Stearns, Vered

Abstract Purpose: Aromatase inhibitor (AI)–associated musculoskeletal symptoms (AIMSS) are common and frequently lead to AI discontinuation. SNPs in candidate genes have been associated with AIMSS and AI discontinuation. E1Z11 is a prospective cohort study designed to validate the association between 10 SNPs and AI discontinuation due to AIMSS. Patients and Methods: Postmenopausal women with stage I to III hormone receptor–positive breast cancer received anastrozole 1 mg daily and completed patient-reported outcome measures to assess AIMSS (Stanford Health Assessment Questionnaire) at baseline, 3, 6, 9, and 12 months. We estimated that 40% of participants would develop AIMSS and 25% would discontinue AI treatment within 12 months. Enrollment of 1,000 women with a fixed number per racial stratum provided 80% power to detect an effect size of 1.5 to 4. SNPs were found in ESR1 (rs2234693, rs2347868, and rs9340835), CYP19A1 (rs1062033 and rs4646), TCL1A (rs11849538, rs2369049, rs7158782, and rs7159713), and HTR2A (rs2296972). Results: Of the 970 evaluable women, 43% developed AIMSS and 12% discontinued AI therapy within 12 months. Although more Black and Asian women developed AIMSS than White women (49% vs. 39%, P = 0.017; 50% vs. 39%, P = 0.004, respectively), the AI discontinuation rates were similar across groups. None of the SNPs were significantly associated with AIMSS or AI discontinuation in the overall population or in distinct cohorts. The OR for rs2296972 (HTR2A) approached significance for developing AIMSS. Conclusions: We were unable to prospectively validate candidate SNPs previously associated with AI discontinuation due to AIMSS. Future analyses will explore additional genetic markers, patient-reported outcome predictors of AIMSS, and differences by race.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The combined analysis of SOFT-TEXT compared outcomes in 4,690 premenopausal women with estrogen/progesterone receptor–positive (ER/PgR+) early breast cancer randomly assigned to 5 years of exemestane + ovarian function suppression (OFS) versus tamoxifen + OFS. After a median follow-up of 9 years, exemestane + OFS significantly improved disease-free survival (DFS) and distant recurrence-free interval (DRFI), but not overall survival, compared with tamoxifen + OFS. We now report DFS, DRFI, and overall survival after a median follow-up of 13 years. In the intention-to-treat (ITT) population, the 12-year DFS (4.6% absolute improvement, hazard ratio [HR], 0.79; 95% CI, 0.70 to 0.90; P < .001) and DRFI (1.8% absolute improvement, HR, 0.83; 95% CI, 0.70 to 0.98; P = .03), but not overall survival (90.1% v 89.1%, HR, 0.93; 95% CI, 0.78 to 1.11), continued to be significantly improved for patients assigned exemestane + OFS over tamoxifen + OFS. Among patients with human epidermal growth factor receptor 2-negative tumors (86.0% of the ITT population), the absolute improvement in 12-year overall survival with exemestane + OFS was 2.0% (HR, 0.85; 95% CI, 0.70 to 1.04) and 3.3% in those who received chemotherapy (45.9% of the ITT population). Overall survival benefit was clinically significant in high-risk patients, eg, women age < 35 years (4.0%) and those with > 2 cm (4.5%) or grade 3 tumors (5.5%). These sustained reductions of the risk of recurrence with adjuvant exemestane + OFS, compared with tamoxifen + OFS, provide guidance for selecting patients for whom exemestane should be preferred over tamoxifen in the setting of OFS. [Media: see text]

