Receptor-positive Metastatic Breast Cancer Research Articles

Predictors of response to CDK4/6i retrial after prior CDK4/6i failure in ER+ metastatic breast cancer

After disease progression on endocrine therapy (ET) plus a CDK4/6 inhibitor, there is no standardized sequence for subsequent treatment lines for estrogen receptor positive (ER+) metastatic breast cancer (MBC). CDK4/6i retrial as a treatment strategy is commonplace in modern clinical practice; however, the available prospective data investigating this strategy have had inconclusive results. To frame this data in a real-world context, we performed a retrospective analysis assessing the efficacy of CDK4/6is in 195 patients who had previous exposure to CDK4/6i in a prior treatment line at our institution. Among patients who had stopped a CDK4/6i due to toxicity, CDK4/6i retrial either immediately after with a different CDK4/6i or in a further treatment line with the same initial CDK4/6i was both safe and effective, with a median time to treatment failure (TTF) of 10.1 months (95%CI, 4.8–16.9). For patients whose disease progressed on a prior CDK4/6i, we demonstrated comparable median TTFs for patients rechallenged with the same CDK4/6i (4.3 months, 95%CI 3.2–5.5) and with a different CDK4/6i (4.7 months, 95%CI 3.7–6.0) when compared to the recent PACE, PALMIRA, and MAINTAIN trials. Exploratory genomic analysis suggested that the presence of mutations known to confer CDK4/6i resistance, such as TP53 mutations, CDK4 amplifications, and RB1 or FAT1 loss of function mutations may be molecular biomarkers predictive of CDK4/6i retrial failure.

432P Exploratory biomarker analysis of trastuzumab deruxtecan versus treatment of physician’s choice in HER2-low, hormone receptor–positive metastatic breast cancer in DESTINY-Breast04

432P Exploratory biomarker analysis of trastuzumab deruxtecan versus treatment of physician’s choice in HER2-low, hormone receptor–positive metastatic breast cancer in DESTINY-Breast04

PIK3CA mutation analysis in circulating tumor cells of patients with hormone receptor positive metastatic breast cancer

In metastatic breast cancer (MBC), blood is a source of circulating tumor cells (CTCs). CTCs may serve as a ‘‘real-time liquid biopsy” as they represent metastatic tumor genetics better than primary tumor. PIK3CA is one of the most important oncogenes in treatment-unresponsive breast cancers. The aim of this study was to detect PIK3CA mutations and hereditary cancer variants in CTCs from MBC patients. Forty-seven blood samples were obtained from 20 MBC patients from at least 1/3 consecutive time points. CTCs were quantified using the CellSearch system and isolated from 11/20 patients with ≥5/7.5 ml CTCs (14/47 blood samples) using the DEPArray system. DNA was extracted and amplified to perform Sanger sequencing on PIK3CA gene. Sequencing revealed a pathogenic PIK3CA mutation in 2/11 (18 %) cases. Subsequently, we evaluated a 26-target hereditary gene panel by Next Generation Sequencing and identified a concomitant pathogenic mutation in the TP53 gene in a patient with a PIK3CA mutation. No pathogenic germline variants were found. Our data support the conclusion that CTCs analysis may be used to identify mutations in patients to identify those more likely to metastasize.

Pyrotinib plus taxanes or vinorelbine for human epidermal growth factor receptor 2-positive metastatic breast cancer: A prospective study.

e13004 Background: Pyrotinib in combination with capecitabine is recommended as the second-line treatment for human epidermal growth factor 2 (HER2)-positive metastatic breast cancer (MBC) in China. The efficacy and safety of pyrotinib combined with non-capecitabine chemotherapy regimens remain unclear. Thus, we conducted this study to evaluate the efficacy and safety of pyrotinib combined with taxanes or vinorelbine in HER2-positive MBC. Methods: Patients with HER2-positive MBC were included to receive pyrotinib combined with taxanes or vinorelbine in Jiangsu Cancer Hospital. Patients received pyrotinib 400mg orally once daily plus taxanes (docetaxel 75-100 mg/m2 on day1, or nab-paclitaxel 125 mg/m2 on days 1 and 8, paclitaxel 80 mg/m2 on days 1 and 8, every 3 week) or vinorelbine 25 mg/m2 on days 1 and 8, every 3 weeks. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS) and safety. Results: Between Nov 20, 2018, and Jan 11, 2023, a total of 101 patients were assigned to pyrotinib plus taxanes group (n=83) and pyrotinib plus vinorelbine group (n=18). The median number of pyrotinib therapy lines was 2 (IQR 1-7), the first line accounted for 23.8%, the second line, and third line and above was 34.6%, 41.6%, respectively. As of May 24, 2023, the median PFS in the total was 11.5 months (95% confidence interval [CI], 8.8-15.7). The median PFS was significantly longer in the pyrotinib plus taxanes group than in the pyrotinib plus vinorelbine group, with median PFS being 12.2 months (95% CI, 9.2-18.6) and 8.4 months (95% CI, 5.5-13.7) (HR=2.2 [95% CI, 1.2-3.9]; P=0.005), respectively. The median PFS in the first-line, second-line, and third-line and above treatment was 28.6 (95% CI, 10.6-NA), 12.2 (95% CI, 8.5-16.3), and 8.3 months (95% CI, 6.3-14.5), respectively. The most common grade 3 or 4 adverse events were diarrhea (22.8%), leukopenia (19.5%), and neutropenia (18.2%). Conclusions: The median PFS of pyrotinib plus taxanes or vinorelbine, especially taxanes, was not inferior even superior to that of pyrotinib combined capecitabine. No increase treatment-related side effects was reported. Thus, the combination of pyrotinib and taxanes or vinorelbine regimen can be an option for HER2-positive MBC. Clinical trial information: ChiCTR2000041217.

