Rastogi, Priya

TPS650 Background: The TAILORx and RxPONDER trials showed that recurrence score (RS) identifies many postmenopausal pts who do not benefit from addition of ACT to endocrine therapy (ET); however, RS also identifies subsets who do benefit (node-neg/high clinical risk/RS 16-20, node-neg/RS 21-25, and node-pos/RS ≤25). Most premenopausal pts in these trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR+/HER2– BC in SOFT/TEXT, we question whether the ACT benefit in TAILORx/RxPONDER was due to chemotherapy-induced OFS. To address this, we developed OFSET, a phase III clinical trial comparing OFS+ET to ACT+OFS+ET. Methods: We hypothesize that addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal pts with early-stage HR+/HER2– tumors, and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival, overall survival, distant recurrence-free interval, breast cancer-free interval, and health-related quality of life (HRQOL). Pts must be node-neg with RS 16-20 (plus high clinical risk), RS 21-25, or have 1-3 positive nodes with RS ≤25. Stratification is by nodal status/RS status (pN0 RS 16-25; pN1 RS 0-15; pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39; ≥40). Pts are randomized after surgery to either OFS+ET or ACT+OFS+ET. ET is an aromatase inhibitor (AI) per physician discretion; or tamoxifen if AI is not tolerated or if OFS is incomplete. Radiotherapy will be administered per protocol guidelines. An HRQOL sub-study will assess severe menopausal symptoms (measured by FACT ESS-19) and pain severity (PROMIS) between arms. Blood and tumor specimens will be collected for future research. We anticipate accrual of 3,960 pts in 7 yrs, 7 mos. Per NSABP B-28/RxPONDER data, 5-yr IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Per TAILORx data, 5-yr IBCFS of pN0 pts on the ACT arm is ~95%. Assuming 56% of pts to be pN0 and 44% pN1, and a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET v OFS+ET, with 1-sided α of 0.025 and 80% power, will require 380 IBCFS events, expected to occur ~11 yrs after study initiation. Accrual is 496/3,960 (from 8/2023 to 1/2026). NCT #: NCT05879926. Clinical trial information: NCT05879926 .

Importance Breast cancer treatment is associated with cancer-related cognitive impairment (CRCI). However, the association of endocrine therapy (ET) vs chemotherapy plus endocrine therapy (CET) with CRCI is poorly understood. Objective To compare patient-reported CRCI between women with breast cancer treated with ET vs CET and to consider whether menopausal status may be associated. Design, Settings, and Participants This was a prespecified secondary analysis of RxPONDER (SWOG S1007), a multinational phase 3 randomized clinical trial of more than 5000 women with hormone receptor−positive ERBB2 -negative (formerly HER2 -negative) breast cancer with 1 to 3 involved lymph nodes and Oncotype DX (21-gene recurrence score) of 25 or less. Participants were enrolled from February 2011 to September 2017, with results first reported in December 2020. Participants were randomly assigned to CET or ET, with ongoing follow-up. This secondary analysis assessed cognitive function using the Patient-Reported Outcomes Measurement Information System Perceived Cognitive Function Concerns (PCF) questionnaire at baseline, 6, 12, and 36 months. Data were analyzed from July 2022 to August 2025. Intervention Random assignment to CET or ET. Main Outcomes and Measures Mean PCF standardized (T) scores by menopausal status over time using generalized estimating equations analysis for continuous outcomes. Results Of the 568 patients who completed the baseline questionnaire and were included in the analysis, 139 (24%) were premenopausal (median [range] age, 47.8 [28.0-56.3] years) and 429 (76%) were postmenopausal (median [range] age, 62.3 [37.3-87.6] years). Among the 274 (48%) who received CET and the 294 (52%) who received ET alone, CET was determined to have a greater negative association with patient-reported CRCI in both the pre- and postmenopausal participants during the 36-month follow-up. In the ET alone group, PCF scores for premenopausal participants decreased from baseline to 6 and 12 months (53.53, 51.51, and 51.72, respectively) but recovered to baseline (54.36) at 36 months. For postmenopausal participants, mean PCF scores were essentially stable (51.72, 51.13, 51.11, and 51.70, respectively); however, in the CET group, PCF scores for both pre- and postmenopausal participants decreased from baseline to 6 and 12 months (premenopausal, 52.84, 49.27, 48.04; postmenopausal, 50.65, 48.39, 47.13, respectively) and did not return to baseline at 36 months (premenopausal, 49.25; postmenopausal, 48.44). The difference in longitudinal mean PCF scores over time between CET and ET groups was −3.02 (95% CI, −5.33 to −0.72; P = .01) for premenopausal and −2.37 (95% CI, −3.92 to −0.82; P = .003) for postmenopausal participants. Conclusions and Relevance This secondary analysis of the RxPONDER found that CET had a greater negative association with patient-reported CRCI compared to ET alone in both pre- and postmenopausal participants over a 36-month follow-up period. Interventions to prevent or treat CRCI are needed to improve the long-term quality of life of these patients treated with chemotherapy. Trial Registration ClinicalTrials.gov Identifier: NCT01272037