12094 Background: The Functional Assessment of Cancer Therapy patient-reported outcomes (PRO) item GP5 (“I am bothered by side effects of treatment”) estimates treatment tolerability. We aimed to extend our previous finding that GP5 predicts early aromatase inhibitor (AI) discontinuation (E1Z03, 96% White) in the racially diverse E1Z11 trial cohort. Methods: E1Z11 was coordinated by the ECOG-ACRIN NCI Community Oncology Research Program (NCORP) Research Base. Postmenopausal women initiating anastrozole per clinical care for ER+ stage I-III breast cancer with a pain score 0-3/10 and no rheumatologic comorbidities were eligible. Accrual of a racially diverse cohort of 1,000 women, including Black and Asian women, was planned. GP5 was administered prior to initiating anastrozole (trial baseline) and at 3, 6, 9 and 12 months. GP5 was scored on a 5-point Likert scale from 0 (not at all) to 4 (very much) and dichotomized as no/little treatment bother (0/1) or moderate/high treatment bother (2-4), consistent with previous analyses. A univariate Cox proportional hazards model estimated baseline GP5’s association with treatment duration via hazard ratio (HR). Early treatment discontinuation status was defined as treatment duration < 12 months with discontinuation not attributed to disease progression or death (n = 4), consistent with previous analyses. Results: 1,046 women enrolled from 6/2013-10/2018 (640 White, 201 Black, 205 Asian), including 590 (56%) from NCORP Community or Minority/Underserved Sites. Approximately 10% (100/987 with GP5 data) reported moderate/high treatment bother prior to initiating anastrozole. Anastrozole discontinuation rate at 1-year was 26.2% overall; it was lower among women with no/little treatment bother (25.7%, GP5 = 0-1) compared to moderate/high treatment bother prior to initiating anastrozole (34.7%, GP5 = 2-4; HR = 1.50, 95% confidence interval [CI]:1.04-2.15, p = 0.027). Subgroup analyses by racial cohort showed a similar predictive effect of GP5 in the White (n = 606, HR = 1.76, 95% CI: 1.12-2.77, p = 0.014) and Black (n = 184, HR = 1.85, 95% CI: 0.92-3.71, p = 0.079) cohorts, but not in the Asian cohort (n = 197, HR = 0.40, 95% CI: 0.10-1.62, p = 0.20). Conclusions: Moderate/high treatment bother prior to starting anastrozole was observed in 10% of patients and associated with a higher risk of early discontinuation, except in Asian patients. Our findings support the presence of a treatment tolerability threshold which can be compromised by pre-treatment burden. Treatment tolerability may also be influenced by cultural and genetic factors, which will be explored in further analysis of genetic and PRO data. Clinical trial information: NCT01824836.

525 Background: Homologous recombination deficiency (HRD) status can be used to identify patients who are eligible for treatment with DNA damaging agents. Using a 3-biomarker Genomic Instability Score (GIS) threshold of ≥42, studies have previously examined the association between HRD status and outcomes in patients with triple negative breast cancer (TNBC). However, evidence suggests that a GIS threshold of ≥33 may be more appropriate. Here, we conducted an exploratory analysis evaluating the ability of ≥33 and ≥42 GIS thresholds to predict response to platinum-based treatment in patients with TNBC. Methods: Patients across 5 cohorts (TBCRC0301, TBCRC0082, NCT013725793, PrECOG 01054, combined cisplatin cohort4) were included in this analysis if they had a primary TNBC diagnosis, received neoadjuvant platinum-based treatment, had a valid GIS, and had known pathologic complete response (pCR) status. GIS was determined by a combination of loss of heterozygosity, telomeric-allelic imbalance, and large-scale state transitions.4,5 BRCA mutation status was defined by loss of function resulting from a pathogenic variant in BRCA1 or BRCA2. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were calculated by comparing binary threshold status and binary pCR status. Results: A total of 204 tumors (158 BRCAwt; 33 BRCAm; 13 unknown) were included; pCR to platinum-based treatment occurred in 55 cases (39 BRCAwt; 14 BRCAm; 2 unknown). Sensitivity, specificity, PPV, and NPV were comparable between the ≥33 and ≥42 GIS thresholds, with the ≥33 threshold producing higher sensitivity values. This was true when thresholds were applied to all samples and to BRCAwt samples only (Table). Among patients who achieved pCR in response to platinum-based treatment, 5.5% of patients in the full cohort and 7.7% of those in the BRCAwt cohort had a GIS between 33-41. Conclusions: To ensure that the majority of patients likely to benefit from treatment are identified, a GIS of ≥33 may be the most appropriate threshold to predict response to platinum-based treatment in patients with TNBC; however, a prospective trial will be needed to confirm these findings. Additional studies will be important to determine whether this threshold may be appropriate to determine eligibility for other DNA-damaging agents such as PARP inhibitors. 