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Background: About half of all breast cancers exhibit low HER2 expression. Despite lack of ERBB2 amplification, HER2-low tumors respond to trastuzumab deruxtecan (T-DXd), leading to the NCCN recommendation of T-DXd both for patients with HER2+ and HER2-low metastatic breast cancer (MBC). It remains however unclear if HER2-low represents a distinct molecular entity, as compared to HER2-0 MBC. Here, we compare the genomic landscape of HER2-low versus HER2-0 breast cancers in a large, single institution cohort. Methods: We identified consecutive patients with MBC seen at Dana-Farber Cancer Institute between 07/2013 and 12/2020. Patients were included if they had HER2-negative MBC per ASCO/CAP Guidelines and had undergone next generation sequencing (NGS) testing with a targeted, tumor-only platform (OncoPanel). Based on the HER2 status of the specimen tested by NGS, patients were divided into 2 groups: (i) HER2-low if immunohistochemistry (IHC) 1+ or 2+ non-amplified, or (ii) HER2-0 if IHC 0. Mutations of interest detected on NGS were classified as oncogenic using the OncoKB tool and additional annotation. Genomic profiles of HER2-low and HER2-0 tumors were compared using Chi-Square and Kruskal-Wallis tests. To determine genomic event enrichment between the two HER2 groups, logistic regression models were used, accounting for background rate and estrogen receptor (ER) expression. ERBB2 copy counts were calculated for tumors with recorded histology-estimated purities and copy-number segmentation using a simple model of allelic gain/loss. Results: Among 1847 patients with HER2-negative MBC, 1043 underwent NGS testing on a HER2-low (n=489, 47%) or HER2-0 sample (n=554, 53%). Most samples were metastatic (71%, n=743) while 29% (n=300) were from primary tumors. 73% had ductal histology, 13% were lobular and 14% had mixed or other histology. ER expression was enriched among HER2-low vs. HER2-0 tumors (76% vs. 60%; p< 0.001). Focusing on the most commonly occurring genetic mutations, no major differences were observed in HER2-low vs. HER2-0 tumors, after correcting for ER status (Table 1). Among all mutational events, any mutation in MPL, CYLD, and MAP3K and oncogenic mutations in TP53 and NF1 were more common in HER2-0, while any mutation in MTOR, RAD21, DNMT3A, and PDGFRA were enriched in HER2-low patients, when controlling for ER status and background mutational rate (p< 0.05). However, no mutation reached significance after accounting for multiple hypothesis testing. Similarly, no deep deletion or high amplification CNV events reached significance for either group. Analysis of tumor mutational burden in HER2-low vs. HER-0 tumors revealed no significant differences (median: 7.26 muts/Mb vs. 7.60 muts/Mb, p=1.00), including when accounting for ER status. Finally, among tumors with sufficient tumor purity for ERBB2 copy count analysis (n=374 and 419 for HER2-low and HER2-0, respectively), HER2-low tumors had a significantly higher number of ERBB2 alleles as compared to HER2-0 (< 2 copies, 15.0% vs. 30.9%, 2 copies 67.4% vs. 60.5%, and >2 copies, 17.6% vs. 8.6%; p< 0.001 by Kruskal-Wallis). Conclusions: To our knowledge, this is the largest comprehensive genomic analysis of HER2-low MBC to date. In our cohort of patients with HER2-negative MBC, the genomic landscape of HER2-low and HER2-0 tumors did not differ significantly, apart from a higher number of ERBB2 alleles. These data further support the notion that HER2-low, as currently defined, is not a distinct molecular subtype of breast cancer. Citation Format: Paolo Tarantino, Hersh V. Gupta, Melissa E. Hughes, Janet L. Files, Sarah Strauss, Gregory Kirkner, Anne-Marie Feeney, Yvonne Y. Li, Ana C. Garrido-Castro, Romualdo Barroso-Sousa, Brittany Bychkovsky, Laura MacConaill, Neal Lindeman, Bruce Johnson, Matthew Meyerson, Sheheryar Kabraji, Rinath Jeselsohn, Xintao Qiu, Rong Li, Henry W. Long, Eric Winer, Deborah A. Dillon, Giuseppe Curigliano, Andrew Cherniack, Sara Tolaney, Nancy U. Lin. HER2-05 Comprehensive genomic characterization of HER2-low breast cancer [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 HER2-05.

