García-Sáenz, José Á.

Abstract Purpose: The aim of PREDICT was to confirm clinical validity and the potential for clinical utility of serial circulating tumor cell (CTC) enumeration in patients with metastatic breast cancer, focusing on its prognostic value in different breast cancer subtypes and clinical settings. Experimental Design: In total, 4,436 individual patient-level data with CTC results from both baseline and one follow-up (CellSearch; Menarini Silicon Biosystems) were analyzed to evaluate the association between CTC detection and overall survival (OS) in the full patient cohort and separately for tumor and treatment types. Results: Using the cutoff ≥1 CTC for CTC positivity, 913 (20.6%) patients had 0 CTCs at both time points (neg/neg) and 325 (7.3%) and 1,189 (26.8%) patients converted from CTC negative to CTC positive (neg/pos) or vice versa (pos/neg), whereas 2,009 (45.3%) patients had at least one CTC at both time points (pos/pos). The median OS for the neg/neg, neg/pos, pos/neg, and pos/pos group was 45.6, 26.1, 32.3, and 17.3 months, respectively (P < 0.0001, global log-rank test). CTC responders (pos/neg) showed a lower risk of death compared with CTC nonresponders (pos/pos; HR, 0.48; 95% confidence interval, 0.44–0.53). Similar results were obtained in subgroup analyses according to hormone receptor and HER2 subtype, treatment type, and with a ≥5 CTC cutoff for CTC positivity. Conclusions: Follow-up CTC assessments strongly predict OS independently from tumor subtype and treatment. New randomized trials to define the clinical utility of CTC monitoring for risk stratification and as an early response marker in metastatic breast cancer are urgently needed.

5589 Background: Imlunestrant is a next-generation oral SERD designed to deliver continuous estrogen receptor (ER) target inhibition aimed to improve outcomes for patients (pts) with ER+ cancers. In the first-in-human Phase 1a/1b EMBER trial (NCT04188548), imlunestrant showed favorable safety, pharmacokinetics, and clinical benefit in pre-treated pts with ER+ advanced breast cancer or EEC. Here, we report updated imlunestrant monotherapy data and the first clinical data of imlunestrant + abemaciclib in ER+ EEC pts from EMBER. Methods: Eligible pts had ER+ EEC previously treated with (or deemed inappropriate for) platinum-containing chemotherapy. Prior fulvestrant or aromatase inhibitor therapy was not allowed. In Phase 1a, pts received imlunestrant alone, and in Phase 1b, pts were randomized (1:1) to imlunestrant alone or with abemaciclib. Plasma samples were collected at baseline (all pts) and at cycle 2 (monotherapy pts) for ctDNA analysis (Guardant 360 assay) to correlate with clinical benefit. Primary endpoints were RP2D of imlunestrant monotherapy and in combination. Secondary endpoints included safety, tolerability, and overall response rate (ORR), clinical benefit rate (CBR: complete or partial response, or stable disease ≥24 weeks), and progression-free survival (PFS) using RECIST v1.1. Results: Overall, 72 pts were treated; 39 pts received monotherapy (33 at 400mg [RP2D] and 6 at 800mg po daily) and 33 pts received imlunestrant (29 at 400mg and 4 at 800mg po daily) + abemaciclib (150mg po twice daily). Baseline characteristics, safety, and preliminary efficacy are presented (Table). For monotherapy, the most common TEAEs (all grade/grade 3) were nausea (36%/3%), diarrhea (26%/0), urinary tract infection (26%/3%), and abdominal pain (21%/8%). For imlunestrant + abemaciclib, the most common TEAEs (all grade/grade 3) were diarrhea (88%/3%), nausea (67%/0), fatigue (49%/9%) and anemia (46%/12%). In the monotherapy arm, pts with deeper (≥ 50%) declines in ctDNA variant allele frequency had a higher CBR (4/7 vs 4/17). Conclusions: Imlunestrant, as monotherapy or with abemaciclib, appears safe and tolerable with preliminary evidence of efficacy in pts with metastatic ER+ EEC. Clinical trial information: NCT04188548 . [Table: see text]

A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity—findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.