Toxicity differences in CDK 4/6 inhibitors seen in Asian and Pacific Islanders.

e13086 Background: Cyclin-dependent kinases (CDK) 4/6 inhibitors are the standard of care, first line treatment for hormone receptor positive metastatic breast cancer and adjuvant high-risk hormone receptor positive early stage breast cancer along with endocrine therapy. There have been multiple clinical trials validating the effectiveness, along with toxicities of these agents; however, the majority of these trials lack ethnic diversity. This shortcoming limits the ability to apply these findings in diverse patient populations, especially among Asian and Pacific Islanders in Hawaii. Objective: To determine if the toxicity profile of CDK 4/6 inhibitors in women with breast cancer is different among patients at a community oncology practice in Hawaii, in which the majority of patients are Asian, Pacific Islander or a combination of both when compared to three landmark trials. Methods: A retrospective analysis of thirty-two patients with hormone receptor positive, HER2 negative metastatic or high risk breast cancer who started endocrine therapy and CDK 4/6 inhibitor therapy (abemaciclib, ribociclib, or palbociclib) between 2018-2023. Graded toxicities of each individual patient based on CTCAE criteria V. 5, along with demographic data was reviewed and compared to three main registration trials for these agents (MONARCH-3, MONALEESA-2, PALOMA-2). Results: Combined results from the three large randomized trials reported an average of 75% of participants were Caucasian, as compared to 15% in the Hawaii data. While 19% percent of participants from the combined large randomized trials reported being of Asian descent, none of these trials reported a breakdown of Asians versus Pacific Islanders. In the Hawaii sample, 41% were reported as Pacific Islander and 41% reported as Asian, 15% Caucasian, with the final 3% reported as Hispanic. Collective analysis of the FDA registration trials contained 0% Pacific Islander, 19.8% Asian, 74.3% White, 1.5% Black, and 4.4% Other. The majority of all toxicities of all grades were higher in the Hawaii population as compared to the three national trials, except for neutropenia with ribociclib and diarrhea with palbociclib (Table). Conclusions: The Hawaii analysis that was primarily comprised of Asians and Pacific Islanders revealed an increased incidence of toxicities, despite starting at lower doses rates for all CDK 4/6 inhibitors. This data analysis begins to highlight the importance of representative populations in clinical trials for the most effective and safest care of diverse populations. [Table: see text]

Efficacy of First-Line Treatment With Pertuzumab and Trastuzumab in Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in Routine Clinical Practice.

The first-line treatment for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) involves a combination of trastuzumab, pertuzumab, and a taxane (TPH). This study assessed the efficacy of trastuzumab and pertuzumab (PH) in routine practice, following the treatment protocols of Uruguay's National Resources Fund (FNR), akin to clinical trials. Patients with advanced MBC treated with PH between 2008 and 2022 per FNR protocols were evaluated. The Kaplan-Meyer method and log-rank test were utilized for analyzing overall survival (OS). Demographic and clinical variables, including age, menopausal status, and hormone receptors (HR), were analyzed. The study included 318 PH-treated patients. The median age was 56 years, with 63.2% being postmenopausal and 60.4% HR and HER-2 positive. With a median follow-up of 17.2 months, the median OS was 29 months. OS varied based on HR status and the presence of metastases at different sites, significantly lower in patients with brain, cutaneous/subcutaneous, and pulmonary metastases. Additionally, OS was higher in patients treated at private institutions compared to public ones. This study demonstrates the disparity in oncological treatment efficacy between clinical trials and clinical reality in Uruguay, emphasizing the importance of authentic environment research for more representative and effective medicine in Latin America.

Comprehensive analysis of TROP2, PD-L1, stromal (s)TILs, and HER2 expression patterns in patients (pts) with metastatic HR+HER2- breast cancer.

1062 Background: Immune checkpoint inhibitors (ICI) have shown limited efficacy in hormone receptor positive (HR+) metastatic breast cancer (mBC) and the optimal ICI-based combination is unknown. The TROP2 antibody-drug conjugate sacituzumab govitecan (SG) demonstrated antitumor activity with a 5.5-month median PFS in endocrine refractory HR+ mBC. Given SG's potential for anticancer immunity, we sought to evaluate expression patterns of biomarkers of interest in HR+ mBC. Methods: This retrospective study included pts with HR+HER2- mBC identified at DFCI between 10/2020 and 12/2021 who received 0-1 prior lines of chemotherapy in the metastatic setting and consented to analysis of archival FFPE tissue samples. We aimed to 1) characterize expression patterns of TROP2 (SP295 H-score), PD-L1 (22C3 CPS), sTILs and HER2 (per central pathology review) in the most recent available sample; 2) assess the prognostic value of selected biomarker combinations for overall survival (OS) defined as the time from consent to either death due to any cause or last follow-up (Cox proportional hazard models; p-value <0.05 considered significant). Results: Among 142 pts included, median age at diagnosis was 46 yrs (IQR: 40–56). Baseline characteristics are shown (Table). At least one biomarker was available for 123 subjects (86.6%). TROP2 expression (n=61) was Medium/High (M-H: 101-300) in 43 pts (70.5%) and Low (L: 0-100) in 18 (29.5%). PD-L1 central assessment (n=120) revealed CPS ≥1 (PD-L1+) in 32 pts (26.7%) and <1 (PD-L1-) in 88 (73.3%); only 7 (5.8%) pts had CPS ≥10. sTILs (n=87) were ≥10% in 14 pts (16.1%) and <10% in 73 (83.9%). When analyzing TROP2 and PD-L1 (n=61), 15 pts (24.6%) were TROP2-M-H/PD-L1+, 28 (45.9%) were TROP2-M-H/PD-L1-, 5 (8.2%) were TROP2-L/PD-L1+, and 13 (21.3%) were TROP2-L/PD-L1-. When analyzing TROP2 and sTILs (n=54), 6 pts (11.1%) were TROP2-M-H/sTILs ≥10%, 32 (59.3%) were TROP2-M-H/sTILs <10%, 2 (3.7%) were TROP2-L/sTILs ≥10% and 14 (25.9%) were TROP2-L/sTILs <10%. For TROP2 and HER2 (n=46), 26 pts (56.5%) had TROP2-M-H/HER2-low tumors, 7 (15.2%) TROP2-M-H/HER2-0, 3 (6.5%) TROP2-L/HER2-low, and 10 (21.7%) TROP2-Low/HER2-0. Median OS (n=138) was 43.8 months; stratification for selected biomarker combinations will be presented although no statistical significance was found. Correlations with NGS data and HER2DX are ongoing and will be presented. Conclusions: Analyzing biomarkers of interest in pts with HR+ mBC unveiled diverse patterns, without associations with OS. Patient characteristics. [Table: see text]

HOPE: Harnessing olaparib, palbociclib, and endocrine therapy for BRCA1/2-associated HR+, HER2- metastatic breast cancer.