Background: It is estimated that 50 thousand patients live with metastatic breast cancer (MBC) in Brazil. A recent Brazilian registry (LACOG 0312) on MBC demonstrated a median overall survival (OS) by breast subtype of 15 months for triple negative, 23 months for HER2 positive, and 42 months for Luminal tumors, which are very similar to developed countries except the HER2 positive group which have limited access to targeted agents in the public health system. Recently, CDK 4/6 inhibitors were approved for the treatment of HR+ HER2-negative MBC with an improvement in progression-free survival (PFS) and ribociclib and abemaciclib demonstrating benefit in OS over endocrine therapy alone, establishing the standard of care in first-line setting for this BC subtype. In Brazil, disparities exist in the incorporation of novel anticancer agents between public and private health systems limiting treatment options for patients with HR+ HER2- negative MBC in the public system, which covers most of the population. The BRAVE study aims to describe the patient journey and current patterns of care for HR+ HER2-negative MBC to identify possible gaps and how health insurance type influences treatment patterns in Brazil. Trial Design: This is an observational, retrospective cohort study. All patients diagnosed with mBC (either de novo or recurrent) in the period of January 2018 to December 2020 at participating centers will be included. Data will be collected from medical records. No interventions are proposed. Enrollment of a total of 300 patients (150 patients from public health care system and 150 patients from private health care system) is planned. ClinicalTrials.gov identifier: NCT05034393. Eligibility: Inclusion criteria: women ≥18 years old; histologically confirmed HR-positive HER2-negative invasive breast cancer; HR-positive, defined as 1% to 100% of tumor nuclei positive for ER and/or PgR as per ASCO/CAP Guideline 2020 or Allred score of ≥3; HER2-negative, defined as IHC result is 0/1+ or 2+ with ISH negative as per ASCO/CAP Guideline 2018; diagnosed with de novo or recurrent metastatic breast cancer between January 2018 and December 2020. Exclusion criteria: male BC; first-line treatment for mBC received through clinical trial. Specific Aims: Primary objective is to describe the first-line (1L) treatment of HR-positive, HER2-negative mBC in Brazil. Secondary objectives are to describe progression-free survival (PFS) in the 1L setting until month 24; describe and compare the 1L treatment of HR-positive, HER2-negative mBC and PFS until month 24 according to the health care coverage (public vs. private); describe timelines from symptoms, histopathological diagnosis, molecular test, and treatment; describe the mBC pathological characterization; describe frequency of diagnostic tests to define breast cancer molecular subtypes; describe the subsequent line of treatment and corresponding PFS; describe overall survival (OS); evaluate PFS and OS according to visceral vs. non-visceral metastatic disease, primary endocrine resistance vs. acquired endocrine resistance, de novo versus recurrent disease, public vs. private health system and pre vs postmenopausal status. Statistical Methods: No a priori sample size calculation was performed. The expected sample size of 150 patients in each group allows description of the proportion of patients using CDK 4/6 inhibitors with two-sided 90% confidence interval ranging from 53.4% to 66.6% when the expected proportion is 60% in the private health system. Present Accrual and Target Accrual: A total of 12 sites of 14 planned were activated. The first patient was enrolled on February 8, 2022. As of June 24, 2022, a total of 122 patients were enrolled, 86 from public and 36 from private health system. The target accrual of 300 patients is expected to be completed by November 2022. Results are expected to be presented by April 2023. Funding: Novartis. Acknowledgements: SAS. Citation Format: Gustavo Werutsky, Tomás Reinert, Daniela D. Rosa, Romualdo Barroso-Sousa, Heloísa Resende, Poliana A. Signorini, Juliana G. Martins Fagundes, Jose Marcio B. Figueiredo, Eduardo Cronemberger, Aline C. Vieira, Jorge Henrique Santos Leal, Luiza Nardin Weis, Ludmila Thommen, Rafaela G. Jesus, Gustavo Gössling, José Bines. Real-World Data on First-line Treatment of HR-positive, HER2-negative, Metastatic Breast Cancer in Brazil (BRAVE Study/LACOG 0221) [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 OT3-07-01.