Background Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

Abstract Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi‐state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non‐carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Abstract Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09–1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words)

This letter to the editor responds to Badoui et al. regarding data on abemaciclib dosages and adverse events.

Abstract Background: Several studies suggest clinical utility of serial circulating tumor cell (CTC) enumeration as a means of assessing response status in metastatic breast cancer (MBC). The aim of this study is to conduct a comprehensive pooled analysis comprising globally available data to further define and explore the role of CTC enumeration as a tool for early treatment monitoring in patients with MBC with a focus on the predictive power in different breast cancer subtypes and clinical settings. Methods: In a global effort, peer-reviewed published studies with data on repeated CTC assessments (CellSearch® technology; Menarini Silicon Biosystems; Bologna, Italy) in MBC patients were screened and investigators were asked to provide individual patient data for this pooled analysis. 2761 cases from 32 data sets with data on both baseline and one follow up CTC assessments were included in the analysis (median time interval between the two CTC assessments 35 days). Data were analyzed using log rank tests and Cox regressions to evaluate the association between serial CTC enumeration results and overall survival (OS) in the full patient cohort and defined subgroups. Results: 588 (21.3%) patients had no CTCs at both time points (neg/neg), 236 (8.5%) patients were CTC negative at baseline and CTC positive at follow up (neg/pos), 712 (25.8%) patients converted from CTC positive at baseline to CTC negative (pos/neg), and 1225 (44.4%) patients had at least one CTC at both time points (pos/pos). Log rank tests showed significant differences in OS between these four CTC change groups (p < 0.0001 for all pairwise comparisons except for the comparison between neg/pos and pos/neg, p = 0.015). Median OS for the neg/neg, neg/pos, pos/neg and pos/pos group was 45.6, 26.1, 34.6, and 17.6 months, respectively. Hazard ratios (HR) (reference group neg/neg) were 1.38 (95% CI 1.16 - 1.64) for the pos/neg group, 1.78 (95% CI 1.43 - 2.22) for the neg/pos group, and 3.06 (95% CI 2.63 - 3.56) for the pos/pos group. Results were similar if a cutoff of 5 CTCs was used for CTC positivity (pos/neg group: HR 1.43, 95% CI 1.25 - 1.63; neg/pos group: HR 2.39, 95% CI 1.91 - 2.99; pos/pos group: HR 3.54, 95% CI 3.12 - 4.02). In total, 2586 patients could be assigned to different tumor subtypes based on known hormone receptor (ER) and HER2 status of the primary tumor: 1513 (58.5%) patients had a luminal-like tumor (ER positive, HER2 negative), 682 (26.4%) patients had a HER2-positive tumor, and 391 (15.1%) patients had a triple-negative tumor. In patients with luminal-like tumors, the hazard ratios were 1.67 (95% CI 1.29 - 2.17), 2.01 (95% CI 1.45 - 2.77), and 3.87 (95% CI 3.09 - 4.83) for the pos/neg, neg/pos, and pos/pos group, respectively. In patients with HER2-positive tumors, the neg/pos group (HR 1.68, 95% CI 1.12 - 2.53) and the pos/pos group (HR 2.11, 95% CI 1.58 - 2.83) showed significantly worse OS compared to the neg/neg group, while in triple-negative patients, the pos/pos group had a significantly shorter OS compared to the neg/neg group (HR 2.99, 95% CI 2.11 - 4.24). The results will be up-dated by inclusion of additional large data sets (CALGB 40502, CALGB 40503, COMET, SWOG S0500, TBCRC 001) for the analysis to be presented at SABCS 2020. Conclusion: This large pooled analysis confirms that at a median of 35 days after treatment initiation, follow-up CTC assessments strongly predict overall survival. These results suggest potential clinical utility of CTC monitoring as early response marker in MBC, especially in luminal-like tumors. Citation Format: Wolfgang J Janni, Tracy C. Yab, Daniel F. Hayes, Massimo Cristofanilli, Francois-Clement Bidard, Michail Ignatiadis, Meredith M. Regan, Catherine Alix-Panabières, William E. Barlow, Carlos Caldas, Lisa A. Carey, Luc Dirix, Tanja Fehm, Jose A. Garcia-Saenz, Paola Gazzaniga, Daniele Generali, Lorenzo Gerratana, Rafael Gisbert-Criado, William Jacot, Zefei Jiang, Evi Lianidou, Mark J.M. Magbanua, Luis Manso, Dimitrios Mavroudis, Volkmar Müller, Elisabetta Munzone, Klaus Pantel, Jean-Yves Pierga, Brigitte Rack, Sabine Riethdorf, Hope S. Rugo, Kostandinos Sideras, Stefan Sleijfer, Jeffrey Smerage, Justin Stebbing, Leon W.M.M. Terstappen, José Vidal-Martínez, Rita Zamarchi, Karthik Giridhar, Thomas W.P. Friedl, Minetta C. Liu. Clinical utility of repeated circulating tumor cell (CTC) enumeration as early treatment monitoring tool in metastatic breast cancer (MBC) - a global pooled analysis with individual patient data [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-08.

