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Background Breast cancer mortality in women has declined statistically significantly over the past several years. In men, it is unclear whether survival has changed over time. We evaluated changes in breast cancer–specific survival (BCSS) and overall survival (OS) in male breast cancer over the past 3 decades. Methods We evaluated men diagnosed with breast cancer between 1988 and 2017, reported in the Surveillance, Epidemiology, and End Results registry. Patients were categorized into 3 groups by year of diagnosis: 1988-1997, 1998-2007, and 2008-2017. BCSS and OS were estimated by Kaplan-Meier, and differences between groups were compared by log-rank test. Multivariable Cox regression evaluated the independent association of year of diagnosis with BCSS and OS. All tests were 2-sided. Results We included 8481 men. Overall, BCSS at 5 years was 83.69%, 83.78%, and 84.41% in groups 1988-1997, 1998-2007, and 2008-2017, respectively (P = .86). There was no statistically significant difference in BCSS between the 3 groups within each stage of disease. Among all patients, OS at 5 years was 64.61%, 67.31%, and 69.05% in groups 1988-1997, 1998-2007, and 2008-2017, respectively (P = .01). In adjusted Cox models, each additional year of diagnosis had no statistically significant association with BCSS (hazard ratio = 1.00, 95% confidence interval = 0.99 to 1.01, P = .75), but there was statistically significant improvement in OS (hazard ratio = 0.99, 95% CI = 0.98 to 0.99, P = .009). Conclusions Over the past 3 decades, there has been no statistically significant improvement in BCSS in male breast cancer. Changes in OS over time are consistent with increasing life expectancy. Efforts to improve BCSS in male breast cancer are warranted.

Purpose: Sensitivity to endocrine therapy (ET) is critical for the clinical benefit from the combination of palbociclib plus ET in hormone receptor–positive/HER2-negative (HR+/HER2−) advanced breast cancer. Bazedoxifene is a third-generation selective estrogen receptor (ER) modulator and selective ER degrader with activity in preclinical models of endocrine-resistant breast cancer, including models harboring ESR1 mutations. Clinical trials in healthy women showed that bazedoxifene is well tolerated. Patients and Methods: We conducted a phase Ib/II study of bazedoxifene plus palbociclib in patients with HR+/HER2− advanced breast cancer who progressed on prior ET (N = 36; NCT02448771). Results: The study met its primary endpoint, with a clinical benefit rate of 33.3%, and the safety profile was consistent with what has previously been seen with palbociclib monotherapy. The median progression-free survival (PFS) was 3.6 months [95% confidence interval (CI), 2.0–7.2]. An activating PIK3CA mutation at baseline was associated with a shorter PFS (HR = 4.4; 95% CI, 1.5–13; P = 0.0026), but activating ESR1 mutations did not impact the PFS. Longitudinal plasma circulating tumor DNA whole-exome sequencing (WES; N = 68 plasma samples) provided an overview of the tumor heterogeneity and the subclonal genetic evolution, and identified actionable mutations acquired during treatment. Conclusions: The combination of palbociclib and bazedoxifene has clinical efficacy and an acceptable safety profile in a heavily pretreated patient population with advanced HR+/HER2− breast cancer. These results merit continued investigation of bazedoxifene in breast cancer.

Purpose: Brain metastases can occur in up to 50% of patients with metastatic HER2-positive breast cancer. Because patients with active brain metastases were excluded from previous pivotal clinical trials, the central nervous system (CNS) activity of the antibody–drug conjugate trastuzumab deruxtecan (T-DXd) is not well characterized. Experimental Design: We studied how T-DXd affects growth and overall survival in orthotopic patient-derived xenografts (PDX) of HER2-positive and HER2-low breast cancer brain metastases (BCBM). Separately, we evaluated the effects of T-DXd in a retrospective cohort study of 17 patients with stable or active brain metastases. Results: T-DXd inhibited tumor growth and prolonged survival in orthotopic PDX models of HER2-positive (IHC 3+) and HER2-low (IHC 2+/FISH ratio < 2) BCBMs. T-DXd reduced tumor size and prolonged survival in a T-DM1–resistant HER2-positive BCBM PDX model. In a retrospective multi-institutional cohort study of 17 patients with predominantly HER2-positive BCBMs, the CNS objective response rate (ORR) was 73% (11/15) while extracranial response rate was 45% (5/11). In the subset of patients with untreated or progressive BCBM at baseline, the CNS ORR was 70% (7/10). The median time on treatment with T-DXd was 8.9 (1.3–16.2) months, with 42% (7/17) remaining on treatment at data cutoff. Conclusions: T-DXd demonstrates evidence of CNS activity in HER2-positive and HER2-low PDX models of BCBM and preliminary evidence of clinical efficacy in a multi-institution case series of patients with BCBM. Prospective clinical trials to further evaluate CNS activity of T-DXd in patients with active brain metastases are warranted. See related commentary by Soffietti and Pellerino, p. 8