Background. Patients (pts) who develop MBC at older ages are underrepresented in clinical trials, are less likely to be included in comprehensive biomarker characterization studies, and experience worse breast cancer-specific survival than their younger counterparts. Elucidating genomic underpinnings of MBC and possible therapeutic targets for older breast cancer patients are critical priorities. Methods. We identified pts age >70 years at MBC diagnosis and a younger cohort (ages 50-69; age < 50), who were treated for MBC at a single center and who had their metastatic (or if not available, the primary) tumor, assessed by a targeted, tumor-only next generation sequencing (NGS) platform (OncoPanel) between 2013-2020. The NGS panel included mutations, copy number variation, tumor mutational burden (TMB), and hypermutation (HM) status, with mutations classified as oncogenic using the OncoKB tool and additional annotation. Copy number events were selected as being “oncogenic” if a high amplification was called for an oncogene or a deep deletion for a tumor suppressor. We compared findings for older (age >70) vs. younger (age < 50 and ages 50-69) MBC pts using Chi-Square and Kruskal-Wallis tests. To determine genomic event enrichment, logistic regression (LR) models were used, controlling for age (continuous), background rate, and tumor subtype (those with unknown subtype [n=27] were excluded from models). False discovery rate (FDR) was used to correct for multiple hypothesis testing. Results. The final analytic cohort included 2,380 pts. The median age at MBC diagnosis was 54.1 years overall (range 18.5- 91.9) and 73.6 years for those age >70. A total of 137 metastatic and 76 primary tumors were sequenced in pts age >70; in those age < 70, 1383 metastatic and 784 primary tumors were sequenced (for age < 50 [n=857] and 50-69 [n=1310]). Older pts were more likely to present with HR+/HER2- tumors (70.9% v. 62.4% v. 52.4%), and less likely to present with HER2+ (9.4% v. 14.4% v. 22.8%) or triple-negative breast cancer (TNBC) (18.8% v. 21.9% vs. 24.0%) at MBC diagnosis (listed >70, 50-69, < 50; P=1e-7). Older pts had higher average TMB vs. younger pts (9.57 in pts > 70, 8.56 in ages 50-69, 7.34 in ages < 50; P=3.5e-5). This was due to older pts having a higher incidence of hypermutation status as defined as TMB >10: 26.3% in age >70, 23.2% in ages 50-69, 16.8% in age < 50. Using q=0.1 as the threshold of significance, the presence of CDH1, PIK3CA, MAP3K1, TET2, and AKT oncogenic mutations were also enriched in older pts, while the presence of oncogenic GATA3, BRCA2, and TP53 mutations, as well as any mutation in BRCA1 were enriched in younger pts (too few oncogenic BRCA1 mutations were present for accurate modeling). The frequency of oncogenic PIK3CA mutations in HR+/HER2- tumors was highest in the oldest pts (44.4% in pts age >70 v. 31.6% in age 50-69 v. 26.7% in age < 50). Of pts who had oncogenic BRCA1/2 mutations identified on tumor-only NGS testing and underwent clinical germline testing (n=7 v. 60 v. 67, oldest to youngest), older pts had the lowest incidence of germline BRCA pathogenic variants (14.3% vs. 47.2.% vs. 67.2%; p=0.01); most BRCA mutations identified on NGS testing in older patients were considered likely somatic. When assessing enrichment in copy number events, ERBB2, RAD21, and BRIP1 amplifications were all significantly less frequent in older pts (q< 0.1), even when accounting for tumor subtype. Conclusions. In a large cohort of pts with MBC, the mutational and copy number landscape for older pts differs from that in younger pts, even after controlling for tumor subtype. Key actionable findings include a higher proportion of high TMB and PIK3CA-mutated tumors, emphasizing the importance of genomic profile testing in this pt population and further exploration of efficacy and tolerability of relevant therapies in those age >70 years. Citation Format: Hersh V. Gupta, Rachel Freedman, Melissa E. Hughes, Yvonne Y. Li, Gregory Kirkner, Janet L. Files, Sarah Strauss, Ana C. Garrido-Castro, Lauren Buckley, Romualdo Barroso-Sousa, Brittany Bychkovsky, Sara Tolaney, Laura MacConaill, Neal Lindeman, Bruce Johnson, Matthew Meyerson, Eric Winer, Deborah A. Dillon, Andrew Cherniack, Nancy U. Lin. Tumor Genomic Landscape in Older Women with Metastatic Breast Cancer (MBC) [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 P5-14-06.

Background: The gut microbiome modulates response and resistance to immune checkpoint inhibitors (ICI) across different cancer types. The objective of this study was to explore the association between fecal microbiome profiles and clinical outcomes in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC) treated with eribulin (E) + pembrolizumab (P) or E alone as part of a randomized phase II study (NCT03051659). Patients and Methods: Metagenomic shotgun sequencing was performed on fecal samples collected prior to randomization from a subset of 26 participating patients (E+P, n = 15; E, n = 11) collected prior to randomization. Sequencing data were processed with MetaPhlAn3 to obtain diversity scores and taxonomic composition profiles. Associations between microbiome diversity, taxonomic composition, and clinical outcomes including survival metrics were assessed using Kaplan-Meier estimation methods and Cox proportional hazard models. Results: In this subset, median follow-up was 21.6 months and median overall survival (OS) was 17.9 months. OS was not statistically significant between two treatment arms as observed in the overall cohort. Metagenomic microbiome analysis revealed higher alpha diversity by inverse Simpson Index values associated with longer survival among all patients (p = 0.004), and in patients in the E + P arm (p = 0.006) but not in the E arm (p = 0.2). At the taxonomic level, longer OS among all patients was associated with a baseline lower relative abundance of Blautia wexlerae (≤0.2%vs >0.2%) (22.1 vs 16.6 months; p = 0.01) and a higher relative abundance of Odoribacter splanchnicus, a common short-chain fatty acid producing gut bacterium (>0.35% vs ≤0.35%) (22.3 vs 11.3 months; p < 0.0001). These associations remained significant after controlling for age, ECOG-PS status, and use or not of prior lines of chemotherapy in the metastatic setting. Conclusions: These results suggest high diversity and composition of the gut microbiome are associated with prolonged OS in HR+ MBC pts receiving eribulin with pembrolizumab. Additional and larger clinical studies are needed to validate these findings and preclinical models are needed to interrogate the mechanisms by which gut microbiome diversity and composition may impact therapeutic response and clinical outcomes in this patient population. Citation Format: Romualdo Barroso-Sousa, Tianyu Li, Ashish V. Damania, Molly K. DiLullo, Tanya Keenan, Gerburg M. Wulf, Laura M. Spring, Elizabeth A. Mittendorf, Jennifer A. Ligibel, Nadim J. Ajami, Jennifer Wargo, Nabihah Tayob, Sara Tolaney. PD11-05 Gut microbiome signatures correlate with overall survival among patients receiving eribulin with or without pembrolizumab for hormone receptor-positive metastatic breast cancer [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 PD11-05.

