Abstract GS1-08: CCTGMA.32, a phase III randomized double-blind placebo controlled adjuvant trial of metformin (MET) vs placebo (PLAC) in early breast cancer (BC): Results of the primary efficacy analysis (clinical trials.gov NCT01101438)
Bibliographic record
Abstract
Abstract Background: MET has been associated with beneficial anti-cancer effects in epidemiologic and preclinical research. It may act indirectly by reversing obesity associated physiologic changes or directly via mitochondrial mediated effects on LKB1/AMPK/mTOR and other mechanisms. MA.32 investigated the effect of MET vs PLAC (in addition to standard therapy) on adjuvant BC outcomes. Design: Randomized, placebo-controlled double-blind Phase III clinical trial conducted within the NCI US National Clinical Trials Network, NCRI (UK) BG, IBCSG. Methods: Between 2010-2013 BC patients < 75 yo without diabetes (DM) with high risk T1-3, N0-3 M0 BC regardless of ER, PgR, HER2 and with adequate cardiac, renal and hepatic function were randomized (stratified for ER/PgR + vs -, BMI < vs > 30 kg/m2, HER2 +ve vs -ve, any vs no chemo) within 1 year of BC diagnosis to MET 850 mg po bid or PLAC bid for 5 years. Dose was reduced for toxicity with re-escalation when possible. Subjects were followed for Invasive Disease-Free Survival (IDFS primary outcome; events included invasive local/regional recurrences, distant recurrences, new ipsilateral/contralateral invasive BCs, new non-breast primary cancers, any death), Overall Survival (OS), Distant Relapse Free Survival (DRFS), BC Specific Survival (BCSS), BC Free Interval (BCFI), contralateral BC and cardiovascular (CV) events/new DM. 3582 subjects were required for 80% power to detect HR 0.76 (431 events). In 2011, entry was restricted to higher risk BC, leading to 80% power to detect HR 0.785 (544 events). In 2016, after the 2nd interim analysis at 29.5 months median F/U, the DSMB recommended (i) the intervention be continued with primary analysis triggered at 544 events be conducted in ER/PgR +ve (any HER2) subjects only and (ii) ER/PgR -ve subjects stop study drug for futility but blinding and follow-up continue. In 2021, a time driven analysis in ER/PgR +ve BC was approved (465 events providing 80% power to detect the original HR 0.76). Time to event survival described by the Kaplan-Meier method. Two-sided log-rank tests adjusting for stratification factors were primarily used to compare IDFS between arms. Cox proportional hazards models were used to identify and adjust for factors significantly related to IDFS. Results: 3649 subjects were enrolled. In the 2533 ER/PgR +ve subjects included in the primary analysis, baseline mean (± SD) age was 52.7 (±9.9 yrs); mean BMI 28.8 (±6.4) kg/m2. Baseline tumor characteristics were balanced: T stage 1/2/3/4 = 832/1351/349/1; N stage 0/1/2/3 = 964/1097/449/23; HER2+ 429. 1901 (75%) received XRT. 2150 (84.9%) received (neo)adj chemo, 2223 (87.8%) (neo)adj hormones and 434 (17.1%) HER2 targeted therapy. Any Grade ≥ 3 toxicity was similar in MET and PLAC arms (21.7% and 18.7%, P = 0.06). Median follow-up was 96.2 (range 0.2-121.0) months with 465 IDFS events (234 MET, 231 PLAC, 76% due to BC). Efficacy results are shown below. MET vs PLACMET vs PLACIDFSOSPopulation Included# subjectsHR (95% CI)HR (95% CI)PRIMARY ANALYSISER/PgR +ve (any HER2)*25331.01 (0.84-1.21). P=0.920.89 (0.64-1.23). P=0.46ER/PgR -ve (any HER211161.01 (0.79-1.30. P=0.92)0.89 (0.64-1.23). P=0.46Exploratory. AnalysisHER2 +ve (any ER/PgR)6200.64 (0.43-0.95. P=0.0260.53 (0.30-0.98. P=0.0398**in ER/PgR pos BC HRs were similar for BCFI, DRFS, BCSS (ranging from 0.98-1.09)Conclusions: MET did not improve IDFS or other BC outcomes in ER/PgR positive or ER/PgR negative BC and should not be used as adjuvant treatment. Exploratory findings suggesting benefit in HER2+ve BC should be further investigated. Funded by: CCSRI, NCI (US), CBCF, BCRF, CRUK, Hold’Em for Life Charity, Apotex (Canada) Citation Format: Pamela J. Goodwin, Bingshu E Chen, Karen A Gelmon, Timothy J Whelan, Marguerite Ennis, Julie Lemieux, Jennifer A Ligibel, Dawn L Hershman, Ingrid A Mayer, Timothy J Hobday, Judith M Bliss, Priya Rastogi, Manuela Rabaglio-Poretti, Som D. Mukherjee, Robert R Mackey, Vandana G Abramson, Conrad Oja, Robert Wesolowski, Alastair M Thompson, Daniel W Rea, Paul M Stos, Lois E Shepherd, Vuk Stambolic, Wendy R Parulekar. CCTGMA.32, a phase III randomized double-blind placebo controlled adjuvant trial of metformin (MET) vs placebo (PLAC) in early breast cancer (BC): Results of the primary efficacy analysis (clinical trials.gov NCT01101438) [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 GS1-08.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.057 | 0.005 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.008 | 0.003 |
| Bibliometrics | 0.002 | 0.004 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.003 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".