Most invasive lobular breast cancers (ILC) are of the luminal A subtype and are strongly hormone receptor–positive. Yet, ILC is relatively resistant to tamoxifen and associated with inferior long-term outcomes compared with invasive ductal cancers (IDC). In this study, we sought to gain mechanistic insights into these clinical findings that are not explained by the genetic landscape of ILC and to identify strategies to improve patient outcomes. A comprehensive analysis of the epigenome of ILC in preclinical models and clinical samples showed that, compared with IDC, ILC harbored a distinct chromatin state linked to gained recruitment of FOXA1, a lineage-defining pioneer transcription factor. This resulted in an ILC-unique FOXA1–estrogen receptor (ER) axis that promoted the transcription of genes associated with tumor progression and poor outcomes. The ILC-unique FOXA1–ER axis led to retained ER chromatin binding after tamoxifen treatment, which facilitated tamoxifen resistance while remaining strongly dependent on ER signaling. Mechanistically, gained FOXA1 binding was associated with the autoinduction of FOXA1 in ILC through an ILC-unique FOXA1 binding site. Targeted silencing of this regulatory site resulted in the disruption of the feed-forward loop and growth inhibition in ILC. In summary, ILC is characterized by a unique chromatin state and FOXA1–ER axis that is associated with tumor progression, offering a novel mechanism of tamoxifen resistance. These results underscore the importance of conducting clinical trials dedicated to patients with ILC in order to optimize treatments in this breast cancer subtype. Significance: A unique FOXA1–ER axis in invasive lobular breast cancer promotes disease progression and tamoxifen resistance, highlighting a potential therapeutic avenue for clinical investigations dedicated to this disease. See related commentary by Blawski and Toska, p. 3668

Extended adjuvant endocrine therapy (eET) improves outcomes in breast cancer survivors. Most studies however have been limited to postmenopausal women, and optimal eET for young survivors is uncertain. We report eET use among participants in the Young Women’s Breast Cancer Study (YWS), a multicenter prospective cohort of women age ≤40 newly diagnosed with breast cancer enrolled between 2006–2016. Women with stage I–III hormone receptor-positive breast cancer, ≥6 years from diagnosis without recurrence were considered eET candidates. Use of eET was elicited from annual surveys sent years 6–8 after diagnosis, censoring for recurrence/death. 663 women were identified as eET candidates with 73.9% (490/663) having surveys eligible for analysis. Among eligible participants, mean age was 35.5 (±3.9), 85.9% were non-Hispanic white, and 59.6% reported eET use. Tamoxifen monotherapy was the most reported eET (77.4%), followed by aromatase inhibitor (AI) monotherapy (21.9%), AI-ovarian function suppression (AI-OFS) (6.8%) and tamoxifen-OFS (3.1%). In multivariable analysis, increasing age (per year odds ratio [OR]: 1.10, 95% confidence interval [CI]: 1.04–1.16), stage (II v. I: OR: 2.86, 95% CI: 1.81–4.51; III v. I: OR: 3.73, 95%CI: 1.87–7.44) and receipt of chemotherapy (OR: 3.66, 95% CI: 2.16–6.21) were significantly associated with eET use. Many young breast cancer survivors receive eET despite limited data regarding utility in this population. While some factors associated with eET use reflect appropriate risk-based care, potential sociodemographic disparities in uptake warrants further investigation in more diverse populations.