TPS615 Background: The TAILORx and RxPONDER trials demonstrated that RS identifies many postmenopausal pts with node-neg and node-pos BC and RS ≤25, who do not benefit from addition of ACT to endocrine therapy (ET). Both trials also showed that certain subsets of premenopausal pts (node-neg/high clinical risk/RS 16-20, node-neg/RS 21-25, and node-pos/RS ≤25) benefited from adding ACT to ET. Most premenopausal pts in these trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR+/HER2- BC in the SOFT/TEXT trials, many questioned whether all or part of the observed ACT benefit in the TAILORx/RxPONDER trials may have been the result of chemotherapy-induced OFS. To address this question, we developed OFSET, a phase III, multicenter clinical trial comparing OFS+ET v ACT+OFS+ET. Methods: We hypothesize that addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early-stage BC pts with HR+/HER2- tumors, and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival, overall survival, distant recurrence-free interval, breast cancer-free interval, and health-related quality of life (HRQOL). Pts must be node-neg with RS 16-20 (plus high clinical risk), or RS 21-25, or have 1-3 positive nodes with RS ≤25. Stratification is by nodal status/RS status (pN0 RS 16-25 v pN1 RS 0-15 and pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39 v ≥40). Pts are randomized after surgery to either OFS+ET or ACT+OFS+ET v ET is an aromatase inhibitor (AI). Choice is per investigator discretion; tamoxifen is allowed if AI is not tolerated or if OFS is incomplete. Radiotherapy will be administered per investigator discretion per protocol guidelines. The HRQOL sub-study will assess differences in severe menopausal symptoms, measured by the FACT ESS-19 score between arms, as well as increased pain severity (PROMIS). Blood and tumor specimens will be collected for future research. Accrual of 3,960 pts is anticipated to be completed in 7 yrs, 7 mos. Per NSABP B-28 and RxPONDER data, 5yr IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Based on TAILORx data, 5yr IBCFS of pN0 pts on the ACT arm is ~95%. Assuming 56% of pts to be pN0 and 44% pN1, and a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET v OFS+ET, with one-sided α of 0.025 and 80% power, will require 380 IBCFS events, expected to occur~11 yrs after study initiation. OFSETwas activated Aug 2023. As of 1-6-25, accrual is: 188/3,960. NCT #: NCT05879926. Support: U10CA180868, -80822, UG1CA189867, U24CA196067. Clinical trial information: NCT05879926 .

