Citations

Abstract Background: Late recurrence of breast cancer after 5 years accounts for about 50% of recurrences in hormone receptor (HR)-positive early breast cancer (EBC). TAILORx established non-inferiority of adjuvant endocrine therapy (ET) given for at least 5 years to chemotherapy plus ET (CET) in EBC and a 21-gene recurrence score (RS) of 11-25, although there was some chemotherapy benefit in women Methods: Eligibility criteria included women 18-75 years with HR-positive, HER2-negative, T1b-T2N0 EBC who agreed to have CT assigned or randomized based on the RS assay. The primary endpoint was invasive disease-free survival (iDFS) in the RS 11-25 group. The “primary analysis” refers to the original prespecified analysis for the primary IDFS endpoint (836 IDFS events at full information in the RS 11-25 group) after a median of 7.5 years. The “updated analysis” was performed after a median followup of 11.0 and 10.4 years in the randomized and overall populations, respectively. Results:10,253 eligible women enrolled between 4/7/06-10/6/10.The updated analysis includes substantially more events that the primary analysis, including IDFS events (1819 vs. 1210), distant recurrences (561 vs. 384), locoregional +/- distant recurrences (764 vs. 543), and deaths (910 vs. 499). The table provides 5 and 12-year event rates (and standard errors) for all arms, and comparisons of the randomized arms. The primary trial conclusions remain unchanged: ET was non-inferior to CET in the randomized group with a RS 11-25. Although recurrence occurred in < 10% by 12 years for a RS 0-25, late recurrence events beyond 5 years exceeded earlier recurrence. Non-recurrence events occurred in about 13% at 12 years (~1%/year), contributing substantially to the IDFS rates. For women Conclusions: The current updated analysis confirms findings from the original primary analysis that ET is non-inferior to CET in HR-positive, HER2-negative, node-negative EBC and a RS 11-25. As in the original primary analysis, the subgroup of women Citation Format: Joseph Sparano, Robert J. Gray, Della Makower, Kathy S. Albain, Daniel F. Hayes, Charles Geyer, Elizabeth Dees, Matthew P. Goetz, John A. Olson Jr, Tracy G. Lively, Sunil Badve, Thomas Saphner, Lynne I. Wagner, Timothy Whelan, Virginia Kaklamani, George Sledge. Trial Assigning Individualized Options for Treatment (TAILORx): An Update Including 12-Year Event Rates [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-05.