Supplementary Figure from PD-1/PD-L1 Inhibition Enhances Chemotherapy-Induced Neuropathic Pain by Suppressing Neuroimmune Antinociceptive Signaling

Supplementary data, tables and figures

Thyroid disorders have emerged as one of the most common immune-related adverse events (irAE), yet optimum management and biomarkers to predict vulnerable individuals remain to be explored. High-dose glucocorticoid (HDG) therapy is routinely recommended for irAEs. However, systematic analysis of the impact of glucocorticoid therapy on the outcome of immune-checkpoint inhibitor (ICI)–induced thyroid disorders is lacking. We analyzed 151 patients with or without ICI-related thyroid disorders. We divided the patients with ICI-related thyroid disorders into two subgroups: those with and without HDG treatment. Our results showed no significant differences between HDG and no HDG groups in terms of the median duration of thyrotoxicosis: 28 (range, 7–85) and 42 (range, 14–273) days, the median time to conversion from thyrotoxicosis to hypothyroidism: 39 days (range, 14–169) and 42 days (range, 14–315) days, the median time to onset of hypothyroidism: 63 (range, 21–190) and 63 (range, 14–489) days, and the median maintenance dose of levothyroxine: 1.5 (range, 0.4–2.3) μg/kg/day, and 1.3 (range, 0.3–2.5) μg/kg/day. The median pretreatment TSH was 2.3 (range, 0.3–5.2) mIU/L and 1.7 (range, 0.5–4.5) mIU/L in patients with and without ICI-related thyroid disorders, respectively. Baseline TSH was significantly higher in patients who developed ICI-related thyroid disorders (P = 0.05). Subgroup analysis revealed significantly higher baseline TSH in male but not in female patients with ICI-induced thyroid dysfunction. Our results show that HDG treatment did not improve the outcome of ICI-related thyroid disorders.

Supplementary Data from PD-1/PD-L1 Inhibition Enhances Chemotherapy-Induced Neuropathic Pain by Suppressing Neuroimmune Antinociceptive Signaling

Cytotoxic agents synergize with immune checkpoint inhibitors and improve outcomes for patients with several cancer types. Nonetheless, a parallel increase in the incidence of dose-limiting side effects, such as peripheral neuropathy, is often observed. Here, we investigated the role of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis in the modulation of paclitaxel-induced neuropathic pain. We found that human and mouse neural tissues, including the dorsal root ganglion (DRG), expressed basal levels of PD-1 and PD-L1. During the development of paclitaxel-induced neuropathy, an increase in PD-L1 expression was observed in macrophages from the DRG. This effect depended on Toll-like receptor 4 activation by paclitaxel. Furthermore, PD-L1 inhibited pain behavior triggered by paclitaxel or formalin in mice, suggesting that PD-1/PD-L1 signaling attenuates peripheral neuropathy development. Consistent with this, we observed that the combined use of anti–PD-L1 plus paclitaxel increased mechanical allodynia and chronic neuropathy development induced by single agents. This effect was associated with higher expression of inflammatory markers (Tnf, Il6, and Cx3cr1) in peripheral nervous tissue. Together, these results suggest that PD-1/PD-L1 inhibitors enhance paclitaxel-induced neuropathic pain by suppressing PD-1/PD-L1 antinociceptive signaling.

