Sonya Reid

BACKGROUND: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. METHODS: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. RESULTS: , were not associated with an increased risk of breast cancer. CONCLUSIONS: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).

PURPOSE Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) improves progression-free survival (PFS) and overall survival (OS) in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) metastatic breast cancer (MBC). Although preclinical and clinical data demonstrate a benefit in changing ET and continuing a CDK4/6i at progression, no randomized prospective trials have evaluated this approach. METHODS In this investigator-initiated, phase II, double-blind placebo-controlled trial in patients with HR+/HER2– MBC whose cancer progressed during ET and CDK4/6i, participants switched ET (fulvestrant or exemestane) from ET used pre-random assignment and randomly assigned 1:1 to the CDK4/6i ribociclib versus placebo. PFS was the primary end point, defined as time from random assignment to disease progression or death. Assuming a median PFS of 3.8 months with placebo, we had 80% power to detect a hazard ratio (HR) of 0.58 (corresponding to a median PFS of at least 6.5 months with ribociclib) with 120 patients randomly assigned using a one-sided log-rank test and significance level set at 2.5%. RESULTS Of the 119 randomly assigned participants, 103 (86.5%) previously received palbociclib and 14 participants received ribociclib (11.7%). There was a statistically significant PFS improvement for patients randomly assigned to switched ET plus ribociclib (median, 5.29 months; 95% CI, 3.02 to 8.12 months) versus switched ET plus placebo (median, 2.76 months; 95% CI, 2.66 to 3.25 months) HR, 0.57 (95% CI, 0.39 to 0.85); P = .006. At 6 and 12 months, the PFS rate was 41.2% and 24.6% with ribociclib, respectively, compared with 23.9% and 7.4% with placebo. CONCLUSION In this randomized trial, there was a significant PFS benefit for patients with HR+/HER2– MBC who switched ET and received ribociclib compared with placebo after previous CDK4/6i and different ET.

PURPOSE Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor–positive/human epidermal growth factor receptor 2–negative (HER2–) metastatic breast cancer (MBC), but it is not known if patients might derive benefit from continuation of CDK4/6i with endocrine therapy beyond initial tumor progression or if the addition of checkpoint inhibitor therapy has value in this setting. METHODS The randomized multicenter phase II PACE trial enrolled patients with hormone receptor–positive/HER2– MBC whose disease had progressed on previous CDK4/6i and aromatase inhibitor (AI) therapy. Patients were randomly assigned 1:2:1 to receive fulvestrant (F), fulvestrant plus palbociclib (F + P), or fulvestrant plus palbociclib and avelumab (F + P + A). The primary end point was investigator-assessed progression-free survival (PFS) in patients treated with F versus F + P. RESULTS Overall, 220 patients were randomly assigned between September 2017 and February 2022. The median age was 57 years (range, 25-83 years). Most patients were postmenopausal (80.9%), and 40% were originally diagnosed with de novo MBC. Palbociclib was the most common previous CDK4/6i (90.9%). The median PFS was 4.8 months on F and 4.6 months on F + P (hazard ratio [HR], 1.11 [90% CI, 0.79 to 1.55]; P = .62). The median PFS on F + P + A was 8.1 months (HR v F, 0.75 [90% CI, 0.50 to 1.12]; P = .23). The difference in PFS with F + P and F + P + A versus F was greater among patients with baseline ESR1 and PIK3CA alterations. CONCLUSION The addition of palbociclib to fulvestrant did not improve PFS versus fulvestrant alone among patients with hormone receptor–positive/HER2– MBC whose disease had progressed on a previous CDK4/6i plus AI. The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.