Abstract Background The phase III RxPONDER trial has affected treatment for node-positive (1-3), hormone receptor-positive, HER2-negative breast cancer with a 21-gene recurrence score (RS) less than 26. We investigated how these findings apply to different racial and ethnic groups within the trial. Methods The trial randomly assigned women to endocrine therapy (ET) or to chemotherapy plus ET. The primary clinical outcome was invasive disease-free survival (IDFS), with distant relapse-free survival (DRFS) as a secondary outcome. Multivariable Cox models were used to evaluate the association between race/ethnicity and survival outcomes, adjusting for clinicopathological characteristics, RS, and treatment. Results A total of 4048 women with self-reported race/ethnicity were included: Hispanic (15.1%), non-Hispanic Black (NHB) (6.1%), Native American/Pacific Islander (0.8%), Asian (8.0%), and non-Hispanic White (NHW) (70%). No differences in RS distribution, tumor size, or number of positive nodes were observed by race/ethnicity. Relative to NHWs, IDFS was worse for NHB participants (5-year IDFS 91.6% vs 87.1%, HR = 1.37; 95% CI = 1.03 to 1.81) and better for Asians (91.6% vs 93.9%, HR = 0.64; 95% CI = 0.46 to 0.91). Relative to NHW, DRFS was worse for NHB participants (5-year DRFS 95.8% vs 91.0%, HR = 1.65; 95% CI = 1.17 to 2.32) and better for Asians (95.8% vs 96.7%, HR = 0.59; 95% CI = 0.37 to 0.95). Adjusting for clinical characteristics, particularly body mass index, diminished the effect of race on outcomes. Chemotherapy treatment efficacy did not differ by race/ethnicity. Conclusions NHB women had worse clinical outcomes compared with NHWs in the RxPONDER trial despite similar RS and comparable treatment. Our study emphasizes the persistent racial disparities in breast cancer outcomes while highlighting complex interactions among contributing factors. Trial Registration ClinicalTrials.gov: NCT01272037.

PURPOSE Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor–positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor–positive, human epidermal growth factor receptor 2–negative BC after adjuvant/neoadjuvant chemotherapy. METHODS Patients were randomly assigned 1:1 to physician's choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor–positive BC. RESULTS One thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%). CONCLUSION One year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.

TPS612 Background: The TAILORx and RxPONDER trials demonstrated that RS identifies many postmenopausal pts with node-neg and node-pos BC and RS ≤25, who do not benefit from addition of ACT to endocrine therapy (ET). Both trials also showed that certain subsets of premenopausal pts (node-neg/high clinical risk/RS 16-20, node-neg/RS 21-25, and node-pos/RS ≤25) benefited from adding ACT to ET. Most premenopausal pts in these trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR+/HER2- BC in the SOFT/TEXT trials, many questioned whether all or part of the observed ACT benefit in the TAILORx/RxPONDER trials may have been the result of chemotherapy-induced OFS. To address this question, we developed OFSET, a phase III, multicenter clinical trial comparing OFS+ET v ACT+OFS+ET. Methods: We hypothesize that addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early-stage BC pts with HR+/HER2- tumors, and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival, overall survival, distant recurrence-free interval, breast cancer-free interval, and health-related quality of life (HRQOL). Pts must be node-neg with RS 16-20 (plus high clinical risk), or RS 21-25, or have 1-3 positive nodes with RS ≤25. Stratification is by nodal status/RS status (pN0 RS 16-25 v pN1 RS 0-15 and pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39 v ≥40). Pts are randomized after surgery to either OFS+ET or ACT+OFS+ET. ET is an aromatase inhibitor (AI). Choice is per investigator discretion; tamoxifen is allowed if AI is not tolerated or if OFS is incomplete. Radiotherapy will be administered per investigator discretion per protocol guidelines. The HRQOL substudy will assess differences in severe menopausal symptoms, measured by the FACT ESS-19 score between arms, as well as increased pain severity (PROMIS). Blood and tumor specimens will be collected for future research. Accrual of 3,960 pts is anticipated to be completed in 7 yrs, 7 mos. Per NSABP B-28 and RxPONDER data, 5yr IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Based on TAILORx data, 5yr IBCFS of pN0 pts on the ACT arm is ~95%. Assuming 56% of pts to be pN0 and 44% pN1, and a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET v OFS+ET, with one-sided α of 0.025 and 80% power, will require 380 IBCFS events, expected to occur~11 yrs after study initiation. OFSET was activated Aug 2023. Clinical trial information: NCT05879926 .