Background: A combination of a taxane, trastuzumab, and pertuzumab (THP) is the standard-of-care (SOC) 1L treatment for patients (pts) with HER2+ mBC; THP demonstrated median progression-free survival (mPFS) of 18.7 mo and overall survival (OS) of 56.5 mo (Swain et al. N Engl J Med. 2015;372:724-734). However, pts eventually develop resistance to treatment. Novel treatment options are necessary in order to delay the emergence of resistance and provide better clinical outcomes, improve quality of life (QOL), and prolong survival in the 1L setting. T-DXd has demonstrated efficacy in pts with heavily pretreated HER2+ mBC, with an objective response rate (ORR) of 61.4%, duration of response (DOR) of 20.8 mo, and mPFS of 19.4 mo (Modi et al. Cancer Res. 2021. Abstract PD3-06). Data from DESTINY-Breast01 supported global approvals of T-DXd in HER2+ mBC. Here we describe a phase 3 trial evaluating the efficacy and safety of T-DXd ± pertuzumab compared with THP in the 1L treatment of HER2+ mBC. Trial design: DESTINY-Breast09 (NCT04784715) is a global, multicenter, randomized, phase 3 trial assessing the efficacy and safety of T-DXd with or without pertuzumab compared with SOC THP as 1L treatment in pts with HER2+ (IHC 3+ or ISH+ assessed locally per ASCO-CAP guidelines and centrally confirmed) advanced or mBC. This study consists of 3 treatment arms: arm A (T-DXd + placebo), arm B (T-DXd + pertuzumab), and arm C (THP). Randomization is 1:1:1 and pts will be stratified by prior treatment status (de novo vs recurrent), hormone receptor status (positive vs negative), and PIK3CA mutation status (detected vs not detected). Pts (N≈1134) must have had no prior chemotherapy or HER2-targeted therapy for advanced or mBC (1 prior line of endocrine therapy is allowed for mBC). The primary endpoint is PFS by blinded independent central review. Secondary endpoints include PFS by investigator assessment, OS, ORR, DOR, PFS2, health-related quality of life (QOL), pharmacokinetics, immunogenicity, and safety. Citation Format: Sara M Tolaney, Romualdo Barroso-Sousa, Zefei Jiang, Yeon Hee Park, Mothaffar Rimawi, Cristina Saura, Andreas Schneeweiss, Masakazu Toi, Tinghui Yu, Jagdish Shetty, Pia Herbolsheimer, Sibylle Loibl. Phase 3 study of trastuzumab deruxtecan (T-DXd) with or without pertuzumab vs a taxane, trastuzumab and pertuzumab in first-line (1L), human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC): DESTINY-Breast09 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-14-02.

Background: While high tumor mutational burden (TMB-H) has been used as a tissue-agnostic biomarker for approval of immune checkpoint inhibitors (ICI), there is a paucity of data regarding efficacy of ICI in TMB-H MBC. The aim of this study was to evaluate if patients with TMB-H HER2-negative MBC benefit from the combination of nivolumab plus ipilimumab. Methods: This is an open-label, single-arm, multicenter, phase 2 study assessing the efficacy of nivolumab 3 mg/kg intravenously (IV) every 14 days plus ipilimumab 1 mg/kg IV every 6 weeks in subjects with TMB-H HER2-negative MBC. Eligible patients were required to have measurable HER2-negative MBC, TMB ≥9 Mut/Mb assessed by a cancer-gene panel evaluating > 300 genes and performed in a CLIA-certified laboratory, and 0-3 prior lines of chemotherapy in the advanced setting. The primary objective was overall response rate (ORR) according to RECIST 1.1. Secondary objectives include safety and tolerability, progression-free survival (PFS), and overall survival (OS). The study followed a two-stage design. In the first stage, 14 patients were enrolled. The study required at least 1 objective response in order to continue to the second stage where an additional 16 patients were enrolled. At least 4 objective responses among the 30 patients would suggest the regimen is worthy of further study. If the true response rate is 25%, the chance that the regimen is declared worthy of further study is > 90%. Tumor biopsies, peripheral blood mononuclear cells, circulating tumor DNA, and stool collection were mandatory and were obtained at baseline and on treatment (end of cycle 1). Results: From February 2019 to June 2021, 31 patients were enrolled across 3 different academic institutions. Among 30 patients who initiated study treatment, the median age was 63 yo, 20 had hormone-receptor positive (HR+) breast cancer and 10 had triple-negative breast cancer (TNBC), and median number of prior lines of chemotherapy was 1.5 (0-3). Among the 10 patients with TNBC, PD-L1 status was known in 7 patients (3 positive and 4 negative). Median TMB was 10.9 Mut/Mb and 16.7% (n = 5) of patients had a TMB ≥14 mut/Mb. After a median follow-up of 9.7 (4.4 - 16.4) months, 4 (13.3%) patients achieved a confirmed objective response (all partial responses) meeting the primary endpoint of this study. The median duration of response has not been reached and 3 of these patients are still progression-free for at least 15 months. Two patients have short follow-up, and one has an unconfirmed partial response and the other has a stable disease at the time of the data cut. Median PFS and OS was respectively 1.4 (95% CI 1.3 - 9.5) months and 8.8 (95% CI 4.2 - not reached). Exploratory analysis did not show a difference in response rate according to HR status and PD-L1 status (data not shown) but tumors with TMB ≥14 mut/Mb had a response rate of 60% vs 4% in the group with TMB between ≥9 and Citation Format: Romualdo Barroso-Sousa, Tianyu Li, Sangeetha Reddy, Leisha A. Emens, Beth Overmoyer, Paulina Lange, Molly K Dilullo, Victoria Attaya, Jeffrey Kimmel, Eric P. Winer, Elizabeth A. Mittendorf, Nabihah Tayob, Sara M. Tolaney. Nimbus: A phase 2 trial of nivolumab plus ipilimumab for patients with hypermutated her2-negative metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-10.