IMPORTANCE: Screening mammography and magnetic resonance imaging (MRI) are recommended for women with ATM, CHEK2, and PALB2 pathogenic variants. However, there are few data to guide screening regimens for these women. OBJECTIVE: To estimate the benefits and harms of breast cancer screening strategies using mammography and MRI at various start ages for women with ATM, CHEK2, and PALB2 pathogenic variants. DESIGN, SETTING, AND PARTICIPANTS: This comparative modeling analysis used 2 established breast cancer microsimulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) to evaluate different screening strategies. Age-specific breast cancer risks were estimated using aggregated data from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium for 32 247 cases and 32 544 controls in 12 population-based studies. Data on screening performance for mammography and MRI were estimated from published literature. The models simulated US women with ATM, CHEK2, or PALB2 pathogenic variants born in 1985. INTERVENTIONS: Screening strategies with combinations of annual mammography alone and with MRI starting at age 25, 30, 35, or 40 years until age 74 years. MAIN OUTCOMES AND MEASURES: Estimated lifetime breast cancer mortality reduction, life-years gained, breast cancer deaths averted, total screening examinations, false-positive screenings, and benign biopsies per 1000 women screened. Results are reported as model mean values and ranges. RESULTS: The mean model-estimated lifetime breast cancer risk was 20.9% (18.1%-23.7%) for women with ATM pathogenic variants, 27.6% (23.4%-31.7%) for women with CHEK2 pathogenic variants, and 39.5% (35.6%-43.3%) for women with PALB2 pathogenic variants. Across pathogenic variants, annual mammography alone from 40 to 74 years was estimated to reduce breast cancer mortality by 36.4% (34.6%-38.2%) to 38.5% (37.8%-39.2%) compared with no screening. Screening with annual MRI starting at 35 years followed by annual mammography and MRI at 40 years was estimated to reduce breast cancer mortality by 54.4% (54.2%-54.7%) to 57.6% (57.2%-58.0%), with 4661 (4635-4688) to 5001 (4979-5023) false-positive screenings and 1280 (1272-1287) to 1368 (1362-1374) benign biopsies per 1000 women. Annual MRI starting at 30 years followed by mammography and MRI at 40 years was estimated to reduce mortality by 55.4% (55.3%-55.4%) to 59.5% (58.5%-60.4%), with 5075 (5057-5093) to 5415 (5393-5437) false-positive screenings and 1439 (1429-1449) to 1528 (1517-1538) benign biopsies per 1000 women. When starting MRI at 30 years, initiating annual mammography starting at 30 vs 40 years did not meaningfully reduce mean mortality rates (0.1% [0.1%-0.2%] to 0.3% [0.2%-0.3%]) but was estimated to add 649 (602-695) to 650 (603-696) false-positive screenings and 58 (41-76) to 59 (41-76) benign biopsies per 1000 women. CONCLUSIONS AND RELEVANCE: This analysis suggests that annual MRI screening starting at 30 to 35 years followed by annual MRI and mammography at 40 years may reduce breast cancer mortality by more than 50% for women with ATM, CHEK2, and PALB2 pathogenic variants. In the setting of MRI screening, mammography prior to 40 years may offer little additional benefit.

LBA1004 Background: CDK 4/6i has demonstrated benefit in progression free survival (PFS) and overall survival (OS) in pts with HR+, HER2- MBC when combined with endocrine therapy (ET). While observational data demonstrate a potential benefit of continuing CDK 4/6i and switching ET at progression, no prospective trials have evaluated this approach. We conducted a phase II, multi-center, randomized, trial to evaluate the efficacy of fulvestrant or exemestane +/- ribociclib in pts with HR+HER2- MBC whose cancer previously progressed on any CDK 4/6i + any ET. Methods: In this investigator-initiated, phase II, double-blind, placebo-controlled trial, men or women with measurable or non-measurable HR+/HER2- MBC whose cancer progressed during CDK 4/6i and ET were randomized 1:1 to fulvestrant or exemestane +/- ribociclib. Pts treated with prior fulvestrant received exemestane as ET in the randomization; if prior exemestane fulvestrant was the ET; if neither, fulvestrant or exemestane was per investigator discretion, though fulvestrant was encouraged. PFS was the primary endpoint, defined as time from randomization to progression of disease or death. A one-sided log-rank test with a sample size of 120 randomized and evaluable pts with a significance level alpha of 2.5%, achieves 80% power to detect an effect size (difference in PFS) of 3 months. Results: Of the 120 randomized evaluable pts, 1 pt was removed due to not taking ET along with ribociclib/placebo. All but 1 pt was female, the median age was 57.0 years, 88 pts (74%) were white, and 21 (17.6%) were Hispanic. For ET, 99 pts received fulvestrant (83%) and 20 pts exemestane (17%). In terms of prior CDK 4/6i, 100 pts previously received palbociclib (84%), 13 pribociclib (11%), 2 abemaciclib (2%), and 4 palbociclib and another CDK 4/6i (3%). There was a statistically significant PFS improvement for pts randomized to fulvestrant or exemestane + ribociclib [median: 5.33 months, 95% CI (Confidence Interval): 3.25–8.12 months] vs. placebo (median: 2.76 months, 95% CI: 2.66–3.25 months): Hazard Ratio (HR) = 0.56 (95% CI: 0.37-0.83), p = 0.004. Similar results were seen in the subset of pts treated with fulvestrant, with a median PFS for those randomized to ribociclib (5.29 months) vs. placebo (2.76 months), HR = 0.59 (95% CI: 0.38-0.91), p = 0.02. At 6 months, 42% were progression-free on the ribociclib arm vs. 24% on placebo. At 12 months, 25% were progression-free on the ribociclib arm vs. 7% on placebo. Additional endpoints will be reported, including overall response rate and safety. Conclusions: In this randomized, placebo-controlled trial, there was a significant PFS benefit for pts with HR+/HER2- MBC to switch ET and receive ribociclib after progression on CDK 4/6i. Clinical trial information: NCT02632045.