505 Background: SWOG S1007 was a phase 3 randomized trial to evaluate the benefit of endocrine therapy alone (ET) or with chemotherapy (CET) in pts with HR+/HER2- invasive breast cancer with recurrence score (RS) ≤ 25. There was no invasive disease-free survival (IDFS) benefit for CET compared to ET in postmenopausal women However, in premenopausal women CET had an IDFS improvement compared to ET (HR=0.60; 95% 0.43-0.83). The objective was to further refine patient subgroups who benefit from CET, we measured baseline hormone levels in S1007 pts to quantify their menstrual status by serum hormone levels and associated clinical outcomes. Methods: Serum estradiol (E), progesterone (P), follicular stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH), and inhibin B (IB) were assessed on baseline serum samples from 1,015 pts who self-reported being premenopausal and age < 55. Magnetic fluorescent bead-based immunoassays ( i.e., Luminex assays) or colorimetric ELISAs were performed at the Biomarker Discovery Laboratory at the University of Kansas Medical Center to measure hormone levels. Associations of the markers (both continuous and dichotomized) with IDFS and distant relapse-free survival (DRFS) were tested for prognosis and prediction of CET benefit using Cox regression. Results: Single baseline measurement of IB, P, E, LH, FSH, or combination of E/LH/FSH, was not prognostic for IDFS or predictive for chemotherapy benefit. However, AMH levels (≥10 pg/mL) showed significant interaction with chemotherapy benefit (p=0.019), and risk increased with continuous AMH with ET alone, but not CET (p=0.03). Compared to ET alone, CET was beneficial in the 79% of premenopausal patients with AMH levels ≥10 pg/mL, a standard cutoff to define normal ovarian reserve (HR=0.48; 95% 0.33-0.69, adjusting for RS). CET was not beneficial in the 21% with AMH < 10 (HR=1.21; 95% 0.60-2.43). Absolute 5-year IDFS benefit of CET for RS ≤ 25 was 7.8% (95.2%-87.4%) for AMH ≥ 10 vs. -1.7% (89.1%-90.8%) for AMH < 10. DRFS showed a similar pattern with CET benefit in AMH ≥10 pg/mL (5-year DRFS benefit: 4.4%; HR=0.41; 95% 0.25-0.68, adjusting for RS) and no benefit in AMH < 10 (5-year DRFS benefit: -0.9%, HR=1.50; 95% 0.62-3.63). Conclusions: Among self-reported premenopausal patients < age 55, pts with baseline serum AMH levels ≥10 pg/mL showed significant benefit from CET compared to patients with AMH levels <10 pg/mL. AMH levels were a better indicator of CET benefit than self-reported menopause status, age, or E/LH/FSH levels. Use of AMH-based selection of patients may inform who most benefits from the addition of adjuvant chemotherapy to ET. Clinical trial information: NCT01272037 .

Abstract Background: Identifying pts with HR-positive/HER2-negative breast cancer (BC) who benefit from adjuvant chemotherapy (ACT) has been a major research focus over the past 20 years. Development and clinical application of genomic classifiers such as the 21-gene recurrence score (RS) has contributed to the biologic understanding of BC and has refined pt selection for ACT. The TAILORx and RxPONDER clinical trials demonstrated that RS identifies many postmenopausal pts with node-negative and node-positive BC and RS &lt; 25, who do not benefit from the addition of ACT to endocrine therapy (ET). However, both trials also showed that certain subsets of premenopausal pts (node-negative/high clinical risk/RS 16-20, node-negative/RS 21-25, and node-positive/RS &lt; 25) benefited from the addition of ACT to ET. Most premenopausal pts in these two trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR-positive/HER2-negative BC in the SOFT and TEXT trials, many questioned whether all or part of the observed ACT benefit in the TAILORx/RxPONDER trials may have been the result of chemotherapy-induced OFS. To address this question, OFSET is a Phase III, multicenter clinical trial evaluating the addition of ACT to OFS+ET vs. OFS+ET alone. Methods: We hypothesize that the addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early-stage BC pts with HR-positive/HER2-negative tumors, and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival (IDFS), overall survival (OS), distant recurrence-free interval (DRFI), breast cancer-free interval (BCFI), and health-related quality of life (HRQOL). Eligible pts must be node-negative with RS 16-20 (plus high clinical risk), or RS 21-25, or have 1-3 positive nodes with RS &lt; 25. Stratification is by nodal status/RS status (pN0 RS 16-25 vs pN1 RS 0-15 and pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39 vs ≥40). Pts are randomized after surgery to either OFS+ET or ACT followed by OFS+ET. ET is an aromatase inhibitor per investigator discretion, but tamoxifen is allowed if pts do not tolerate the AI or if OFS is incomplete. Radiation therapy will be administered per investigator discretion according to protocol guidelines. The HRQOL sub-study will assess differences in severe menopausal symptoms, measured by the FACT ESS-19 score, between the arms, as well as increased pain severity (PROMIS) during ACT+OFS+ET compared to OFS+ET. Blood and tumor specimens will be collected for future research. The accrual of 3,960 pts is anticipated to be completed in seven years and seven mos. Based on data from NSABP B-28 and RxPONDER, the 5-year IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Based on data from TAILORx, the 5-year IBCFS of pN0 pts on the ACT arm is ~95%. Assuming 56% of the pts to be pN0 and 44% pN1, a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET vs. OFS+ET, with one-sided alpha of 0.025 and 80% power will require 380 IBCFS events, which are expected to occur ~11 years after study initiation. The OFSET study is expected to be activated in the third quarter of 2023. Current accrual (06-19-2023) is 0/3,960 Support: U10CA180868, U10CA180822, UG1CA189867, U24CA196067. NCT05879926. Citation Format: Eleftherios Mamounas, Gong Tang, Shannon Puhalla, Sandra Swain, Patricia Ganz, N. Lynn Henry, Reena Cecchini, Sonya Reid, Priya Rastogi, Charles Geyer, Julia White, Amy Clark, Tufia Haddad, Gregory Vidal, Norman Wolmark. NRG-BR009: Phase III Trial Evaluating Addition of Adjuvant Chemotherapy to Ovarian Function Suppression + Endocrine Therapy in Premenopausal Women with pN0-1, HR+/HER2- Breast Cancer and Oncotype Recurrence Score ≤25 (OFSET) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-02.