Purpose:In contrast to recurrence after initial diagnosis of stage I–III breast cancer [recurrent metastatic breast cancer (rMBC)], de novo metastatic breast cancer (dnMBC) represents a unique setting to elucidate metastatic drivers in the absence of treatment selection. We present the genomic landscape of dnMBC and association with overall survival (OS).Experimental Design:Targeted DNA sequencing (OncoPanel) was prospectively performed on either primary or metastatic tumors from 926 patients (212 dnMBC and 714 rMBC). Single-nucleotide variants, copy-number variations, and tumor mutational burden (TMB) in treatment-naïve dnMBC primary tumors were compared with primary tumors in patients who ultimately developed rMBC, and correlated with OS across all dnMBC.Results:When comparing primary tumors by subtype, MYB amplification was enriched in triple-negative dnMBC versus rMBC (21.1% vs. 0%, P = 0.0005, q = 0.111). Mutations in KMTD2, SETD2, and PIK3CA were more prevalent, and TP53 and BRCA1 less prevalent, in primary HR+/HER2− tumors of dnMBC versus rMBC, though not significant after multiple comparison adjustment. Alterations associated with shorter OS in dnMBC included TP53 (wild-type: 79.7 months; altered: 44.2 months; P = 0.008, q = 0.107), MYC (79.7 vs. 23.3 months; P = 0.0003, q = 0.011), and cell-cycle (122.7 vs. 54.9 months; P = 0.034, q = 0.245) pathway genes. High TMB correlated with better OS in triple-negative dnMBC (P = 0.041).Conclusions:Genomic differences between treatment-naïve dnMBC and primary tumors of patients who developed rMBC may provide insight into mechanisms underlying metastatic potential and differential therapeutic sensitivity in dnMBC. Alterations associated with poor OS in dnMBC highlight the need for novel approaches to overcome potential intrinsic resistance to current treatments.

Figures S1-S14

Supplementary Methods

Kaplan-Meier Curves for Progression-Free Survival and Overall Survival by high TMB {greater than or equal to}7 mutations/Mb and PTEN alterations in Chemotherapy-Treated mTNBC. (A) Progression-free survival and (C) overall survival by tumor mutational burden

Tables S1-S12

Purpose:Few patients with metastatic triple-negative breast cancer (mTNBC) benefit from immune checkpoint inhibitors (ICI). On the basis of immunotherapy response correlates in other cancers, we evaluated whether high tumor mutational burden (TMB) ≥10 nonsynonymous mutations/megabase and PTEN alterations, defined as nonsynonymous mutations or 1 or 2 copy deletions, were associated with clinical benefit to anti-PD-1/L1 therapy in mTNBC.Experimental Design:We identified patients with mTNBC, who consented to targeted DNA sequencing and were treated with ICIs on clinical trials between April 2014 and January 2019 at Dana-Farber Cancer Institute (Boston, MA). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were correlated with tumor genomic features.Results:Sixty-two women received anti-PD-1/L1 inhibitors alone (23%) or combined with targeted therapy (19%) or chemotherapy (58%). High TMB (18%) was associated with significantly longer PFS (12.5 vs. 3.7 months; P = 0.04), while PTEN alterations (29%) were associated with significantly lower ORR (6% vs. 48%; P = 0.01), shorter PFS (2.3 vs. 6.1 months; P = 0.01), and shorter OS (9.7 vs. 20.5 months; P = 0.02). Multivariate analyses confirmed that these associations were independent of performance status, prior lines of therapy, therapy regimen, and visceral metastases. The survival associations were additionally independent of PD-L1 in patients with known PD-L1 and were not found in mTNBC cohorts treated with chemotherapy (n = 90) and non-ICI regimens (n = 169).Conclusions:Among patients with mTNBC treated with anti-PD-1/L1 therapies, high TMB and PTEN alterations were associated with longer and shorter survival, respectively. These observations warrant validation in larger datasets.

