collected at the 18-month assessment. A parallel survey was sent to physicians who had enrolled patients in the study.Results: Of 519 patients who had not withdrawn at a time point earlier than 18 months, 87.8% responded to this survey. A total of 175 physicians participated. We found considerable variation in patient preferences, particularly for modest survival benefits: for 2 months of benefit, 57% would consider 6 months of chemotherapy, whereas 96% of patients would consider 6 months of chemotherapy for 24 months. Race and education were associated with the choices. Physicians who responded were less likely to accept chemotherapy for modest benefit.Conclusions: Among patients who received contemporary adjuvant chemotherapy in a randomized controlled trial, we found substantial variation in preferences regarding benefits that justified undergoing chemotherapy. Differences between patients' and physicians' choices were also apparent. Eliciting preferences regarding risks and benefits of adjuvant chemotherapy is critical. Cancer 2017;123:2821-28. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Obesity at diagnosis is associated with poor prognosis in women with breast cancer, but few reports have been adjusted for treatment factors.Methods: CALGB 9741 was a randomized trial of dose density and sequence of chemotherapy for node-positive breast cancer. All patients received doxorubicin, cyclophosphamide, and paclitaxel, dosed by actual body weight. Height and weight at diagnosis were abstracted from patient records, and the PAM50 assay was performed from archived specimens using the NanoString platform. Relationships between body mass index (BMI), PAM50, and recurrence-free and overall survival (RFS and OS) were evaluated using proportional hazards regression, adjusting for number of involved nodes, estrogen receptor (ER) status, tumor size, menopausal status, drug sequence, and dose density. All statistical tests were two-sided.Results: Baseline height and weight were available for 1909 of 2005 enrolled patients; 1272 additionally had subtype determination by PAM50. Median baseline BMI was 27.4kg/m(2). After 11 years of median follow-up, there were 619 RFS events and 543 deaths. Baseline BMI was a statistically significant predictor of RFS (adjusted hazard ratio [HR] for each five-unit increase in BMI = 1.08, 95% confidence interval [CI] = 1.02 to 1.14, P = .01) and OS (adjusted HR = 1.08, 95% CI = 1.01 to 1.14, P = .02) BMI and molecular phenotypes were independent prognostic factors for RFS, with no statistically significant interactions detected.Conclusions: BMI at diagnosis was a statistically significant prognostic factor in a group of patients receiving optimally dosed chemotherapy. Additional research is needed to determine the impact of weight loss on breast cancer outcomes and to evaluate whether this impact is maintained across tumor subtypes. [ABSTRACT FROM AUTHOR]

A response by Jennifer A. Ligibel and colleagues to a letter to the editor about their article "Body Mass Index, PAM50 Subtype, and Outcomes in Node-Positive Breast Cancer: CALGB 9741," published in a previous issue is presented.

Purpose: Human epidermal growth factor receptor 2 (HER2)-directed therapy improves local control among women with HER2-positive breast cancer. This retrospective analysis evaluates the safety and efficacy of radiation therapy (RT) among patients receiving adjuvant trastuzumab emtansine (T-DM1) or paclitaxel (T) plus trastuzumab (H) in the ATEMPT (Adjuvant Trastuzumab Emtansine Versus Paclitaxel in Combination With Trastuzumab) trial; Translational Breast Cancer Research Consortium (TBCRC) 033.Methods and Materials: Patients with stage I HER2-positive breast cancer were randomized 3:1 to receive adjuvant T-DM1 or TH after mastectomy or breast-conserving surgery (BCS). Breast RT was required after BCS and permitted after mastectomy. Patients receiving T-DM1 began RT after 12 weeks of therapy and received RT concurrently with T-DM1. Patients receiving TH began RT after paclitaxel, but concurrent with trastuzumab. RT records were retrospectively reviewed to determine details of radiation delivery and acute RT-related toxicity.Results: Protocol therapy was initiated by 497 patients. Among the 299 BCS patients, 289 received whole breast RT (WBRT) and 10 partial breast. Among WBRT patients, 40.2% in the T-DM1 arm and 41.5% of TH patients received hypofractionated (≥2.5 Gy/fraction) RT. Eight mastectomy patients received RT, all conventional fractionation. Skin toxicity (grade ≥2) was seen in 33.9% of patients in the T-DM1 arm and 23.2% in the TH arm (P = .11). In conventionally fractionated WBRT patients, 44.7% had a grade ≥2 skin toxicity compared with 17.9% of patients receiving hypofractionation (P < .001). Five patients experienced pneumonitis after RT (T-DM1: n = 4, 1.0%; TH: n = 1, 0.9%). Three-year invasive disease-free survival was 97.8% for T-DM1 (95% confidence interval, 96.3-99.3) and 93.4% for TH (95% confidence interval, 88.7-98.2). Among the 18 invasive disease-free survival events, 7 were isolated locoregional recurrences (2, T-DM1; 5, TH).Conclusions: RT was well-tolerated when given concurrently with either T-DM1 or TH. Among BCS patients, hypofractionation resulted in lower grade ≥2 acute skin toxicity even with concurrent anti-HER2 therapy. Although follow-up was short, local recurrences were uncommon, attesting to the efficacy of HER2-directed therapy combined with RT. [ABSTRACT FROM AUTHOR]

Background: In a previous analysis of this phase 3 trial, first-line ribociclib plus letrozole resulted in significantly longer progression-free survival than letrozole alone among postmenopausal patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether overall survival would also be longer with ribociclib was not known.Methods: Here we report the results of the protocol-specified final analysis of overall survival, a key secondary end point. Patients were randomly assigned in a 1:1 ratio to receive either ribociclib or placebo in combination with letrozole. Overall survival was assessed with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods after 400 deaths had occurred. A hierarchical testing strategy was used for the analysis of progression-free survival and overall survival to ensure the validity of the findings.Results: After a median follow-up of 6.6 years, 181 deaths had occurred among 334 patients (54.2%) in the ribociclib group and 219 among 334 (65.6%) in the placebo group. Ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole. Median overall survival was 63.9 months (95% confidence interval [CI], 52.4 to 71.0) with ribociclib plus letrozole and 51.4 months (95% CI, 47.2 to 59.7) with placebo plus letrozole (hazard ratio for death, 0.76; 95% CI, 0.63 to 0.93; two-sided P = 0.008). No new safety signals were observed.Conclusions: First-line therapy with ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole in patients with HR-positive, HER2-negative advanced breast cancer. Median overall survival was more than 12 months longer with ribociclib than with placebo. (Funded by Novartis; MONALEESA-2 ClinicalTrials.gov number, NCT01958021.). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]