1. Ann Oncol. 2020;31(11):1518-25 2. J Nucl Med. 2015;56(1):31-7. 3. Breast Cancer Res Treat. 2015;151(3):629-38. 4. Clin Cancer Res. 2016;22(15):3764-73. 5. Breast Cancer Res Treat. 2014;16(6):1-9. [Table: see text]

Abstract Background: Patients with homologous recombin ation (HR) deficient tumors may benefit from treatment with DNA damaging agents. Markers of genomic instability can be used to identify HR deficiency, including a 3-biomarker Genomic Instability Score (GIS). For patients with ovarian cancer (OC), the FDA-approved GIS threshold for identifying HR deficiency is 42, set as the 5th percentile for BRCA deficient tumors. Recently, a lower 1st percentile cutoff of 33 was explored in OC; this threshold was significantly associated with improved outcome after platinum-based treatment.1,2 Determining an optimal GIS threshold for different types of tumors is crucial, as the GIS distribution may vary between different cancers and even between different cancer subtypes. We propose GIS thresholds for breast cancer separately for triple-negative breast cancer (TNBC) and estrogen receptor-positive (ER+) breast cancer, using the exploratory threshold of 33 for OC as a comparator. Methods: GISs in BRCA deficient tumors were determined for patients newly diagnosed with varying stages of OC, TNBC, or ER+ breast cancer across 5 cohorts (Timms et al,3 TCGA,4 Abkevich et al,5 TBCRC008,6 the OlympiaD trial7). GIS was determined as a combination of loss of heterozygosity, telomeric-allelic imbalance, and large-scale state transitions. BRCA deficiency was defined by loss of function resulting from a pathogenic variant in BRCA1 or BRCA2 or by methylation of the BRCA1 promoter region, with loss of heterozygosity in the affected gene. GIS distributions in different cancer types and subtypes were compared using the Kolmogorov-Smirnov test. A normal distribution was fit to GISs in BRCA deficient ER+ breast tumors. The 1st percentile of the fitted distribution was chosen as the threshold. Results: A total of 561 OC tumors (190 BRCA deficient), 99 TNBC tumors (44 BRCA deficient), and 406 ER+ breast tumors (76 BRCA deficient) were included across the 5 cohorts. When score distributions were evaluated for BRCA deficient tumors, the GIS distribution within ER+ breast cancer was significantly different than for OC (p=9.6x10-5) and TNBC (p=3.2x10-4). This indicates that different GIS thresholds are appropriate for breast cancer subtypes and that the GIS threshold developed for OC is not appropriate for ER+ breast cancer. The 1st percentile of a normal distribution fit in BRCA deficient ER+ breast cancer tumors yields a threshold of 24. Using this threshold, 45.1% (183/406; 75 BRCA deficient, 108 BRCA intact) of ER+ breast tumors were HR deficient. In contrast, the GIS distribution for TNBC was not significantly different than for OC (p=0.77). Using the exploratory threshold of 33, 63.6% (63/99; 44 BRCA deficient, 19 BRCA intact) of TNBC tumors were HR deficient. Conclusions: When compared to OC, the distribution of GIS in BRCA deficient tumors was different for ER+ breast cancer, but not for TNBC. These findings are consistent with the fact that OC and TNBC are known to have similar molecular signatures.8 Exploratory thresholds of 24 for ER+ breast cancer, and 33 for TNBC and OC could be examined to determine if these cutoffs are associated with a benefit from treatment with DNA targeting agents. Clinical validity and utility of these more inclusive 1% thresholds would require demonstration of correlation with clinical outcomes. The threshold difference observed between these cancer subtypes also suggests that cancer or cancer subtype specific thresholds may be needed as evaluations of HR deficiency expands beyond OC to identify candidates for PARP inhibitors. References: 1 Mol Cancer Res. 2018;16(7):1103-11. 