10616 Background: Thepoly (ADP-ribose) polymerase inhibitor olaparib yields superior progression-free survival, response rates and patient-reported outcomes compared with chemotherapy in patients with BRCA1- or BRCA2- ( BRCA1/2) associated metastatic breast cancer (MBC). Fulvestrant and palbociclib improve outcomes in patients with hormone receptor-positive (HR+) MBC. HOPE (NCT03685331) is a phase I trial to evaluate combination olaparib (O), fulvestrant (F), and palbociclib (P) in patients with BRCA1/2-associated HR+, HER2 negative MBC. Methods: A 3+3 dose escalation was used to assess safety and preliminary efficacy of O, F and P. Eligible participants (pts) had HR+ MBC, a germline (g) or somatic (s) mutation in BRCA1/2, measurable/evaluable disease, any/no prior endocrine therapy, and 0-2 prior lines of chemotherapy for MBC. Prior PARPi and CDK4/6i were permitted but not in combination. Palbociclib was added after a 28-day safety run-in (Cycle 0) of O + F alone. Fulvestrant dose was 500mg IM on day 1 of each 28-day cycle. Dose level 0 (DL0, starting level) was F, O 300mg orally BID continuously, P 75mg orally daily on days 1-21; DL-1 was F, O 250mg orally BID, P 75mg orally daily on days 1-21. The primary endpoint was MTD (adverse events (AEs) based on CTCAE v5.0). Dose limiting toxicity (DLT) period included Cycles 0 and 1. A 30% DLT rate was acceptable; 6 pts had to be treated at a dose for it to be declared MTD. RECIST v1.1 was used to evaluate response. Results: Eight treated pts (s BRCA1:1 ;g BRCA2:6; s BRCA2:1 ) had median (M) age 47; M 0 (0-2) prior lines of endocrine therapy and 0 (0-1) prior chemotherapies for MBC. Three pts each had received O, F, and CDK4/6i as part of their standard of care treatment before study. At DL0, 2/2 pts had DLT with persistent grade(G) 3 neutropenia. Among 6 pts treated at DL-1, none experienced DLT, but 3 pts missed doses of study treatment due to cytopenias (G3 neutropenia, G3 leukopenia, G3 thrombocytopenia) during the DLT period. Following the DLT period, 1 pt reduced O to 200mg orally daily and 1 discontinued P based on provider discretion due to cytopenias (G3 neutropenia, G3 thrombocytopenia). Grade 3 AEs occurring in >1 pt related to study treatment were: neutrophil count decrease (G3/2, n=5/2); white blood cell decrease (G3/2/1, n=3/2/2); platelet count decrease (G3/2/1, n=2/0/1). Overall related AEs in >50% of pts were anemia (n=7), fatigue (n=6) and nausea (n=5). Best responses were CR/PR/SD/PD in 1/1/5/1 pts. Conclusions: MTDof O, F and P (DL-1) was reached and demonstrated antitumor activity. Although no AEs meeting protocol-specified DLT criteria were observed at MTD, hematologic toxicity at this dose complicated drug delivery and required close monitoring during and after the DLT period. Combinations utilizing PARP1 selective inhibitors, lower doses of therapy or sequential rather than combination therapy may improve feasibility. Clinical trial information: NCT03685331 .

Abstract PO1-06-03: Efficacy of First-line Treatments for Hormone Receptor-positive, Human Epidermal Growth Factor Receptor 2-positive Metastatic Breast Cancer: A Systematic Literature Review and Network Meta-analysis Feasibility Assessment

Abstract Background: A comprehensive summary of clinical evidence for first-line (1L) treatments for hormone receptor-positive, human epidermal growth factor receptor 2-positive (HR+/HER2+) advanced or metastatic breast cancer (mBC) is needed to understand which treatments have been evaluated and the outcomes associated with different treatments. Understanding the available clinical evidence for HR+/HER2+ mBC 1L treatments can also inform the feasibility of network meta-analyses (NMAs) to estimate relative treatment effects where head-to-head trials are not available. The objective was to prepare a systematic summary of clinical trials of 1L treatments for HR+/HER2+ mBC and assess the feasibility of NMAs for key efficacy outcomes. Methods: A systematic literature review (SLR) was conducted per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Clinical trials evaluating 1L treatments for adults with HR+/HER2+ mBC published between January 2000 and January 2023 were identified via predefined searches of databases (Embase, MEDLINE, Cochrane Library), relevant congress proceedings, and ClinicalTrials.gov (updating a previous SLR covering January 2000 to December 2020). Study design characteristics, patient characteristics, and efficacy outcomes were extracted from identified trials. An NMA feasibility assessment that considered network connectivity and cross-study heterogeneity was conducted for four efficacy outcomes of interest: progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR). Results: After screening, 37 records reporting on 23 unique studies (11 randomized controlled trials [RCTs] and 12 single-arm trials; 35 study arms in total) were selected. Included trials were mostly phase II or phase III multi-country studies that evaluated a HR+ or HER2+ population, with outcomes being reported for the subgroup of patients with the HR+/HER2+ subtype. Treatments evaluated included one or two anti-HER2 therapies (AHTs) + endocrine therapy (ET) (5/35 study arms), AHTs + chemotherapy (CT) (20/35), AHTs + ET + CT (2/35), AHTs alone (5/35), and ET alone (3/35). For HR+/HER2+ patients, PFS and OS were reported by 17/23 and 10/23 studies, respectively. Reported median PFS and OS ranged from 2.4-23.7 months and 23.9-66.7 months, respectively. Among the 11 included RCTs, hazard ratios and/or Kaplan-Meier curves, which were considered a requirement for NMAs for time to event outcomes, were reported for PFS and OS by 9 and 6 studies, respectively. Among these studies, reported median PFS and OS ranged from 2.4-19.2 months and 23.9-57.9 months, respectively. For HR+/HER2+ patients, ORR and CBR were reported by 13/23 and 6/23 studies, respectively. Assuming all CTs could be considered equivalent treatments and all ETs could be considered equivalent treatments, NMAs involving networks of 9, 6, 6, and 3 treatments were feasible for PFS, OS, ORR, and CBR, respectively. Some patient characteristics including time since mBC diagnosis and proportion with bone metastases were not reported consistently across trials. However, included studies were broadly comparable based on study design characteristics, outcome definitions and other reported patient characteristics such as age and Eastern Cooperative Oncology Group performance status. Conclusion: Clinical trials in 1L HR+/HER2+ mBC have evaluated various combinations of AHTs, CTs, and ETs, with most study arms being AHTs + CT. Although efficacy outcomes of interest were not consistently reported across trials, NMAs were found to be feasible for PFS, OS, ORR, and CBR based on available data. Citation Format: Priyanka Sharma, Chau Dang, Christopher Drudge, Amrita Debnath, Manvir Rai, Eric Gauthier, Edward Broughton. Efficacy of First-line Treatments for Hormone Receptor-positive, Human Epidermal Growth Factor Receptor 2-positive Metastatic Breast Cancer: A Systematic Literature Review and Network Meta-analysis Feasibility Assessment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-03.

