Olson, John A.

Abstract Background: Late recurrence of breast cancer after 5 years accounts for about 50% of recurrences in hormone receptor (HR)-positive early breast cancer (EBC). TAILORx established non-inferiority of adjuvant endocrine therapy (ET) given for at least 5 years to chemotherapy plus ET (CET) in EBC and a 21-gene recurrence score (RS) of 11-25, although there was some chemotherapy benefit in women Methods: Eligibility criteria included women 18-75 years with HR-positive, HER2-negative, T1b-T2N0 EBC who agreed to have CT assigned or randomized based on the RS assay. The primary endpoint was invasive disease-free survival (iDFS) in the RS 11-25 group. The “primary analysis” refers to the original prespecified analysis for the primary IDFS endpoint (836 IDFS events at full information in the RS 11-25 group) after a median of 7.5 years. The “updated analysis” was performed after a median followup of 11.0 and 10.4 years in the randomized and overall populations, respectively. Results:10,253 eligible women enrolled between 4/7/06-10/6/10.The updated analysis includes substantially more events that the primary analysis, including IDFS events (1819 vs. 1210), distant recurrences (561 vs. 384), locoregional +/- distant recurrences (764 vs. 543), and deaths (910 vs. 499). The table provides 5 and 12-year event rates (and standard errors) for all arms, and comparisons of the randomized arms. The primary trial conclusions remain unchanged: ET was non-inferior to CET in the randomized group with a RS 11-25. Although recurrence occurred in < 10% by 12 years for a RS 0-25, late recurrence events beyond 5 years exceeded earlier recurrence. Non-recurrence events occurred in about 13% at 12 years (~1%/year), contributing substantially to the IDFS rates. For women Conclusions: The current updated analysis confirms findings from the original primary analysis that ET is non-inferior to CET in HR-positive, HER2-negative, node-negative EBC and a RS 11-25. As in the original primary analysis, the subgroup of women Citation Format: Joseph Sparano, Robert J. Gray, Della Makower, Kathy S. Albain, Daniel F. Hayes, Charles Geyer, Elizabeth Dees, Matthew P. Goetz, John A. Olson Jr, Tracy G. Lively, Sunil Badve, Thomas Saphner, Lynne I. Wagner, Timothy Whelan, Virginia Kaklamani, George Sledge. Trial Assigning Individualized Options for Treatment (TAILORx): An Update Including 12-Year Event Rates [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-05.

Abstract Background Black race is associated with worse outcomes in early breast cancer. We evaluated clinicopathologic characteristics, the 21-gene recurrence score (RS), treatment delivered, and clinical outcomes by race and ethnicity among women who participated in the Trial Assigning Individualized Options for Treatment. Methods The association between clinical outcomes and race (White, Black, Asian, other or unknown) and ethnicity (Hispanic vs non-Hispanic) was examined using proportional hazards models. All P values are 2-sided. Results Of 9719 eligible women with hormone receptor–positive, HER2-negative, node-negative breast cancer, there were 8189 (84.3%) Whites, 693 (7.1%) Blacks, 405 (4.2%) Asians, and 432 (4.4%) with other or unknown race. Regarding ethnicity, 889 (9.1%) were Hispanic. There were no substantial differences in RS or ESR1, PGR, or HER2 RNA expression by race or ethnicity. After adjustment for other covariates, compared with White race, Black race was associated with higher distant recurrence rates (hazard ratio [HR] = 1.60, 95% confidence intervals [CI] = 1.07 to 2.41) and worse overall survival in the RS 11-25 cohort (HR = 1.51, 95% CI = 1.06 to 2.15) and entire population (HR = 1.41, 95% CI = 1.05 to 1.90). Hispanic ethnicity and Asian race were associated with better outcomes. There was no evidence of chemotherapy benefit for any racial or ethnic group in those with a RS of 11-25. Conclusions Black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy in the Trial Assigning Individualized Options for Treatment. Similar to Whites, Black women did not benefit from adjuvant chemotherapy if the 21-gene RS was 11-25. Further research is required to elucidate the basis for this racial disparity in prognosis.

PURPOSE Cancer-related cognitive impairment (CRCI) is common during adjuvant chemotherapy and may persist. TAILORx provided a novel opportunity to prospectively assess patient-reported cognitive impairment among women with early breast cancer who were randomly assigned to chemoendocrine therapy (CT+E) versus endocrine therapy alone (E), allowing us to quantify the unique contribution of chemotherapy to CRCI. METHODS Women with a 21-gene recurrence score of 11 to 25 enrolled in TAILORX were randomly assigned to CT+E or E. Cognitive impairment was assessed among a subgroup of 552 evaluable women using the 37-item Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire, administered at baseline, 3, 6, 12, 24, and 36 months. The FACT-Cog included the 20-item Perceived Cognitive Impairment (PCI) scale, our primary end point. Clinically meaningful changes were defined a priori and linear regression was used to model PCI scores on baseline PCI, treatment, and other factors. RESULTS FACT-Cog PCI scores were significantly lower, indicating more impairment, at 3, 6, 12, 24, and 36 months compared with baseline for both groups. The magnitude of PCI change scores was greater for CT+E than E at 3 months, the prespecified primary trial end point, and at 6 months, but not at 12, 24, and 36 months. Tests of an interaction between menopausal status and treatment were nonsignificant. CONCLUSION Adjuvant CT+E is associated with significantly greater CRCI compared with E at 3 and 6 months. These differences abated over time, with no significant differences observed at 12 months and beyond. These findings indicate that chemotherapy produces early, but not sustained, cognitive impairment relative to E, providing reassurance to patients and clinicians in whom adjuvant chemotherapy is indicated to reduce recurrence risk.