2 Cancers. 2021;13(5):946. 3 Br J Cancer. 2012;107(10):1776-82. 4 Nature. 2012;490(7418):61-70. 5 Breast Cancer Res. 2014;16(145):1-9. 6 J Nucl Med. 2015;56(1):31-7. 7 NEJM. 2017;377(17):1700. 8 Int J Mol Sci. 2016;17(5):759. Citation Format: Kirsten M Timms, Lauren Lenz, Chris Neff, Cara Solimeno, Darl Flake, Judy C Boughey, Matthew P Goetz, Andrea Richardson, Anna Maria Storniolo, Alexander Gutin, Roisin M Connolly, Vered Stearns, Jerry S Lanchbury. Identifying homologous recombination deficiency in breast cancer: Genomic instability score thresholds differ in breast cancer subtypes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-09.

12003 Background: AIMSS are common and frequently lead to early discontinuation of adjuvant AI therapy. Single nucleotide polymorphisms (SNPs) in candidate genes have been associated with AIMSS and AI discontinuation. The primary objective of E1Z11 was to validate previously identified associations between 10 specific SNPs in candidate genes and AI discontinuation due to AIMSS in a community-based, racially diverse cohort. Methods: Postmenopausal women with hormone receptor-positive stage I-III breast cancer enrolled onto a prospective multi-site cohort study, the majority through the NCI Community Oncology Research Program (NCORP). Participants received anastrozole 1 mg oral daily, and completed patient-reported outcomes (PROs) at baseline, 3, 6, 9, and 12 months. AIMSS was defined as >20% increase in Stanford Health Assessment Questionnaire (HAQ) score over baseline occurring within 1 year of AI therapy. We projected 40% would develop AIMSS and 25% would discontinue AI treatment within 1 year, informing a planned enrollment of 1000 women with a fixed number per strata (600 Caucasian, 200 African-American [AA] & 200 Asian) to provide 80% power to detect an effect size of 1.5-4. SNPs include ESR1 (rs2234693, rs2347868, rs9340835), CYP19A1 (rs1062033, rs4646), TCL1A (rs11849538, rs2369049, rs7158782, rs7159713), and HTR2A (rs2296972). Hardy-Weinberg equilibrium (HWE) was evaluated within each racial subset. SNP genotypes were coded as additive effects on the log odds ratio by coding as 0, 1 or 2 for the count of the minor allele. A Cochran-Armitage trend test was used with a 1-sided alpha of 0.0025 (Bonferroni correction for 10 tests). Results: We enrolled 999 evaluable women (616 Caucasian, 184 AA, 199 Asian). Genotyping was successful in 974 (98%). AIMSS developed in 43%, and AI therapy was discontinued in 12% within 1 year. While more AA and Asians developed AIMSS compared to Caucasians (48% vs 38%, p=0.017; 50% vs 38%, p=0.004), AI discontinuation rates were similar across racial groups. HWE was satisfied for all SNPs at the 5% alpha level, except for TCL1A/rs11849538 (p=0.002) in the AA cohort. None of the 10 SNPs were significantly associated with AI discontinuation or development of AIMSS in the overall population, or in any of the 3 cohorts. Conclusions: Although AIMSS were more common in AA and Asians, AI discontinuation rates were similar in the 3 cohorts. We were unable to prospectively validate 10 SNPs in 4 genes previously associated with AI discontinuation due to AIMSS. Future analyses will include other predictors of AIMSS, PROs, and additional genetic markers for the entire cohort and by race. Support: NCI UG1CA189828, UG1CA233196, UG1CA233277, UG1CA233320, UG1CA233178, UG1CA233160, UG1CA232760, UG1CA233341, UG1CA233329, U10CA180821, UG1CA189821, UG1CA189830, U10CA180888, UG1CA189859, UG1CA189863, UG1CA189971. Clinical trial information: NCT01824836.