Abstract PO4-04-10: Selection criteria for second-line treatments after Cyclin-dependent kinase 4/6 inhibitors failure in Hormone Receptor positive metastatic breast cancer patients: the preliminary experience of the HERMIONE-13 trial

Abstract BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represent the standard of care for hormone receptor-positive (HR+)/Human Epidermal Growth Factor 2 negative (HER2-) metastatic breast cancer (MBC); no consensus actually exists for second-line (2L) treatments. The HERMIONE-13 trial evaluates the adopted therapeutic options after CDK4/6i failure and the potential factors that influence these choices. METHODS: HERMIONE-13 is a retrospective and prospective multicentric observational trial involving 15 Italian Centers. Information about therapies after disease progression to CDK4/6i from January 2016 until December 2020 was collected for the present analysis, aiming at evaluating which are the clinical criteria guiding the choice of 2L therapy after CDK4/6i failure. RESULTS: 114 pts have been enrolled: 14 pts (12.3%) received neoadjuvant treatment, 80 (70.2%) adjuvant therapy, of whom 46 (57.5%) chemotherapy (CT)+ endocrine therapy (ET) and 33 (41.3%) ET alone. Among the 79 pts treated with adjuvant ET, 44 pts (55.7%) showed primary or secondary endocrine resistance. 39 pts (34.2%) received first-line (1L) CDK 4/6i in combination with Fulvestrant (F), the remaining with aromatase inhibitors (AIs). Median duration of 1L CDK4-6i was 10.4 months (interquartile range (IQR) 4.7-17.4). Median age at 2L start was 59.5 years (IQR 51-68). As 2L therapy, 79 pts (69.3%) received CT±targeted therapy (TT) and 35 (30.7%) ET±TT. Visceral metastases at the beginning of 2L were documented in 46 pts (40.4%). Comorbidities were present in 48 (42.9%) of the pts, mainly cardiac diseases (25, 22.3%); 71 pts (63.4%) showed a 1L-related adverse events (AEs) (NA: 2 pts), mainly hematological toxicity (60, 53.6%). Among 79 pts treated with adjuvant ET, 60 (76%) were addressed to 2L CT±TT, while 19 (24%) to an ET-based therapy. A longer duration of 1L was observed in pts treated with 2L ET±TT (12.5 months, 7.2-22.2) in comparison with those treated with CT±TT (8.7 months, 4.2-14.9). The majority of pts treated with 1L F+CDK 4/6i underwent 2L CT-based treatment, as summarized in Table 1. Analyzing the population treated with 2L CT±TT, we observed that median age was 58 years (49-67), slightly lower than that of pts treated with ET±TT (63, 54-69). Among pts with visceral metastases, 30 pts (65.2%) were addressed to 2L CT±TT and 16 pts (34.8%) to ET±TT; CT±TT was also the favorite choice for the majority of pts with concomitant disease (33, 68.8%) and with previous CDK4/6i-related toxicity (47, 66.2%). Among age, visceral metastases, comorbidities, adjuvant treatment, duration of 1L therapy, use of 1L F and 1L related AEs, univariate analysis revealed that previous use of adjuvant ET (p=0.021), 1L F (p< 0.001), duration of 1L treatment (p=0.043) and age at 2L start (p=0.053) are all factors influencing the choice of 2L therapy. At the multivariate logistic regression model, only the use of F in association with CDK4/6i as 1L treatment and age at 2L therapy were associated with the choice between ET±TT vs CT± TT, with a backward selection, as summarized in table 2. CONCLUSION: The preliminary results of our study suggest that previous F in combination with CDK4/6i is a statistically confirmed predictor of choice for subsequent CT, whereas the increase in age is significantly associated with the choice for ET. Further research is needed to investigate the optimal sequencing of treatments following CDK4/6i and to determine predictive factors of response to 2L therapies. Table 1 2L choices in 1L F+CDK 4/6i pts. Table 2 Statistical model with the significant variables. Citation Format: Marina Elena Cazzaniga, Emanuela Rossi, Antonella Turla, Massimo Ambroggi, Alice Baggi, Rossana Berardi, Fulvio Borella, Serena Capici, Federica Cicchiello, Luigi Coltelli, Ugo De Giorgi, Antonella Ferro, Ornella Garrone, Monica Giordano, Elisabetta Landucci, Marco Mazzotta, Gabriella Moretti, Raffaella Palumbo, Francesca Fulvia Pepe, Patrizia Vici, Fable Zustovich, Viola Cogliati. Selection criteria for second-line treatments after Cyclin-dependent kinase 4/6 inhibitors failure in Hormone Receptor positive metastatic breast cancer patients: the preliminary experience of the HERMIONE-13 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-10.