503 Background: To correlate clinical features of estrogen receptor positive breast cancer with somatic mutations, massively parallel sequencing (MPS) was applied to tumor and normal DNAs accrued from patients treated with neoadjuvant aromatase inhibitors (AI). Methods: MPS was applied to 77 baseline tumor biopsy samples from the preoperative letrozole trial (JACS 2009: 208, 906) and the Z1031 trial (JCO 2011: 29, 2342) followed by targeted sequencing in another 240 trial samples. Standard statistical approaches were used to compare mutation status and clinical parameters and pathway-based correlation was used to assess interactions between signaling perturbations induced by gene mutations and response to neoadjuvant AI. Results: Eighteen genes were significantly mutated above background. Aside from PIK3CA mutations, the list is dominated by loss-of-function mutations in tumor suppressor genes. Five (RUNX1, CBFP, MYH9, MLL3 and SF3B1) have been previously linked to benign and malignant hematopoietic disorders. Clinical correlation revealed that TP53 mutation was associated with PAM50 LumB status, high-grade histology and high proliferation rates whereas loss-of-function mutations in MAP3K1 associate with PAM50 lumA status, low proliferation rates, and low grade histology. Mutations in GATA3 were associated with greater suppression of proliferation upon AI treatment suggesting mutGATA3 may predict endocrine response. Notably, mutations in MAP3K1 were more common in PIK3CA mutant cases, suggesting cooperation. Pathway analysis demonstrated that rare MAP2K4 mutations produce similar pathway perturbations as MAP3K1 mutation, a logical finding since MAP2K4 is a substrate for MAP3K1. Signaling network patterns driven by lncRNA MALAT1 mutations were associated with multiple poor clinical outcome features. Rare mutations in druggable kinases included two in the kinase domain of HER2. Conclusions: Tumor heterogeneity in luminal-type breast cancer is driven by specific patterns of somatic mutations, however most druggable or potentially prognostic mutations are infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing approaches and large scale investigations.

503 Background: TAILORx established that endocrine therapy (ET) alone is non-inferior to adjuvant chemotherapy (CT) plus ET in EBC and a 21-gene RS of 11-25, with some benefit if ≤50 years (y) with RS 16-25 (PMID: 29860917). We evaluated whether clinical risk (tumor size & histologic grade) provides additional prognostic information to RS, a secondary trial objective. Methods: Clinical risk by was assessed by Adjuvant! (version 8.0) using MINDACT criteria (PMID 27557300), defined as low clinical risk (LCR - tumor ≤3 cm and low grade, <2 cm and intermediate grade, or ≤1 cm and high grade) or high clinical risk (HCR -not meeting LCR criteria). Results: Of 9427 women with RS and clinical risk information, 70% were LCR and 30% HCR, with comparable distribution by age ( ≤50 vs. >50). The RS was 26-100 in 9% of LCR and 27% of HCR patients, with similar distributions by age. Although LCR/HCR provided additional prognostic information in each RS category for iDFS, including RS 0-10 (9-year rates 86.7% vs. 75.7% LCR vs. HCR), 11-25 (85.4% vs. 78.9%), and 26-100 (82.0% vs. 70.4%), iDFS rates were similar irrespective of CT (no vs. yes) in the entire RS 11-25 cohort whether LCR (85.8% vs. 85.1%) or HCR (79.8% vs. 77.9%). DRFI rates were also similar irrespective of CT in the RS 11-25 cohort or > 50y group whether LCR (96.0% vs. 96.1% overall; 96.5% vs. 96.0% > 50y) or HCR (92.3% vs. 89.9% overall; 91.7% vs. 90.7% >50y). For women ≤50y, the absolute reduction in distant recurrence from CT with a RS of 16-20 (N=923) was -0.2% (standard error [SE]±2.1%) for LCR vs. 6.5%(SE±4.9%) for HCR (vs. 1.6%[SE±1.9%] overall), whereas for a RS 21-25 (N=492) it was 6.4% (SE±4.9%) for LCR vs. 8.6% (SE±6.2%) for HCR (vs. 6.5%[SE±3.7%] overall). Conclusions: Clinical risk stratification provides additional prognostic information to the 21-gene RS, but not prediction of CT benefit in the overall TAILORx population or those > 50y, and facilitates more refined estimates of absolute CT benefit for women ≤50y with a RS 16-25. (Funded by National Cancer Institute, Komen Foundation, Breast Cancer Research Foundation). Clinical trial information: NCT00310180.