PURPOSE Predictive biomarkers to identify patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer who may benefit from targeted therapy alone are required. We hypothesized that early measurements of tumor maximum standardized uptake value corrected for lean body mass (SULmax) on 18 F-labeled fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) would predict pathologic complete response (pCR) to pertuzumab and trastuzumab (PT). PATIENTS AND METHODS Patients with stage II or III, estrogen receptor–negative, HER2-positive breast cancer received four cycles of neoadjuvant PT. 18 F-labeled fluorodeoxyglucose positron emission tomography-computed tomography was performed at baseline and 15 days after PT initiation (C1D15). Eighty evaluable patients were required to test the null hypothesis that the area under the curve of percent change in SULmax by C1D15 predicting pCR is ≤ 0.65, with a one-sided type I error rate of 10%. RESULTS Eighty-eight women were enrolled (83 evaluable), and 85% (75 of 88) completed all four cycles of PT. pCR after PT alone was 22%. Receiver operator characteristic analysis of percent change in SULmax by C1D15 yielded an area under the curve of 0.72 (80% CI, 0.64 to 0.80; one-sided P = .12), which did not reject the null hypothesis. However, between patients who obtained pCR and who did not, a significant difference in median percent reduction in SULmax by C1D15 was observed (63.8% v 41.8%; P = .004) and SULmax reduction ≥ 40% was more prevalent (83% v 52%; P = .03; positive predictive value, 31%). Participants not obtaining a 40% reduction in SULmax by C1D15 were unlikely to obtain pCR (negative predictive value, 91%). CONCLUSION Although the primary objective was not met, early changes in SULmax predict response to PT in estrogen receptor–negative and HER2-positive breast cancer. Once optimized, this quantitative imaging strategy may facilitate tailoring of therapy in this setting.

10509 Background: PST allows for improved surgical outcomes and response assessment without compromising long term outcomes. PST is an attractive model for assessing surrogate markers of response to therapy. We hypothesized that changes in tumor standardized uptake values corrected for lean body mass (SUL) max on FDG- PET by cycle 1 day 15 (C1D15) of therapy would predict pathological complete response (pCR) to PST in women with stage 2-3, grade 2-3, HER2-negative breast cancer. Methods: TBCRC008 is a multicenter placebo-controlled trial that investigates pCR following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel with or without vorinostat. FDG-PET followed by tumor biopsies were performed at baseline and C1D15. We correlated % reduction in SULmax on FDG-PET (PERCIST 1.0; Wahl RL, J Nuc Med 2009) with pCR (no invasive cancer in breast/axilla). We compared % reduction in SULmax between responders (pCR) and non responders (no pCR) using nonparametric Wilcoxon rank sum test. We explored association of % reduction in SULmax at pre-specified cutoff with response using Fisher’s exact test and logistic regression. We correlated baseline, C1D15, and % change in Ki67 at C1D15 with pCR. Results: Accrual is complete. Of 62 women enrolled (10/2009-11/2011), 40 have completed study PST and surgery (median age 47.5 [range 30-68], ER-positive 67%). Overall pCR was 26%. In an intent to treat analysis (n=39), we observed a significant difference in median % reduction in SULmax between responders vs not (66.6% vs 32.4%, p <0.001). We observed a higher proportion of reduction in SULmax ≥ 60% in responders vs not (80% vs 3.5%, p <0.001). The differences in baseline, C1D15 and % change in Ki67 were not significant between responders and non-responders. Conclusions: Change in SULmax on FDG-PET 15 days after initiating PST was significantly greater in patients with pCR versus no pCR. Future studies will determine whether altering therapy based on early changes in SULmax will improve pCR. Unblinded data from all participants will be presented at the meeting.