Abstract BACKGROUND: Abnormalities of the PI3kinase/AKT/mTOR signaling network are common in breast cancer (BC) and are associated with endocrine resistance. Everolimus, an mTOR-inhibitor increased PFS when combined with endocrine therapy (ET) in the metastatic setting and is thought to revert endocrine resistance. S1207 is a phase III randomized, placebo-controlled trial evaluating the role of everolimus in combination with ET in the adjuvant setting among patients with high-risk hormone receptor-positive, HER2-negative BC (NCT01674140). METHODS: Eligible patients were >18 years of age with histologically confirmed invasive hormone receptor-positive and HER2-negative high-risk BC. Four risk groups were defined as: 1) > 2cm node-negative disease (or pN1mi), and either an Oncotype DX® Recurrence Score (RS) > 25 or MammaPrint® high-risk category (MP high); 2) 1-3 positive nodes and either RS >25, MP high or a pathological grade 3 tumor; 3) >4 positive lymph nodes. Patients treated with neoadjuvant chemotherapy were eligible if: 4) after surgery had >1 lymph node involvement. Patients were randomized 1:1 to physician’s choice adjuvant ET in combination with one year of everolimus (10 mg PO daily) or ET plus placebo stratified by risk group. The primary endpoint was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test. Secondary endpoints included overall survival (OS) and safety. The hazard ratio (HR) for treatment efficacy was estimated using Cox regression with stratification by risk groups. Subset analyses included preplanned evaluation within risk group and exploratory analyses of menopausal status and age. RESULTS: 1,939 patients were randomized between September 2013 and May 2019, of them 1,792 were eligible and included in the analysis (896 per arm). Primary reason for ineligibility was timing after chemotherapy/radiation or not high risk. Median age was 54 years (22-85) and 32% were premenopausal. With a median follow-up of 50.5 months, there were 389 IDFS events as of May 2022 (data cutoff). 5-year IDFS was 74.8% among patients treated with everolimus and 73.9% among patients treated with placebo, HR=0.93 (95% CI 0.76-1.14). However, the proportional hazards assumption was violated (p=0.02) suggesting differential treatment effect over time. The HR during the one year of treatment was 0.72 (95% CI 0.47-1.10) while after one year it was 1.00 (95% CI 0.80-1.26). The 5-year OS was 87.6% in the everolimus arm and 85.5% in the placebo arm, HR=0.98 (95% CI 0.75-1.28). Analysis by risk group did not show higher everolimus benefit as risk increased. No difference in IDFS or OS was seen among postmenopausal patients (IDFS HR=1.08 [95% CI 0.85-1.36], OS HR=1.19 [95% CI 0.87-1.61]). Among premenopausal patients, everolimus was associated with improved IDFS (HR=0.63 [95% CI 0.43-0.93]) and OS (HR=0.48 [95% CI 0.26-0.88]). Treatment completion of randomized therapy was lower in the everolimus arm compared to placebo (47.9% v 72.7%). Grade 3 and 4 toxicities were noted in 6.5% and 0.5% of patients in the placebo arm and in 31.2% and 3.7% in the everolimus arm respectively. CONCLUSIONS: Addition of one year of adjuvant everolimus to standard adjuvant ET did not improve IDFS or OS and was associated with low completion rate and increased AEs. Among premenopausal patients there was a benefit in IDFS and OS that is hypothesis generating. Future translational studies will evaluate potential predictors of everolimus benefit and drug toxicity. Citation Format: Marianna Chavez, Jieling Miao, Lajos Pusztai, Matthew P. Goetz, Priya Rastogi, Patricia A. Ganz, Eleftherios (Terry) Mamounas, Soonmyung Paik, Hanna Bandos, Wajeeha Razaq, Anne O’Dea, Virginia Kaklamani, Andrea L.M. Silber, Lisa E. Flaum, Eleni Andreopolu, Joseph Baar, Albert G. Wendt, Jennifer F. Carney, Priyanka Sharma, Julie R. Gralow, Danika L. Lew, William E. Barlow, Gabriel N. Hortobagyi. Results from a phase III randomized, placebo-controlled clinical trial evaluating adjuvant endocrine therapy +/- 1 year of everolimus in patients with high-risk hormone receptor-positive, HER2-negative breast cancer: SWOG S1207 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-07.