Extended methods and results, including e-references

The increasing burden of cancer represents a substantial problem for Latin America and the Caribbean. Two Lancet Oncology Commissions in 2013 and 2015 highlighted potential interventions that could advance cancer care in the region by overcoming existing challenges. Areas requiring improvement included insufficient investment in cancer control, non-universal health coverage, fragmented health systems, inequitable concentration of cancer services, inadequate registries, delays in diagnosis or treatment initiation, and insufficient palliative services. Progress has been made in key areas but remains uneven across the region. An unforeseen challenge, the COVID-19 pandemic, strained all resources, and its negative effect on cancer control is expected to continue for years. In this Series paper, we summarise progress in several aspects of cancer control since 2015, and identify persistent barriers requiring commitment of additional resources to reduce the cancer burden in Latin America and the Caribbean.

Background In early trials, hypersensitivity reactions (HSRs) to paclitaxel were common, thus prompting the administration of antihistamines and corticosteroids before every paclitaxel dose. We tested the safety of omitting corticosteroids after cycle 2 during the paclitaxel portion of the dose‐dense (DD) doxorubicin‐cyclophosphamide (AC)–paclitaxel regimen. Patients, Materials, and Methods In this prospective, single‐arm study, patients who completed four cycles of DD‐AC for stage I–III breast cancer received paclitaxel 175 mg/m2 every 2 weeks for four cycles. Patients received a standard premedication protocol containing dexamethasone, diphenhydramine, and a histamine H2 blocker prior to the first two paclitaxel cycles. Dexamethasone was omitted in cycles three and four if there were no HSRs in previous cycles. We estimated the rate of grade 3–4 HSRs. Results Among 127 patients enrolled, 125 received more than one dose of protocol therapy and are included in the analysis. Fourteen (11.2%; 90% confidence interval, 6.9%–20.0%) patients had any‐grade HSRs, for a total of 22 (4.5%; 3.1%–6.4%) HSRs over 486 paclitaxel cycles. Any‐grade HSRs occurred in 1.6% (0.3%–5.0%), 6.5% (3.3%–11.3%), 7.4% (3.9%–12.5%), and 2.6% (0.7%–6.6%) of patients after paclitaxel cycles 1, 2, 3, and 4, respectively. Dexamethasone use was decreased by 92.8% in cycles 3 and 4. Only one patient experienced grade 3 HSR in cycles 3 or 4, for a rate of grade 3/4 HSR 0.4% (0.02%–2.0%) (1/237 paclitaxel infusions). That patient had grade 2 HSR during cycle 2, and the subsequent grade 3 event occurred despite usual dexamethasone premedication. A sensitivity analysis restricted to patients not known to have received dexamethasone in cycles 3 and 4 found that any‐grade HSRs occurred in 2.7% (3/111; 0.7%–6.8%) and 0.9% (1/109; 0.05%–4.3%) of patients in cycle 3 and 4, respectively. Conclusion Corticosteroid premedication can be safely omitted in cycles 3 and 4 of dose‐dense paclitaxel if HSRs are not observed during cycles 1 and 2. Implications for Practice Because of the potential for hypersensitivity reactions (HSRs) to paclitaxel, corticosteroids are routinely prescribed prior to each dose, on an indefinite basis. This prospective study, including 125 patients treated with 486 paclitaxel cycles, demonstrates that corticosteroids can be safely omitted in future cycles if HSRs did not occur during cycles 1 and 2 of paclitaxel and that this strategy reduces the use of corticosteroids in cycles 3 and 4 by 92.8% relative to current standard of care., To avoid hypersensitivity reactions, corticosteroids are routinely prescribed before each dose of paclitaxel. This article reports the results of a study that focused on whether corticosteroids could be safely omitted in later cycles of treatment if reactions did not occur during earlier cycles.

Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59–1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659., A randomized phase 2 clinical trial has recently shown no benefit of the combination eribulin and pembrolizumab over pembrolizumab alone in HR + metastatic breast cancer patients (NCT03051659). Here, the authors are reporting the final OS data and biomarker analyses on a subset of samples to analyze molecular correlates

Precision medicine has provided new perspectives in oncology, yielding research on the use of targeted therapies across different tumor types, regardless of their site of origin, a concept known as tissue-agnostic indication. Since 2017, the Food and Drug Administration (FDA) has approved the use of three different agents for tumor-agnostic treatment: pembrolizumab (for patients with microsatellite instability or high tumor mutational burden) and larotrectinib and entrectinib (both for use in patients harboring tumors with NTRK fusions). Importantly, the genomic alterations targeted by these agents are uncommon or rare in breast cancer, and little information exists regarding their efficacy in advanced breast cancer. In this review, we discuss the prevalence of these targets in breast cancer, their detection methods, the clinical characteristics of patients whose tumors have these alterations, and available data regarding the efficacy of these agents in breast cancer.