Abstract PO4-15-04: Differential genomic profiling of progesterone receptor (PR) negative, estrogen receptor (ER) positive HER2-negative metastatic breast cancer (MBC) through circulating tumor DNA

Abstract Background: MBC is usually classified based on ER and HER2 status. Although the absence of PR expression is commonly associated with a poorer response to endocrine therapy (ET) and an unfavorable prognosis, data regarding the underlining molecular features that occur in this subgroup are still unclear. The aim of this study was to investigate genomic differences between ER/PRpos HER2neg (PRpos) and ERpos PR/HER2neg (PRneg) MBC through circulating tumor DNA (ctDNA) profiling in a large multicenter consortium. Methods: This retrospective study analyzed a cohort of 1089 patients at Weill Cornell Medicine, Northwestern University, Massachusetts General Hospital, and Washington University in St. Louis with HER2neg MBC and ctDNA testing by Guardant360. Oncogenic pathway status (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, and PI3K) was defined based on previous research (Sanchez-Vega et al. Cell, 2018). Associations across single nucleotide variations (SNVs), copy number variations (CNVs), pathway classification, and ER/PR status were tested by multinomial logistic regression and corrected for significant clinical characteristics (i.e., lines of treatment, metastatic sites). Prognosis was analyzed through Cox regression for overall survival (OS) defined from time of ctDNA collection. Results: Among the 1089 analyzed patients, PRpos was the most represented subtype (N:580, 53%), followed by PRneg (N:300, 28%) and Triple Negative (TNBC) (N:209, 19%). In the hormone receptor positive subgroup, bone (N:663, 75%), liver (N:323, 37%) and lymph nodes (N:314, 36%) were the main sites of distant involvement. The TNBC group was exposed to significantly fewer lines of therapy (RRR:0.37, P= 0.005 for ≥5 lines). As compared to PRneg, TNBC had less frequent and PRpos had more frequent bone involvement (RRR:0.44, P< 0.001 and RRR:1.80, P< 0.001, respectively) and less frequent liver involvement (RRR:0.64, P=0.019 and RRR:0.71, P=0.020, respectively for TNBC and PRpos). After multivariable analysis, a significant difference with respect to PRneg was observed in SNVs for the PI3K and P53 pathways for TNBC (RRR 0.49 P = 0.013 and RRR 4.06 P < 0.001, respectively) but not for PRpos. On a single gene level, a lower incidence in CDH1 SNVs (RRR 0.09 P = 0.036) and a higher incidence of ESR1 SNVs (RRR 0.09 P = 0.036) was present in PRpos compared to PRneg. TNBC, on the other hand, was characterized by a lower prevalence of KRAS SNVs (RRR 0.09 P = 0.036) and PIK3CA SNVs (RRR 0.25 P < 0.001) and a higher prevalence of TP53 SNVs (RRR 0.09 P < 0.001). No ESR1mutations were detected in TNBC. Median OS was 15 months (mo) for TNBC, 21 mo for PRneg and 31 mo for PRpos (P < 0.001). The differential prognostic impact of ctDNA features on OS was then analyzed across the PRpos and PRneg subpopulations. ESR1 SNVs was prognostic for both subgroups in univariable analysis (HR 2.19 P < 0.001 and HR 1.96 P = 0.001 for PRpos and PRneg, respectively). In multivariable analysis corrected for lines of therapy, ESR1 SNVs retained its significance only in the PRpos subgroup (HR 1.41 P = 0.021) together with NF1 SNVs (HR 2.04 P = 0.034). On the other hand, TP53 SNVs had a significant impact on OS in the PRneg subgroup (HR 2.02 P = 0.014). Conclusions: Our study confirmed the prognostic impact of PR status in ER positive, HER2 negative MBC. Moreover, it suggested a differential profile in terms of ctDNA-detectable genomic features and their impact on survival, including well-established markers such as ESR1 SNVs, with a potential relevance for disease subtyping and future algorithms for drug development trials. Citation Format: Lorenzo Gerratana, Andrew Davis, Arielle Medford, Carolina Reduzzi, Katherine Clifton, Emily Podany, Whitney Hensing, Marko Velimirovic, Ami N. Shah, Lorenzo Foffano, Laura Munoz Arcos, Eleonora Nicolò, Charles S. Dai, Jennifer Keenan, Amir Behdad, Seth Wander, William Gradishar, Cynthia Ma, Fabio Puglisi, Aditya Bardia, Massimo Cristofanilli. Differential genomic profiling of progesterone receptor (PR) negative, estrogen receptor (ER) positive HER2-negative metastatic breast cancer (MBC) through circulating tumor DNA [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-15-04.

Abstract PO5-19-05: A Phase II Trial of Stereotactic Body Radiation Therapy and Fluoroestradiol Positron Emission Tomography in Patients with Oligoprogressive Estrogen Receptor Positive Metastatic Breast Cancer

Abstract Background: The term oligoprogression (OP) refers to a clinical scenario in which patients with diffuse metastatic disease on systemic therapy have a limited number of metastases that have progressed or are new whereas the majority of metastases are stable or improved. OP disease is increasingly being encountered in clinical practice due to improvements in systemic therapy. Treating OP disease with local ablative therapies may therefore prolong the time to more diffuse progression necessitating a change in systemic therapy and may therefore lead to improved overall survival in these patients. Only one study has evaluated the role of SBRT in patients with OP MBC. This trial accrued 47 patients with OP MBC, with 2/3 having triple negative disease. There was no difference in PFS between patients that received SBRT versus those that did not (4.2 months vs. 4.4 months, p=0.2). Whether ablative therapies are beneficial in subtypes of breast cancer that have many effective systemic therapies available, such as ER+ breast cancer, remains an open question and an unmet clinical need. Design: Phase II study for patients with OP ER+ MBC (1-4 new and/or progressing metastatic lesions). Eligible patients will receive stereotactic body radiation therapy (SBRT) to the OP lesions. SBRT will be delivered to each lesion in 3-5 fractions. Each patient’s systemic therapy regimen will be held during study therapy and will resume upon completion of study therapy. Patients will then be restaged at 12 weeks post-SBSRT. Patients that have at least stable disease at that time point will continue on their systemic therapy and then be re-staged 12 weeks later (24 weeks after SBRT). This study will also study the role of ER-targeted positron emission tomography (PET) imaging with 16α-18F-Fluoro-17β-Fluroestradiol (FES) in the OP ER+ patient population with FES PET scans obtained at baseline, and at each of the 2 follow-up imaging timepoints. A key secondary hypothesis is that the use of FES PET in addition to standard imaging at baseline and in follow-up will help confirm patients have OP disease and will help assess for new lesions on subsequent restaging. Eligibility: Key inclusion criteria: age≥18 yo; histologically confirmed ER+/HER2- metastatic breast cancer; the presence of metastatic breast cancer at the time of study entry with progression in 1-4 lesions (including new lesions); SBRT must be feasible for all progressing lesions. Key Exclusion Criteria: >2 lines of systemic therapy for metastatic disease; intracranial disease progression Objective: To determine whether using SBRT to treat OP lesions allows ER+ breast cancer patients to continue on their current systemic therapy for at least 24 weeks post SBRT. Objective: To assess whether FES-PET increases the number of lesions found prior to SBRT; To determine the impact of SBRT on patient quality of life; time to next line systemic therapy; PFS Statistical Methods Simon 2 stage optimal design with α=0.05 and 1-β=0.80. The null hypothesis is that the proportion of patients that remain on their original systemic therapy ≥24 weeks (2 restaging scans) post-treatment is 20%. The alternative hypothesis is that the proportion of patients that remain on their original systemic therapy after 2 restaging scans is 50%. In stage 1, 8 patients that proceed to SBRT will be enrolled. The study will be terminated if only 0 or 1 subjects remain on original systemic therapy after 2 restaging scans. However, if ≥2 patients remain on original systemic therapy after 2 restaging, then an additional 10 patients would be enrolled for a total of 18 patients. The null hypothesis will be rejected if ≥6 patients remain on their original systemic therapy after 2 restaging scans. Contact Information: Jose G. Bazan (jbazan@coh.org) Funding Source: City of Hope Comprehensive Cancer Center Citation Format: Jose Bazan, Joanne Mortimer, Yun-Rose Li. A Phase II Trial of Stereotactic Body Radiation Therapy and Fluoroestradiol Positron Emission Tomography in Patients with Oligoprogressive Estrogen Receptor Positive Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-05.