Figure S9

Observational studies report that physical activity and metformin are associated with improved clinical outcome in patients with cancer. Inflammation is one biological mechanism hypothesized to mediate these associations. In this phase II, multicenter, 2 × 2 factorial trial, 139 patients with breast and colorectal cancer who completed standard therapy were randomized to one of four treatment groups for 12 weeks: exercise alone, metformin alone, exercise and metformin, or control. Inflammation outcomes included high-sensitivity C-reactive protein (hs-CRP), soluble tumor necrosis factor alpha receptor two (sTNFαR2), and IL6. The primary modeling strategy evaluated the trial product estimand that was quantified using a generalized linear mixed model. Compared with control, exercise alone reduced hs-CRP [−30.2%; 95% confidence interval (CI), −50.3, −1.0] and IL6 (−30.9%; 95% CI, −47.3, −9.5) but did not change sTNFαR2 (1.0%; 95% CI, −10.4, 13.9). Compared with control, metformin alone did not change hs-CRP (−13.9%; 95% CI, −40.0, 23.4), sTNFαR2 (−10.4%; 95% CI, −21.3, 2.0), or IL6 (−22.9%; 95% CI, −42.3, 2.0). Compared with control, exercise and metformin reduced sTNFαR2 (−13.1%; 95% CI, −22.9, −1.0) and IL6 (−38.7%; 95% CI, −52.3, −18.9) but did not change hs-CRP (−20.5%; 95% CI, −44.0, 12.7). The combination of exercise and metformin was not synergistic for hs-CRP, sTNFαR2, or IL6. In survivors of breast and colorectal cancer with low baseline physical activity and without type 2 diabetes, exercise and metformin reduced measures of inflammation that are associated with cancer recurrence and mortality.

Pattern of HER2 amplification in the subset of HER2 heterogeneous tumors. Heatmap generated using data from central pathology evaluation of HER2 heterogeneity. The graphic includes patients classified as HER2 heterogeneous depicted in each row. The color code to the right of the heatmap refers to the percentage of HER2 amplified cells per core biopsy tumor area. Core biopsy tumor areas, A, B and C were obtained from core biopsy site 1 and D, E and F from core biopsy site 2.

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

FISH raw counts

Figure S8

Summary of clinically informative (TARGET) genes.

Figure S5

Figure S4

Supplementary Methods, Figures S1 - S20. Figure S1. Branched evolution leads to tissue-sampling bias in primary tumor samples. Figure S2. Results of ABSOLUTE on samples from patient 418. Figure S3. 2D Bayesian clustering analysis of point-mutation CCF distributions in case 418. Figure S4. Bayesian clustering of private point-mutation CCF distributions in all sequenced tissue samples from case 418. Figure S5. Genetic alterations supporting phylogeny construction in case 418. Figure S6. Phylogenetic tree for case 418 Figure S7. Evolutionary relationships between primary tumor-samples and brain metastasis samples Figure S8. Detection of homozygous deletion in CDKN2A in the brain metastasis of case 24. Figure S9. Amplification of FGFR1 and MYC detected in the brain metastasis of case 331. Figure S10. Additional alterations under investigation for association with various targeted therapies. Figure S11. Power for paired-detection of somatic mutations. Figure S12. Amplification of CCNE1 detected in the brain metastasis of case 314. Figure S13. Amplification of EGFR detected in the brain metastasis of case 314. Figure S14. Amplification of MYC detected in the brain metastasis of case 308. Figure S15. Amplification of MYC detected in the brain metastasis of case 138. Figure S16. Amplifications of CDK6 and MET detected in the brain metastasis of case 138. Figure S17. Amplifications of CCNE1 and AKT2 detected in the brain metastasis of case 138. Figure S18. Amplification of EGFR detected in a regional lymph node from case 296. Figure S19. Power for somatic mutation detection in 86 matched primary-tumor and brain-metastasis samples. Figure S20. Calling of amplifications in primary-tumor samples and paired brain metastases.

Supplemental Table 1

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Supplemental Table 2

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Supplemental Table 5

Supplemental Table 7

Supplemental Table 4

Supplementary File 1. Power for detection of somatic point mutations in coding exons of TARGET genes. The description for the plots in Supplementary File 1 can be found in the Legend of Supplementary Figure S1.

