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Androgen receptor (AR) inhibitor therapy is a developing treatment for AR-positive breast cancer (BC) with ongoing clinical trials. AR splice variant-7 (AR-V7) is a truncated variant of AR that leads to AR inhibitor therapy resistance in prostate cancer; recent studies have identified AR-V7 in BC and theorized that AR-V7 can have a similar impact. This study assessed the prevalence and clinicopathologic features associated with AR-V7 in a large BC cohort. BC samples were evaluated by MSK-Fusion targeted RNAseq for AR-V7 detection and MSK-IMPACT targeted DNAseq, including triple-negative tumors with no driver alteration and estrogen receptor-positive/ESR1 wildtype tumors progressing on therapy. Among 196 primary and metastatic/recurrent cases (196 RNAseq, 194DNAseq), 9.7% (19/196) were AR-V7 positive and 90.3% (177/196) AR-V7 negative. All AR-V7 positive BC were AR-positive by immunohistochemistry (19/19). The prevalence of AR-V7 by receptor subtype (N = 189) was: 18% (12/67) in ER-/PgR-/HER2-negative BC, 3.7% (4/109) in ER-positive/HER2-negative BC, and 15.4% (2/13) in HER2-positive BC; AR-V7 was detected in one ER-positive/HER2-unknown BC. Apocrine morphology was observed in 42.1% (8/19) of AR-V7 positive BC and 3.4% (6/177) AR-V7 negative BC (P

Purpose/Objective(s) We hypothesize that there is an oligoprogressive state in metastatic cancer, in which disease control can be improved with local therapy to progressive lesions only. This study therefore evaluated the impact of stereotactic body radiotherapy (SBRT) to sites of oligoprogression in patients with metastatic non-small-cell lung cancer (NSCLC) and breast cancer with 1-5 progressive lesions. Materials/Methods We enrolled patients with metastatic NSCLC or breast cancer who received ≥ 1 line of systemic therapy and had oligoprogressive lesions amenable to SBRT. There was no upper limit of non-progressive lesions. Oligoprogression was defined as Response Evaluation or Positron Emission Tomography Response Criteria in Solid Tumors documented progression ≤ 5 individual lesions. Stratification factors included number of progressive sites (1 vs. 2-5), prior systemic therapy (immunotherapy vs. other), primary tumor (NSCLC vs. breast), and tumor marker status (driver mutation and hormone receptor status). Patients were randomized 1:1 between SBRT to all progressive sites plus palliative standard of care (SOC) vs. palliative SOC only. Systemic therapy was per physician's discretion. The primary endpoint was progression-free survival (PFS). We used a randomized phase II design with a one-sided alpha of 0.05 and a power of 0.80, yielding a target accrual of 160 patients. PFS was compared using one-sided stratified log-rank test. One interim analysis was planned. Results From January 2019 to May 2021, 102 patients were randomized - 58 NSCLC (30 in the SBRT arm) and 44 breast (22 in each arm). Median age was 67. Most patients (75%) had > 1 site of oligoprogression and 47% had > 5 total metastatic lesions. Fifty-five (54%) patients received immunotherapy. The majority of NSCLC (86%) did not harbor an actionable driver mutation and 32% of breast cancer were triple negative. Baseline factors were balanced between arms. At a median follow-up of 51 weeks, 71 patients progressed and 30 died. Median PFS was 22 weeks in the SBRT arm vs. 10 weeks in the palliative SOC arm (p=0.005). This was driven entirely by the PFS benefit from SBRT in the NSCLC patients (44 weeks with SBRT vs. 9 weeks with SOC; p=0.004). No difference in median PFS was seen in the breast cohort (18 weeks with SBRT vs. 17 weeks with SOC; p=0.5). In multivariable Cox model inclusive of stratification factors, age, sex, lines of systemic therapy, and change of systemic therapy, the PFS benefit of SBRT remained substantial in the NSCLC cohort (Hazard Ratio: 0.38; 95% CI: 0.18-77; p=0.007). Grade ≥2 adverse events occurred in 8 patients in the SBRT arm, including 1 grade 3 pneumonitis. Conclusion Inthis pre-planned interim analysis of the first and largest randomized trial of radiotherapy for oligoprogressive metastatic NSCLC and breast cancer, we demonstrated the benefit of SBRT to sites of oligoprogression on overall PFS, meeting the primary endpoint. The mechanism of the differential benefits between NSCLC and breast cohorts merits further evaluation.

The incidence of obesity, a leading modifiable risk factor for common solid tumors, is increasing. Effective interventions are needed to minimize the public health implications of obesity. Although the mechanisms linking increased adiposity to malignancy are incompletely understood, growing evidence points to complex interactions among multiple systemic and tissue-specific pathways including inflamed white adipose tissue. The metabolic and inflammatory consequences of white adipose tissue dysfunction collectively provide a plausible explanation for the link between overweight/obesity and carcinogenesis. Gaining a better understanding of these underlying molecular pathways and developing risk assessment tools that identify at-risk populations will be critical in implementing effective and novel cancer prevention and management strategies.

Background TNBCs are a heterogeneous group characterized by lack of ER/PR/HER2 expression. Doane et al described a subgroup of TNBC associated with AR-dependent growth. While expression of EGFR and p53 are common in TNBC, their role in AR+ TNBC is less clear. We report the rates of EGFR and p53 expression and clinicopathologic features of AR+ TNBC from a retrospective cohort at MSKCC. Methods We identified 1,032 patients (pts) with resectable, TNBC (ER/PR 1 cm) with each tumor represented by 3 cores. AR was tested with DAKO Clone AR441, dilution (dil) 1:500; ratio of DAB nuclear staining to hematoxylin signal >1 SD above mean was defined as AR+. EGFR and p53 were tested with Thermo-Scientific Clone EP38Y, dil 1:50 and DAKO Clone D07, dil 1:50 respectively. Scoring: 0-1+ negative, 2-3+ positive. Fisher's exact test used to evaluate correlation between AR with EGFR and p53. RFS and OS evaluated using Kaplan-Meier methods. Clinicopathologic variables by AR status were compared using Chi-square/t-tests. Results 166 pts had adequate cores for AR testing. 10% were AR+ (17/166). 160 pts were evaluable for EGFR and 164 pts for p53. Median (med) followup: AR + =6 years (y), AR- = 5.6y. Adjuvant chemotherapy received: AR+ 82%, AR- 87%, P = 0.40. EGFR was expressed more frequently in AR- than AR+ TNBCs (111/143 (78%) vs 9/17 (53%); P =0.04). p53 expression was similar in AR- and AR+ TNBC (82/147 (56%) vs 7/17 (41%); P =0.30). Clinicopathologic variables based on AR and EGFR status appeared similar. 3y RFS and OS data are below. Conclusion Consistent with published reports, loss of AR expression correlates with EGFR expression. In contrast, no association was observed with p53 and AR. These data are hypothesis generating regarding the mechanism of interaction of AR and EGFR in TNBC. -3 year RFS (95% CI) -3 year OS (95% CI) AR+ 76% (47-90) 88% (59-97) AR- 81% (74-87) 93% (87-96) AR+ EGFR+ (n = 9) 67% (39-98) 78% (36-94) AR+ EGFR- (n = 8) 88% (39-98) 100% AR- EGFR+ (n = 111) 82% (73-88) 91% (84-95) AR_ EGFR- (n = 32) 81% (61-92) 97% (80-100) Disclosure All authors have declared no conflicts of interest.