ImportanceAnthracyclines increase the risk for congestive heart failure (CHF); however, long-term cumulative incidence and risk factors for CHF after anthracycline therapy are not well defined in population-based studies.ObjectiveTo compare the long-term cumulative incidence of CHF in patients with breast cancer or lymphoma treated with anthracycline therapy compared with healthy controls from the same community.Design, Setting, and ParticipantsThis retrospective population-based case-control study included data from the Rochester Epidemiology Project. Participants included residents of Olmsted County, Minnesota, diagnosed with breast cancer or lymphoma from January 1985 through December 2010 matched for age, sex, and comorbidities with healthy controls, with a final ratio of 1 case to 1.5 controls. Statistical analysis was performed between July 2017 and February 2022.ExposuresCancer treatment and CHF risk factors.Main Outcomes and MeasuresThe main outcome was new-onset CHF, as defined by the modified Framingham criteria. Cox proportional hazards regression was used to estimate hazard ratios (HRs) to compare the risk of CHF in participants with cancer vs controls, adjusted for age, sex, diabetes, hypertension, hyperlipidemia, coronary artery disease, obesity, and smoking history.ResultsA total of 2196 individuals were included, with 812 patients with cancer and 1384 participants without cancer. The mean (SD) age was 52.62 (14.56) years and 1704 participants (78%) were female. Median (IQR) follow-up was 8.6 (5.2-13.4) years in the case group vs 12.5 (8.7-17.5) years in the control group. Overall, patients with cancer had higher risk of CHF compared with the control cohort even after adjusting for age, sex, diabetes, hypertension, coronary artery disease, hyperlipidemia, obesity, and smoking status (HR, 2.86 [95% CI, 1.90-4.32]; P < .001). After adjusting for the same variables, CHF risk was greater for patients with cancer receiving anthracycline (HR, 3.25 [95% CI, 2.11-5.00]; P < .001) and was attenuated and lost statistical significance for patients with cancer not receiving anthracyclines (HR, 1.78 [95% CI, 0.83-3.81]; P = .14). Higher cumulative incidence for patients treated with anthracyclines vs comparator cohort was observed at 1 year (1.81% vs 0.09%), 5 years (2.91% vs 0.79%), 10 years (5.36% vs 1.74%), 15 years (7.42% vs 3.18%), and 20 years (10.75% vs 4.98%) (P < .001). There were no significant differences in risk of CHF for patients receiving anthracycline at a dose of less than 180 mg/m2 compared with those at a dose of 180 to 250 mg/m2 (HR, 0.54 [95% CI, 0.19-1.51]) or at a dose of more than 250 mg/m2 (HR, 1.23 [95% CI, 0.52-2.91]). At diagnosis, age was an independent risk factor associated with CHF (HR per 10 years, 2.77 [95% CI, 1.99-3.86]; P < .001).Conclusions and RelevanceIn this retrospective population-based case-control study, anthracyclines were associated with an increased risk of CHF early during follow-up, and the increased risk persisted over time. The cumulative incidence of CHF in patients with breast cancer or lymphoma treated with anthracyclines at 15 years was more than 2-fold that of the control group.

Background: Abemaciclib is the first and only cyclin-dependent kinases 4 and 6 inhibitor approved for adjuvant treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), node-positive, and high-risk early breast cancer (EBC), with indications varying by geography. Premenopausal patients with HR+, HER2− tumors may have different tumor biology and treatment response compared to postmenopausal patients. Objectives: We describe the efficacy and safety of abemaciclib plus endocrine therapy (ET) for the large subgroup of premenopausal patients with HR+, HER2− EBC in monarchE. Design: Randomized patients (1:1) received adjuvant ET with or without abemaciclib for 2 years plus at least 3 additional years of ET as clinically indicated. Methods: Patients were stratified by menopausal status (premenopausal versus postmenopausal) at diagnosis. Standard ET (tamoxifen or aromatase inhibitor) with or without gonadotropin-releasing hormone agonist was determined by physician’s choice. Invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) by menopausal status were assessed at data cutoff on 1 April 2021 (median follow-up of 27 months). Results: Among randomized patients, 2451 (43.5%) were premenopausal and 3181 (56.4%) were postmenopausal. The choice of ET for premenopausal patients varied considerably between countries. Treatment benefit was consistent across menopausal status, with a numerically greater effect size in premenopausal patients. For premenopausal patients, abemaciclib with ET resulted in a 42.2% and 40.3% reduction in the risk of developing IDFS and DRFS events, respectively. Absolute improvement at 3 years was 5.7% for IDFS and 4.4% for DRFS rates. Safety profile for premenopausal patients was consistent with the overall safety population. Conclusion: Abemaciclib with ET demonstrated clinically meaningful treatment benefit for IDFS and DRFS versus ET alone regardless of menopausal status and first ET, with a numerically greater benefit in the premenopausal compared to the postmenopausal population. Safety data in premenopausal patients are consistent with the overall safety profile of abemaciclib.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The combined analysis of SOFT-TEXT compared outcomes in 4,690 premenopausal women with estrogen/progesterone receptor–positive (ER/PgR+) early breast cancer randomly assigned to 5 years of exemestane + ovarian function suppression (OFS) versus tamoxifen + OFS. After a median follow-up of 9 years, exemestane + OFS significantly improved disease-free survival (DFS) and distant recurrence-free interval (DRFI), but not overall survival, compared with tamoxifen + OFS. We now report DFS, DRFI, and overall survival after a median follow-up of 13 years. In the intention-to-treat (ITT) population, the 12-year DFS (4.6% absolute improvement, hazard ratio [HR], 0.79; 95% CI, 0.70 to 0.90; P < .001) and DRFI (1.8% absolute improvement, HR, 0.83; 95% CI, 0.70 to 0.98; P = .03), but not overall survival (90.1% v 89.1%, HR, 0.93; 95% CI, 0.78 to 1.11), continued to be significantly improved for patients assigned exemestane + OFS over tamoxifen + OFS. Among patients with human epidermal growth factor receptor 2-negative tumors (86.0% of the ITT population), the absolute improvement in 12-year overall survival with exemestane + OFS was 2.0% (HR, 0.85; 95% CI, 0.70 to 1.04) and 3.3% in those who received chemotherapy (45.9% of the ITT population). Overall survival benefit was clinically significant in high-risk patients, eg, women age < 35 years (4.0%) and those with > 2 cm (4.5%) or grade 3 tumors (5.5%). These sustained reductions of the risk of recurrence with adjuvant exemestane + OFS, compared with tamoxifen + OFS, provide guidance for selecting patients for whom exemestane should be preferred over tamoxifen in the setting of OFS. [Media: see text]