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. Two years of adjuvant abemaciclib combined with endocrine therapy (ET) resulted in a significant improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) that persisted beyond the 2-year treatment period in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative, node-positive, high-risk early breast cancer (EBC). Here, we report 5-year efficacy results from a prespecified overall survival (OS) interim analysis. In the intent-to-treat population, with a median follow-up of 54 months, the benefit of abemaciclib was sustained with hazard ratios of 0.680 (95% CI, 0.599 to 0.772) for IDFS and 0.675 (95% CI, 0.588 to 0.774) for DRFS. This persistence of abemaciclib benefit translated to continuous separation of the curves with a deepening in 5-year absolute improvement in IDFS and DRFS rates of 7.6% and 6.7%, respectively, compared with rates of 6% and 5.3% at 4 years and 4.8% and 4.1% at 3 years. With fewer deaths in the abemaciclib plus ET arm compared with the ET-alone arm (208 v 234), statistical significance was not reached for OS. No new safety signals were observed. In conclusion, abemaciclib plus ET continued to reduce the risk of developing invasive and distant disease recurrence beyond the completion of treatment. The increasing absolute improvement at 5 years is consistent with a carryover effect and further supports the use of abemaciclib in patients with high-risk EBC.

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 coprimary 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. Metformin has been associated with lower cancer risk in epidemiologic and preclinical research. In the MA.32 randomized adjuvant breast cancer trial, metformin ( v placebo) did not affect invasive disease-free or overall survival. Here, we report metformin effects on the risk of new cancer. Between 2010 and 2013, 3,649 patients with breast cancer younger than 75 years without diabetes with high-risk T1-3, N0-3 M0 breast cancer (any estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) were randomly assigned to metformin 850 mg orally twice a day or placebo twice a day for 5 years. New primary invasive cancers (outside the ipsilateral breast) developing as a first event were identified. Time to events was described by the competing risks method; two-sided likelihood ratio tests adjusting for age, BMI, smoking, and alcohol intake were used to compare metformin versus placebo arms. A total of 184 patients developed new invasive cancers: 102 metformin and 82 placebo, hazard ratio (HR), 1.25; 95% CI, 0.94 to 1.68; P = .13. These included 48 contralateral invasive breast cancers (27 metformin v 21 placebo), HR, 1.29; 95% CI, 0.72 to 2.27; P = .40 and 136 new nonbreast primary cancers (75 metformin v 61 placebo), HR, 1.24; 95% CI, 0.88 to 1.74; P = .21. Metformin did not reduce the risk of new cancer development in these nondiabetic patients with breast cancer.