Abstract PO4-12-10: Sacituzumab Govitecan Toxicity Outcomes In Arab Patients with Metastatic Breast Cancer

Abstract Background: The Arab population is often underrepresented in clinical trials, which limits our knowledge of drug safety and efficacy in this population due to genetic variability that can affect drug metabolism and adverse events (AEs). Sacituzumab govitecan (SG) is approved for metastatic triple negative breast cancer (mTNBC), and recently hormone receptor positive metastatic breast cancer (HR+ MBC). Here we report toxicity outcomes and RDI in Arab population. Methods: A multi-center retrospective study of patients with mTNBC and HR+ MBC treated with SG from January 2021 until May 2023 was conducted. Demographics and clinical variables including site of metastases, prior lines of therapy, relative dose intensity (RDI), adverse events (AEs) were collected. For continuous variables, Mann-U Whitney and Kruskal Wallis tests were used to compare mean, median, standard deviation, and range. For categorical variables, Fisher's exact tests and Pearson Chi-square tests were used. SAS v9.4 was used to perform statistical analysis at a significance level of 0.05. Results: A total of 35 patients was enrolled. The median age at diagnosis of metastatic breast cancer was 39 years interquartile range (IQR) (35, 44). The median age at starting SG was 44.5 years IQR (38,50). The majority of patients (65%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1, (21%) of the patients had an ECOG PS of 0, and (15%) had an ECOG PS of 2. 48.6% received 3 or more lines of prior therapy in the metastatic setting while 51.4% received less than 3 lines of prior therapy in the metastatic setting. 77.1% of patients had 3 or > organs involved with metastatic disease, while 22.9% of patients had < 3 organ involved. The most common metastatic sites were the lung (54.3%), liver (62.9%), bone (68.6%), and brain (45.7%). The median RDI of SG was 100% for a sample of 34 individuals, with one missing value IQR (94%,100%). The rate of overall AEs was (77.1%), with the most common AEs being; neutropenia (44.4%), diarrhea (37.0%), anemia (22.2%), thrombocytopenia (22.2%), nausea (14.8%), and vomiting (7.4%). Garde 3 AEs rate was 34.3%. The most common grade 3 adverse events were diarrhea (11.4%), fatigue (5.7%), and alopecia (2.9%). The rate of treatment interruption and dose reduction due to AEs was 31.4%. Only one patient (2.9%) had to discontinue SG treatment due to adverse events. Conclusion: The study suggests that SG is safe and well-tolerated in young Arab patient population. The sample consisted of relatively young patients, which may reflect a reluctance to prescribe SG to older Arab patients. Caution should be exercised when generalizing the findings due to limitations of the study. Further studies with larger sample sizes are needed to validate these findings and to explore the efficacy of SG in Arab patients with mTNBC and HR+ MBC. Citation Format: Maymouna Altarturi, Kausar Suleman, Adhar AlSayed, Humaid Al-Shamsi, Aydah Alawadhi, Bassam Basuliamn, Sabah Alaklabi. Sacituzumab Govitecan Toxicity Outcomes In Arab Patients with Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-12-10.

Abstract ED10-01: PI3K past, present, and future

Abstract The PI3K pathway has long remained a fertile ground for drug discovery in cancer, including in estrogen receptor positive metastatic breast cancer. It has also remained a pathway difficult to drug effectively due to on target toxicities. New strategies to overcome these toxicities have manifested in novel drug types and management strategies for patients. Here I discuss the PI3K pathway in signaling and oncogenesis, current therapies inhibiting PI3K, mechanisms limiting efficacy, and increasing the PI3K therapeutic window with a focus on mutant selective PI3K inhibitors. Finally, I will expound on the translational future of the PI3K field, highlighting advances in biomarker discovery, tumor correlative analysis, and patient advocacy. Citation Format: N. Vasan. PI3K past, present, and future [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr ED10-01.

Abstract PO1-19-11: Phase 3 Study of Tucatinib or Placebo in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy for HER2+ Metastatic Breast Cancer (HER2CLIMB-05, Trial in Progress)

Abstract Background The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in patients with untreated and/or active BM (Murthy et al. NEJM 2020, Curigliano et al. Ann Oncol 2022). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 patients will be enrolled. Eligible patients will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Patients will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Patients with hormone receptor-positive disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS, time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a two-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in Austria, Chile, Greece, Italy, Japan, Poland, Portugal, Spain, the US, and several other European, APAC, and LATAM countries. This abstract was previously presented at ESMO-BC 2022, FPN (Final Publication Number): 415, by Veronique Dieras (reused with permission). Citation Format: Erika Hamilton, Junji Tsurutani, Giuseppe Curigliano, Miguel Martín, Ciara O'Sullivan, Joo Hyuk Sohn, Konstantinos Tryfonidis, Libero Santarpia, Shan Yang, Véronique Diéras. Phase 3 Study of Tucatinib or Placebo in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy for HER2+ Metastatic Breast Cancer (HER2CLIMB-05, Trial in Progress) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-11.