LBA1 Background: In hormone receptor (HR)-positive, HER2-negative, axillary node (AN)-negative breast cancer, the 21-gene expression assay (Oncotype DX Recurrence Score [RS]) is prognostic for distant recurrence, prognostic for low recurrence with endocrine therapy alone if low (0-10), and predictive of chemotherapy benefit if high (26 or higher). We performed a prospective, randomized trial of endocrine therapy (ET) versus chemoendocrine therapy (CET) in women with a mid-range RS of 11-25. Methods: Eligibility criteria included women 18-75 years of age with HR-positive, HER2-negative, axillary node (AN)-negative breast cancer and tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and int/high grade) and agreed to have chemotherapy assigned or randomized based on the RS. Women with a mid-range RS (11-25) were randomized to receive ET or CET. The primary endpoint was invasive disease-free survival (iDFS), and the trial was designed to show non-inferiority for ET alone by not rejecting equality (hazard ratio [HR] margin up to 1.322 for omission of chemotherapy, 1-sided type I error rate 10%, type II error rate 5%). The target sample size was adjusted to compensate for non-adherence to randomized treatment, and the protocol-specified final analysis was triggered after 835 iDFS events. Results: Of the 10,253 eligible women enrolled between 4/7/06-10/6/10, 6711 (65.5%) had a RS of 11-25 and adequate information. There were 836 iDFS events at final analysis with a median followup of 90 months. ET was non-inferior to CET for iDFS (HR 1.08, 95% confidence intervals [CI] 0.94, 1.24, p=0.26) in the intention-to-treat (ITT) population. ET was also non-inferior for distant recurrence-free interval (DRFI; HR 1.03, p=0.80), recurrence-free interval (RFI; HR 1.12, p=0.28), and overall survival (OS; HR 0.97, p=0.80). Nine year rates were similar for iDFS (83.3% vs. 84.3%), DRFI (94.5% vs. 95.0%), RFI (92.2% vs. 92.9%), and OS (93.9% vs. 93.8%). Recurrence accounted for 338 (41.6%) the first iDFS event, of which 199 (23.8%) were distant recurrences. Treatment interaction tests were significant for age (iDFS p=0.03; RFI p= 0.02), but not menopause, tumor size, grade, or RS (continuous or RS 11-15, 16-20, 21-25). Conclusions: In women with HR-positive, HER2-negative, AN-negative breast cancer and a RS of 11-25, adjuvant ET was not inferior to CET in the ITT analysis. (Funded by NCI, BCRF, and Komen Foundation.) Clinical trial information: NCT00310180.

Abstract Purpose: Preoperative aromatase inhibitor (AI) therapy has demonstrated efficacy in hormone receptor (HR)-positive postmenopausal breast cancer. However, many patients have disease that is either intrinsically resistant to AIs or that responds initially but develops resistance after prolonged exposure. We have shown that patients with breast tumors expressing the deregulated forms of cyclin E [low molecular weight forms (LMW-E)] have poor overall survival. Herein, we hypothesize that LMW-E expression can identify HR-positive tumors that are unresponsive to neoadjuvant AI therapy due to the inability of AIs to induce a cytostatic effect. Experimental Design: LMW-E was examined in breast cancer specimens from 58 patients enrolled in the American College of Surgeons Oncology Group Z1031, a neoadjuvant AI clinical trial. The mechanisms of LMW-E–mediated resistance to AI were evaluated in vitro and in vivo using an inducible model system of cyclin E (full-length and LMW-E) in aromatase-overexpressing MCF7 cells. Results: Breast cancer recurrence-free interval was significantly worse in patients with LMW-E–positive tumors who received AI neoadjuvant therapy, compared with those with LMW-E negative tumors. Upon LMW-E induction, MCF7 xenografts were unresponsive to letrozole in vivo, resulting in increased tumor volume after treatment with AIs. LMW-E expression overcame cell-cycle inhibition by AIs in a CDK2/Rb-dependent manner, and inhibition of CDK2 by dinaciclib reversed LMW-E–mediated resistance, whereas treatment with palbociclib, a CDK4/6 inhibitor, did not. Conclusions: Collectively, these findings suggest that cell-cycle deregulation by LMW-E mediates resistance to AIs and a combination of CDK2 inhibitors and AIs may be an effective treatment in patients with HR-positive tumors that express LMW-E. Clin Cancer Res; 23(23); 7288–300. ©2017 AACR.

Abstract Significant endocrine therapy–resistant tumor proliferation is present in ≥20% of estrogen receptor–positive (ER+) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair (MMR) complex (MLH1/3, PMS1/2), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER+ breast cancer abrogates CHK2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER+ breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit aromatase inhibitor–resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of patients with breast cancer who exhibit marked resistance to the current standard of care. Significance: MutL deficiency in a subset of ER+ primary tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy–resistant tumors. Therefore, markers of MutL dysregulation could guide CDK4/6 inhibitor use in the adjuvant setting, where the risk benefit ratio for untargeted therapeutic intervention is narrow. Cancer Discov; 7(10); 1168–83. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1047