Abstract Androgen receptor (AR) is expressed in 80% to 90% of estrogen receptor α–positive (ER+) breast cancers. Accumulated evidence has shown that AR is a tumor suppressor and that its expression is associated with improved prognosis in ER+ breast cancer. However, both a selective AR agonist (RAD140) and an AR inhibitor (enzalutamide, ENZ) have shown a therapeutic effect on ER+ breast cancer, so the potential for clinical application of AR-targeting therapy for ER+ breast cancer is still in dispute. In this study, we evaluated the efficacy of ENZ and RAD140 in vivo and in vitro in AR+/ER+ breast cancer models, characterizing the relationship of AR and ER levels to response to AR-targeting drugs and investigating the alterations of global gene expression and chromatin binding of AR and ERα after ENZ treatment. In the AR-low setting, ENZ directly functioned as an ERα antagonist. Cell growth inhibition by ENZ in breast cancer with low AR expression was independent of AR and instead dependent on ER. In AR-high breast cancer models, AR repressed ERα signaling and ENZ promoted ERα signaling by antagonizing AR. In contrast, RAD140 activated AR signaling and suppressed AR-high tumor growth by deregulating ERα expression and blocking ERα function. Overall, analysis of the dynamic efficacies and outcomes of AR agonist, and antagonist in the presence of different AR and ERα levels reveals regulators of response and supports the clinical investigation of ENZ in selected ER+ tumors with a low AR/ER ratio and AR agonists in tumors with a high AR/ER ratio. Significance: The ratio of androgen receptor to estrogen receptor in breast cancer dictates the response to AR-targeted therapies, providing guidelines for developing AR-directed treatment strategies for patients with breast cancer.

Neoadjuvant chemotherapy (NAC) remains the cornerstone of the treatment for triple negative breast cancer (TNBC), with the goal of complete eradication of disease. However, for patients with residual disease after NAC, recurrence and mortality rates are high and the identification of novel therapeutic targets is urgently needed. We quantified tyrosine phosphorylation (pTyr)-mediated signaling networks in chemotherapy sensitive (CS) and resistant (CR) TNBC patient-derived xenografts (PDX), to gain novel therapeutic insights. The antitumor activity of SFK inhibition was examined in vivo. Treated tumors were further subjected to phosphoproteomic and RNAseq analysis, to identify the mechanism of actions of the drug. We identified Src Family Kinases (SFKs) as potential therapeutic targets in CR TNBC PDXs. Treatment with dasatinib, an FDA approved SFK inhibitor, led to inhibition of tumor growth in vivo. Further analysis of post-treatment PDXs revealed multiple mechanisms of actions of the drug, confirming the multi-target inhibition of dasatinib. Analysis of pTyr in tumor specimens suggested a low prevalence of SFK-driven tumors, which may provide insight into prior clinical trial results demonstrating a lack of dasatinib antitumor activity in unselected breast cancer patients. Taken together, these results underscore the importance of pTyr characterization of tumors, in identifying new targets, as well as stratifying patients based on their activated signaling networks for therapeutic options. Our data provide a strong rationale for studying SFK inhibitors in biomarker-selected SFK-driven TNBC.