Abstract PO1-04-14: PLK1 Inhibitor Onvansertib Extends the Response and Overcomes Resistance to Paclitaxel in Palbociclib-resistant HR+ Breast Cancer Patient-derived Xenografts

Abstract Paclitaxel is a first-line chemotherapy for hormone receptor positive (HR+) metastatic breast cancer patients after progression on a combination of endocrine and CDK4/6 inhibitor therapy. Response rate to paclitaxel ranges between 20-40%, and most patients progress due to intrinsic or acquired resistance, leaving them with limited treatment choices. Therapeutic strategies to overcome paclitaxel resistance and extend its clinical benefit are urgently needed. Paclitaxel-resistant tumors have increased expression of polo-like kinase 1 (PLK1), a serine-threonine-protein kinase that regulates mitosis and cell cycle progression. PLK1 has also been shown to mediate resistance to CDK4/6 inhibitor palbociclib in HR+ breast cancer. Onvansertib is an orally bioavailable, highly potent, and selective PLK1 inhibitor in clinical development. Onvansertib exhibited synergy in vitro and showed potent anti-tumor activity in vivo in combination with paclitaxel in ovarian cancer and triple negative breast cancer (TNBC) preclinical models. A phase 1b/2 clinical trial is ongoing to evaluate the safety and efficacy of onvansertib plus paclitaxel in advanced TNBC (NCT05383196). Here we investigated whether the potential of onvansertib and paclitaxel combination could be extended to HR+ breast cancer. Co-treatment with onvansertib and paclitaxel synergistically inhibited the viability of HR+ breast cancer cell lines (MCF-7, T-47D, EFM-19, CAMA-1, ZR-75-1). Compared to the single agents, the combination induced increased apoptosis. The combination was further tested in vivo in patient-derived xenograft (PDX) models. To this end, six HR+ breast cancer PDXs with intrinsic or acquired resistance to palbociclib were established from primary breast tumors (n=1) or metastatic bone biopsies (n=5). The PDX tumors were engrafted subcutaneously in nude mice and the effect of onvansertib (45 mg/kg, oral, 5 days a week) and paclitaxel (15-25mg/kg, IP, once a week) was investigated as monotherapy and in combination. The combination of onvansertib and paclitaxel was tolerated with minimal toxicity and showed enhanced anti-tumor activity compared to either agent alone in all 6 PDX models. Paclitaxel and onvansertib monotherapies had little to no anti-tumor activity in 4 out of 6 PDX models (HBCx124palboR25, HBCx-139 palboR5, HBCx-202 and HBCx-131). Importantly, the combination of onvansertib and paclitaxel induced strong anti-tumor activity in these 4 models. Tumor regression was observed in the 2 PDX models with acquired resistance to palbociclib, HBCx-124palboR25 and HBCx-139palboR5, with 62% (5/8 mice) and 54% (6/11 mice) complete response rates, respectively. The combination showed tumor stasis in HBCx-131 and induced tumor regression in HBCx-202, established from patient resistant to palbociclib. In 2 of the 6 PDXs, paclitaxel exhibited anti-tumor activity, inducing tumor regression in HBCx-137paboR26 and tumor stasis in HBCx-86. In comparison, the combination of onvansertib and paclitaxel had greater activity, inducing tumor regression in both models with a higher rate of complete response than the monotherapy. Complete response rates for paclitaxel versus the combination were 62% and 100% in the HBCx-137palboR26 model and 0% and 67% in the HBCx-86 model. Notably, the antitumor activity of the onvansertib and paclitaxel combination was very durable, showing a robust delay in tumor relapse after stopping therapy. Together, our data strongly support that combining paclitaxel with the PLK1 inhibitor onvansertib extends its benefit and overcomes paclitaxel resistance, and represents a promising therapeutic strategy for HR+ breast cancer patients after progression on a combination of endocrine and CDK4/6 inhibitor therapy. Citation Format: Maya Ridinger, Pierre Painsec, Sreeja Sreekumar, Dalia Gonzalez, Davis Klein, Laura Sourd, Elodie Montaudon, Paul Cottu, Tod Smeal, Elisabetta Marangoni. PLK1 Inhibitor Onvansertib Extends the Response and Overcomes Resistance to Paclitaxel in Palbociclib-resistant HR+ Breast Cancer Patient-derived Xenografts [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-14.

Abstract PO1-04-13: CARDIAC-STAR: Prevalence of Cardiovascular Comorbidities in Hormone Receptor Positive Human Epidermal Growth Factor Negative metaStatic breasT cAnceR

Abstract BACKGROUND: Baseline cardiovascular (CV) comorbidities can impact treatment decisions for patients (pts) with metastatic breast cancer (mBC). There is limited data on the prevalence of CV comorbidities at the time of hormone receptor positive human epidermal growth factor negative (HR+/HER2-) mBC diagnosis. The primary objective of this study is to describe the prevalence of pre-existing CV comorbidities in women and men with newly diagnosed HR+/HER2- mBC. A secondary objective is to describe the first documented cancer treatment for patients with or without CV comorbidities. METHODS: Women and men ≥18 years of age with newly diagnosed HR+/HER2- mBC from 01/2016 to 12/2021 were included in this retrospective, observational study using the Merative™ Marketscan® Commercial and Medicare Databases which is nationally representative. Evidence of mBC was defined as having two or more claims containing one or more diagnosis code for BC at least 30 days apart and at least two secondary malignancy diagnosis codes. Previously published claims-based algorithms were used to identify the HR+/HER2- molecular subtype. The index date is defined as the date of first mBC diagnosis. Patients had a 1-year pre-index period for observation of CV comorbidities and a 6-month post-index period for first documented cancer treatmen RESULTS: We identified 5,452 pts with HR+/HER2- mBC, 99% of whom were female, with a median age of 58 years (yrs) (IQR 13), and 83% having a health plan from an employer; i.e., are still employed. At mBC diagnosis, 3,335 pts (61.2%) had at least one pre-existing CV comorbidity (see Table). The most reported CV comorbidities were hypertension (50.7%), hyperlipidemia (33.7%), and diabetes (19.2%). The median age of pts with or without a CV comorbidity was 61 and 52 yrs, respectively; 16.2% with CV comorbidities were ≥75 yrs. Additional data, including first documented treatment, will be presented at the meeting. CONCLUSIONS: The prevalence of CV comorbidities in pts with HR+/HER2- mBC is often underrecognized. In this analysis, more than half of pts had at least one CV comorbidity by mBC diagnosis. CV comorbidities may impact treatment decisions in the HR+/HER2- mBC population, particularly in older pts. Table Citation Format: Susan Dent, Avirup Guha, Heather Moore, Rachael McCaleb, Irene Arias, Stella Stergiopoulos, Benjamin Li, Doris Makari, Michael Fradley. CARDIAC-STAR: Prevalence of Cardiovascular Comorbidities in Hormone Receptor Positive Human Epidermal Growth Factor Negative metaStatic breasT cAnceR [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-13.