Abstract Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72–0.86)]; >0–<5 years versus ≥10 years since last full-term birth [1.31 (1.11–1.55)]; ever versus never use of oral contraceptives [0.91 (0.87–0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen–progestin therapy [0.61 (0.54–0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02–1.21) for current versus never smoking. Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

Abstract Background Abemaciclib demonstrated efficacy in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Here we provide a comprehensive summary of the most common adverse events (AEs), their management, and whether AEs or dose reductions influenced progression-free survival (PFS), in the MONARCH 2 and 3 trials. Materials and Methods Incidence of the most clinically relevant AEs, management, and outcomes were summarized. Time-dependent covariate analyses examined the impact of dose reductions on PFS. PFS was estimated for patients with and without early onset of diarrhea or neutropenia. Results The most frequently reported AE was diarrhea, with clinically significant diarrhea (grade ≥2) reported for 42.8% of patients taking abemaciclib. Median time to onset was 1 week, and duration ranged from 6 to 12 days, depending on grade and study. Diarrhea was adequately managed by antidiarrheal medication (72.8%), dose omissions (17.3%), and reductions (16.7%). The highest rates of grade ≥2 diarrhea were observed in the first cycles and decreased in subsequent cycles. Neutropenia (grade ≥3) occurred in 25.4% of abemaciclib-treated patients. Neutropenia resolved with dose omissions (16.8%) and/or dose reductions (11.2%). Incidence of febrile neutropenia (0.7%) or other relevant grade ≥3 hematological events (<9%) was low. Venous thromboembolic events (5.3%) were primarily treated with anticoagulants. Interstitial lung disease/pneumonitis (3.4%) was treated with corticosteroids and/or antibiotics. PFS benefit of abemaciclib was not impacted by dose reductions or early onset of toxicities. Conclusion Abemaciclib was generally well tolerated. The most common AEs were effectively managed by supportive medications, and/or dose adjustments, with no detriment to PFS. Implications for Practice Treatment with abemaciclib plus fulvestrant or nonsteroidal aromatase inhibitors is generally well tolerated in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. In MONARCH 2 and MONARCH 3, any-grade diarrhea and grade ≥3 neutropenia were effectively managed with supportive medication and/or dose adjustment. Venous thromboembolic events were treated with anticoagulants and did not often require treatment discontinuation. Interstitial lung disease/pneumonitis was infrequent and treated with corticosteroids and/or antibiotics. Clinicians should be aware of and implement management strategies, including dose adjustments according to local labels, for commonly occurring and serious adverse events to ensure continued treatment and optimize clinical benefit/risk ratio.