AbstractBackground:Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Patients with TNBC are primarily treated with neoadjuvant chemotherapy (NAC). Response to NAC is prognostic, with reductions in low overall survival and disease-free survival rates in those patients who do not achieve pathological complete response (pCR). Based on this premise, we focused on patients with residual disease and hypothesized that paired analysis of primary and residual TNBC tumors following NAC could identify unique biomarkers associated with post-NAC recurrence.Methods and Results: We investigated 24 TNBC tumors from 12 patients with pre- and post-NAC data, including four patients who recurred shortly after surgery(<24 months) and eight who remained recurrence-free (> 48 months). These tumors were collected from a prospective NAC breast cancer study (BEAUTY) conducted at the Mayo Clinic. Differential expression analysis of pre-NAC biopsies showed minimal gene expression differences between early recurrent and non-recurrent TNBC tumors; however, post-NAC samples demonstrated a significant alteration in expression patterns in response to intervention. Topological-level differences associated with early recurrence were implicated in 251 gene sets, and an independent assessment of microarray gene expression data from the paired NAC I-SPY1 trial confirmed 56 genesets. Underlying these 56 gene sets, 113 genes were observed to be differentially expressed in the I-SPY1 and BEAUTY post-NAC studies. An independent (n=392) breast cancer data set with relapse-free survival (RFS) data was used to refine our gene list to a 17 gene signature. A three-fold cross-validation analysis of the gene signature with the combined BEAUTY and I-SPY1 data yielded an average AUC of 0.88 for six machine learning models. Due to the limited studies with pre-and post-NAC TNBC tumor data, further validation of the signature is needed.Conclusion:Analysis of multi-omics data from post-NAC TNBC chemoresistant tumors showed downregulation of mismatch repair, purin, and tubulin pathways. Additionally, weidentified a 17 gene signature in TNBC associated with post-NAC recurrence enriched with down-regulation of immune genes.

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. These NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of ductal carcinoma in situ and the workup and locoregional management of early stage invasive breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org .

Abstract Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with low overall survival rates and high molecular heterogeneity; therefore, few targeted therapies are available. The luminal androgen receptor (LAR) is the most consistently identified TNBC subtype, but the clinical utility has yet to be established. Here, we constructed a novel genomic classifier, LAR-Sig, that distinguishes the LAR subtype from other TNBC subtypes and provide evidence that it is a clinically distinct disease. A meta-analysis of seven TNBC datasets (n = 1086 samples) from neoadjuvant clinical trials demonstrated that LAR patients have significantly reduced response (pCR) rates than non-LAR TNBC patients (odds ratio = 2.11, 95% CI: 1.33, 2.89). Moreover, deconvolution of the tumor microenvironment confirmed an enrichment of luminal epithelium corresponding with a decrease in basal and myoepithelium in LAR TNBC tumors. Increased immunosuppression in LAR patients may lead to a decreased presence of cycling T-cells and plasma cells. While, an increased presence of myofibroblast-like cancer-associated cells may impede drug delivery and treatment. In summary, the lower levels of tumor infiltrating lymphocytes (TILs), reduced immune activity in the micro-environment, and lower pCR rates after NAC, suggest that new therapeutic strategies for the LAR TNBC subtype need to be developed.