Cost of disease progression among US patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.

Aim: The objectives were to investigate the differences in per patient per month (PPPM) healthcare resource utilization (HCRU) and costs among commercially insured and Medicare Advantage patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (mBC) who experience disease progression in 12months compared with those who don't investigate the impact of progression timing on cumulative healthcare costs. Patients & methods: This claims-based study included patients diagnosed with mBC between 1January 2013 and 30April 2020 and received HER2-targeted therapy. Patients were categorized as progressed or nonprogressed. For objective one, monthly HCRU and costs were assessed for up to two lines of therapy (LOTs). Data were summarized descriptively and compared using a generalized linear model (GLM). For objective two, patients with at least 6 months of follow-up were assessed and cumulative healthcare costs were estimated in the 3 years following the start of LOT1 or LOT2 using a GLM and Kaplan-Meier weighting. Results: Among the 4113 patients in the study sample, 3406 had at least 12 months of follow-up (or less if due to death). Compared with nonprogressed patients, progressed patients had higher mean PPPM healthcare costs (LOT1: $22,014 vs $18,372, p<0.001; LOT2: $19,643 vs $16,863, p=0.001), and HCRU, including number of emergency room visits and inpatient stays (both p<0.001) in the 12 months following LOT start. Progressed patients had higher 3-year mean cumulative healthcare costs than nonprogressed patients following LOT1 and LOT2 and this difference was greater for patients who progressed earlier. Conclusion: Disease progression was associated with significant increases in HCRU and costs. Delays in progression were associated with lower cumulative healthcare costs. Earlier use of more clinically effective treatments to delay progression may reduce the economic burden among these patients.

Efficacy and safety of Trastuzumab Emtansine in treating human epidermal growth factor receptor 2-positive metastatic breast cancer in Chinese population: a real-world multicenter study.

Trastuzumab emtansine (T-DM1) has been approved worldwide for treating metastatic breast cancer (mBC) in patients who have received first-line therapy, shown disease progression, and are human epidermal growth factor receptor 2 (HER2)-positive. T-DM1 received approval in China to treat early-stage breast cancer (BC) in 2020 and for mBC in 2021. In March 2023, T-DM1 was included in medical insurance coverage, significantly expanding the eligible population. This post-marketing observational study aimed to assess the safety and effectiveness of T-DM1 in real-world clinical practice in China. This study enrolled 31 individuals with HER2-positive early-stage BC and 70 individuals with HER2-positive advanced BC from 8 study centers in Shandong Province, China. The T-DM1 dosage was 3.6 mg/kg injected intravenously every 3 weeks until the disease advanced or the drug toxicity became uncontrollable, whichever occurred earlier. Additionally, efficacy and safety information on T-DM1 were collected. During the 7-month follow-up period, no recurrence or metastases were observed in patients who had early-stage BC. The disease control rate was 31.43% (22/70) in patients with advanced BC. The most common adverse effect of T-DM1 was thrombocytopenia, with an incidence of 69.31% (70/101), and the probability of Grade ≥ 3 thrombocytopenia was 11.88% (12/101). This real-world study demonstrated that T-DM1 had good efficacy and was well tolerated by both HER2-positive early-stage BC and mBC patients.

CDK4/6 Inhibitor Efficacy in ESR1-Mutant Metastatic Breast Cancer

BackgroundIn estrogen receptor–positive metastatic breast cancer, ESR1 mutations (ESR1m) are a common mechanism of acquired resistance to aromatase inhibitors (ArIh). However, the impact ESR1 alterations have on CDK4/6 inhibitor (CDK4/6i) sensitivity has not been established. Analyses of CDK4/6i trials suggest that the endocrine therapy partner and specific ESR1 allele may affect susceptibility. We analyzed a real-world data set to investigate CDK4/6i efficacy in ESR1m metastatic breast cancer and associated clinical factors.MethodsESR1m were identified by analysis of circulating-tumor deoxyribonucleic acid. The GuardantINFORM database contains genomic information from tumors linked with claims data. Patients who started a CDK4/6i within 30 days of sequencing were categorized as having ESR1m or non-ESR1–mutant (non-ESR1m) breast cancer. Data were analyzed to determine the real-world time-to-next-treatment, defined as the start of a breast cancer treatment to initiation of the subsequent treatment.ResultsOne hundred forty-five patients with ESR1m and 612 with non-ESR1m metastatic breast cancer were analyzed. ESR1m and non-ESR1m tumors had similar real-world time-to-next-treatment on CDK4/6i regimens (hazard ratio, 1.02; 95% confidence interval, 0.82 to 1.23). Duration on therapy in the first-line and second-line plus treatment settings were comparable regardless of ESR1 status. We stratified treatment duration by concurrent endocrine therapy, and patients with ESR1m had worse outcomes on ArIh but comparable real-world time-to-next-treatment on fulvestrant.ConclusionsThese data suggest ESR1 variants are not associated with pan-CDK4/6i resistance and are consistent with the hypothesis that CDK4/6 blockade combined with a selective estrogen receptor degrader is potentially an effective option for ESR1m metastatic breast cancer.