1006 Background: Patients (pts) with ER-/PR- MBC do not benefit from endocrine treatment (tx). Doane et al (Oncogene 2006;25:3994) described a subset of ER-/PR- BC with a gene expression profile similar to ER+ BC but characterized by AR expression and AR-dependent growth in vitro. Hence, we conducted a multicenter phase II trial (NCT00468715) of the AR antagonist, bicalutamide (B) for pts with AR+ ER-/PR- MBC. Methods: Pts with ER-/PR- (IHC <10%) MBC were consented to AR testing, confirmed centrally at MSKCC. If AR+ (DAKO IHC ≥10%), pts were eligible for tx if ECOG performance status (PS) <2 and normal organ function. No limit on prior tx except prior trastuzumab required if HER2+. Eligible AR+ pts who consented to tx received B 150mg orally daily in 28-day cycles (C). Toxicity assessed q4wks, response q12wks. Primary endpoint = clinical benefit rate (CBR): CR + PR + stable disease (ds) >6mo (SD). B would be considered worthy of further study if ≥4/28 pts have clinical benefit. Results: As of 12/21/11,436 pts consented for AR testing. 24 were ineligible, 12 await testing. 47/400 tested were AR+ (12%). 26 received tx with B (6 ineligible for tx, 15 are eligible for tx with B at progression (POD) if clinically appropriate and study slots remains). Two AR+ pts treated with B were ER+ and removed from study. Three have received tx <12wks. Treated pt characteristics (n=24): median(med)age 64 (41-83), PS 0 (0-1), HER2+ 1, visceral metastases 17. Prior chemotherapy: neo/adjuvant 16; med # regimens for MBC 1 (0-8). Med C# 3 (2-49+). Best response: (21 evaluable pts): CBR 19% (95% CI 5-42%), SD>6mo 4, CR/PR 0, SD<6mo 3, POD 14. Conclusions: ~12% of ER-/PR- MBC pts are AR+. For these pts, AR-inhibition with B is feasible, well tolerated, and has activity based on pre-specified criteria. This study has closed to accrual for AR testing as of 1/2012. These results of the primary endpoint are not expected to change by accrual of the 2 remaining pts. Supported by TBCRC/Breast Cancer Alliance/AstraZeneca. [Table: see text]

PURPOSE This focused update addresses the use of Onco type DX in guiding decisions on the use of adjuvant systemic therapy. METHODS ASCO uses a signals approach to facilitate guideline updating. For this focused update, the publication of the Trial Assigning Individualized Options for Treatment (TAILORx) evaluating noninferiority of endocrine therapy alone versus chemoendocrine therapy for invasive disease–free survival in women with Onco type DX scores provided a signal. An expert panel reviewed the results of TAILORx along with other published literature on the Onco type DX assay to assess for evidence of clinical utility. UPDATED RECOMMENDATIONS For patients with hormone receptor–positive, axillary node–negative breast cancer whose tumors have Onco type DX recurrence scores of less than 26, there is little to no benefit from chemotherapy, especially for patients older than age 50 years. Clinicians may recommend endocrine therapy alone for women older than age 50 years. For patients 50 years of age or younger with recurrence scores of 16 to 25, clinicians may offer chemoendocrine therapy. Patients with recurrence scores greater than 30 should be considered candidates for chemoendocrine therapy. Based on informal consensus, the panel recommends that oncologists may offer chemoendocrine therapy to these patients with recurrence scores of 26 to 30. Additional information can be found at www.asco.org/breast-cancer-guidelines .