Even though multiple resistance mechanisms and pathways for cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have been discovered, the complete landscape of resistance is still being elucidated. Moreover, the optimal subsequent therapy to overcome resistance remains uncertain.To address this, we carried out a phase I/II clinical trial of exemestane plus everolimus and palbociclib, triplet therapy for CDK4/6i-resistant hormone receptor–positive (HR+), HER2-metastatic breast cancer, one of the first trials evaluating CDK4/6i after CDK4/6i progression. With an observed clinical benefit rate of 18.8% (n = 6/32), the trial did not meet its primary efficacy endpoint. However, we leveraged the multi-omics tumor data from these patients to study the landscape of CDK4/6i resistance and to identify correlates of response to triplet therapy.We generated whole exome sequencing from 24 tumor and 17 ctDNA samples and transcriptome sequencing from 27 tumor samples obtained from 26 patients in the trial. Genomic and evolutionary analysis recapitulated the spectrum of known resistance genes (ERBB2, NF1, AKT1, RB1, ESR1) and pathways (RTK/MAPK, PI3K/AKT/mTOR, cell cycle, estrogen receptor), discovered potential new mechanisms of resistance in these pathways (ERBB2 amplification, BRAFV600E, MTORT1977R), and identified a patient with co-existing tumor lineages with distinct activating ERBB2 mutations, potentially the first case of convergent evolution of HER2 activation following CDK4/6i therapy. Joint genomic and transcriptomic analysis revealed that genomic resistance mechanisms were associated with transcriptomic features in their respective pathways, suggesting that transcriptomic features could be used to identify the pathways driving resistance. In particular, the mutually exclusive ESR1 and ERBB2/BRAF mutations, were each linked with high activity in distinct pathway signatures (estrogen receptor pathway vs RTK/MAPK pathway, respectively) and were exclusive to distinct molecular subtypes (Luminal A or Luminal B vs HER2-E, respectively). Overall, incorporating clinical and multi-omics features in CDK4/6i-resistant tumors enabled identification of known or putative drivers of resistance to the prior CDK4/6i and anti-estrogen therapies in nearly every patient (n = 22/23), including several patients in which transcriptomic features were the sole drivers. Genomic and transcriptomic features – particularly PI3K/AKT/mTOR mutations and/or high mTORC1 pathway activity - suggested that clinical benefit to combined estrogen receptor, CDK4/6, and mTOR inhibition was correlated with activation of the mTOR pathway.Our results illustrate how transcriptome sequencing provides complementary and additional information to genome sequencing, and how integrating both may help better identify patients likely to respond to CDK4/6i therapies.SignificanceCombined endocrine, CDK4/6 inhibitor, and mTOR inhibitor therapy showed limited benefit in patients with HR+ metastatic breast cancer who had progressed on a prior CDK4/6 inhibitor. Multi-omics analysis of tumors from this trial identified novel genomic and transcriptomic drivers of CDK4/6i resistance, known or putative drivers of resistance in 22/23 patients, and correlates of response to the trial therapy. Integrated genome and transcriptome sequencing may better identify factors that determine response to CDK4/6i therapy and help select optimal therapy.

PURPOSE In metastatic triple-negative breast cancer (mTNBC), consistent biomarkers of immune checkpoint inhibitor (ICI) therapy benefit remain elusive. We evaluated the immune, genomic, and transcriptomic landscape of mTNBC in patients treated with ICIs. METHODS We identified 29 patients with mTNBC treated with pembrolizumab or atezolizumab, either alone (n = 9) or in combination with chemotherapy (n = 14) or targeted therapy (n = 6), who had tumor tissue and/or blood available before ICI therapy for whole-exome sequencing. RNA sequencing and CIBERSORTx-inferred immune population analyses were performed (n = 20). Immune cell populations and programmed death-ligand 1 expression were assessed using multiplexed immunofluorescence (n = 18). Clonal trajectories were evaluated via serial tumor/circulating tumor DNA whole-exome sequencing (n = 4). Association of biomarkers with progression-free survival and overall survival (OS) was assessed. RESULTS Progression-free survival and OS were longer in patients with high programmed death-ligand 1 expression and tumor mutational burden. Patients with longer survival also had a higher relative inferred fraction of CD8+ T cells, activated CD4+ memory T cells, M1 macrophages, and follicular helper T cells and enrichment of inflammatory gene expression pathways. A mutational signature of defective repair of DNA damage by homologous recombination was enriched in patients with both shorter OS and primary resistance. Exploratory analysis of clonal evolution among four patients treated with programmed cell death protein 1 blockade and a tyrosine kinase inhibitor suggested that clonal stability post-treatment was associated with short time to progression. CONCLUSION This study identified potential biomarkers of response to ICIs among patients with mTNBC: high tumor mutational burden; presence of CD8+, CD4 memory T cells, follicular helper T cells, and M1 macrophages; and inflammatory gene expression pathways. Pretreatment deficiencies in the homologous recombination DNA damage repair pathway and the absence of or minimal clonal evolution post-treatment may be associated with worse outcomes.