Intratumor heterogeneity is postulated to cause therapeutic resistance. To prospectively assess the impact of HER2 (ERBB2) heterogeneity on response to HER2-targeted therapy, we treated 164 patients with centrally confirmed HER2-positive early-stage breast cancer with neoadjuvant trastuzumab emtansine plus pertuzumab. HER2 heterogeneity was assessed on pretreatment biopsies from two locations of each tumor. HER2 heterogeneity, defined as an area with ERBB2 amplification in >5% but P < 0.0001, adjusted for hormone receptor status). Single-cell ERBB2 FISH analysis of cellular heterogeneity identified the fraction of ERBB2 nonamplified cells as a driver of therapeutic resistance. These data suggest HER2 heterogeneity is associated with resistance to HER2-targeted therapy and should be considered in efforts to optimize treatment strategies.Significance:HER2-targeted therapies improve cure rates in HER2-positive breast cancer, suggesting chemotherapy can be avoided in a subset of patients. We show that HER2 heterogeneity, particularly the fraction of ERBB2 nonamplified cancer cells, is a strong predictor of resistance to HER2 therapies and could potentially be used to optimize treatment selection.See related commentary by Okines and Turner, p. 2369.This article is highlighted in the In This Issue feature, p. 2355

Supplementary Tables 1 and 2

Figure S3

Figure S2

Supplementary File 3. Detailed plots of the data used for phylogenetic inference in each case. The description for the plots in Supplementary File 3 can be found in the Legend of Supplementary Figure S13-S17.

Supplementary material

Supplementary File 2. Detailed plots of SCNA calls in TARGET genes. The description for the plots in Supplementary File 2 can be found in the Legend of Supplementary Figure S3.

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Supplemental Table 8

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Supplementary Figure from Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers

Supplemental Figure 1: Consort diagram

Purpose:The identification of patients with homologous recombination deficiency (HRD) beyond BRCA1/2 mutations is an urgent task, as they may benefit from PARP inhibitors. We have previously developed a method to detect mutational signature 3 (Sig3), termed SigMA, associated with HRD from clinical panel sequencing data, that is able to reliably detect HRD from the limited sequencing data derived from gene-focused panel sequencing.Experimental Design:We apply this method to patients from two independent datasets: (i) high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) from a phase Ib trial of the PARP inhibitor olaparib in combination with the PI3K inhibitor buparlisib (BKM120; NCT01623349), and (ii) TNBC patients who received neoadjuvant olaparib in the phase II PETREMAC trial (NCT02624973).Results:We find that Sig3 as detected by SigMA is positively associated with improved progression-free survival and objective responses. In addition, comparison of Sig3 detection in panel and exome-sequencing data from the same patient samples demonstrated highly concordant results and superior performance in comparison with the genomic instability score.Conclusions:Our analyses demonstrate that HRD can be detected reliably from panel-sequencing data that are obtained as part of routine clinical care, and that this approach can identify patients beyond those with germline BRCA1/2mut who might benefit from PARP inhibitors. Prospective clinical utility testing is warranted.

Supplementary tables 1-4 and supplementary figure legend

Purpose:Brain metastases can occur in up to 50% of patients with metastatic HER2-positive breast cancer. Because patients with active brain metastases were excluded from previous pivotal clinical trials, the central nervous system (CNS) activity of the antibody–drug conjugate trastuzumab deruxtecan (T-DXd) is not well characterized.Experimental Design:We studied how T-DXd affects growth and overall survival in orthotopic patient-derived xenografts (PDX) of HER2-positive and HER2-low breast cancer brain metastases (BCBM). Separately, we evaluated the effects of T-DXd in a retrospective cohort study of 17 patients with stable or active brain metastases.Results:T-DXd inhibited tumor growth and prolonged survival in orthotopic PDX models of HER2-positive (IHC 3+) and HER2-low (IHC 2+/FISH ratio < 2) BCBMs. T-DXd reduced tumor size and prolonged survival in a T-DM1–resistant HER2-positive BCBM PDX model. In a retrospective multi-institutional cohort study of 17 patients with predominantly HER2-positive BCBMs, the CNS objective response rate (ORR) was 73% (11/15) while extracranial response rate was 45% (5/11). In the subset of patients with untreated or progressive BCBM at baseline, the CNS ORR was 70% (7/10). The median time on treatment with T-DXd was 8.9 (1.3–16.2) months, with 42% (7/17) remaining on treatment at data cutoff.Conclusions:T-DXd demonstrates evidence of CNS activity in HER2-positive and HER2-low PDX models of BCBM and preliminary evidence of clinical efficacy in a multi-institution case series of patients with BCBM. Prospective clinical trials to further evaluate CNS activity of T-DXd in patients with active brain metastases are warranted.See related commentary by Soffietti and Pellerino, p. 8

Figures S1 and S2