399. Goodwin PJ, Dowling RJO, Ennis M, Chen BE, Parulekar WR, Shepherd LE, Burnell MJ, Vander Meer R, Molckovsky A, Gurjal A, Gelmon KA, Ligibel JA, Hershman DL, Mayer IA, Whelan TJ, Hobday TJ, Rastogi P, Rabaglio M, Lemieux J, Thompson AM, Rea DW, Stambolic V. Effect of metformin versus placebo on metabolic factors in the MA.32 randomized breast cancer trial. npj Breast cancer 2021;7(1):74. doi: 10.1038/s41523-021-00275-z. Epub 2021 June 8. (IBCSG 40-11) (Journal Impact Factor 6.000).

Dr. Goodwin et al investigated metformin, the anti-diabetes drug, impact on metabolic factors in non-diabetic women to determine whether this impact varies by baseline BMI (body mass index), insulin, and rs11212617 SNP in the Canadian Cancer Trials Group (CCTG) MA.32, a double-blind placebo-controlled randomized adjuvant breast cancer trial. Between 2010 and 2013, 3649 non-diabetic women with T1-3, N0-3, M0 breast cancer were randomized. Pretreatment and 6-month on-treatment fasting plasma was centrally assayed for insulin, leptin, and highly sensitive C-reactive protein (hsCRP). Glucose was measured locally, and homeostasis model assessment (HOMA) calculated. Genomic DNA was analyzed for the rs11212617 SNP which has been linked to glycemic response to metformin in some studies. Using Wilcoxon rank and t-tests, absolute and relative change of metabolic factors (metformin versus placebo) were compared. Regression models were adjusted for baseline differences and assessed interactions with baseline BMI, insulin, and the SNP. Results showed metformin (vs placebo) led to significant improvements in weight and metabolic factors; these changes did not differ by rs11212617 allele status. Results have been published in npj Breast Cancer.

398. Pimentel I, Chen BE, Lohmann AE, Ennis M, Ligibel J, Shepherd L, Hershman DL, Whelan T, Stambolic V, Mayer I, Hobday T, Lemieux J, Thompson A, Rastogi P, Gelmon K, Rea D, Rabaglio M, Ellard S, Mates M, Bedard P, Pitre L, Vandenberg T, Dowling RJO, Parulekar W, Goodwin PJ. The effect of metformin vs placebo on sex hormones in Canadian Cancer Trials Group MA.32. J Natl Cancer Inst 2021;113(2):192-193. doi: 10.1093/jnci/djaa082. (IBCSG 40-11) (Journal Impact Factor 11.577).

Dr. Pimentel et al investigated metformin, the anti-diabetes drug, impact on sex hormones and the effects of the minor allele of the rs11212617 SNP in a subgroup of nondiabetic, postmenopausal women with hormone receptor-negative breast cancer enrolled onto the Canadian Cancer Trials Group (CCTG) MA.32, a double-blind placebo-controlled randomized adjuvant breast cancer trial. 312 women were eligible. Using Wilcoxon sum rank tests and regression models, change in levels of prespecified sex hormones (estradiol, SHBG, and bioavailable testosterone) from baseline to 6 months between metformin and placebo arms was compared. Results showed that metformin lowered estradiol levels, independent of BMI. Results have been published in the Journal of the National Cancer Institute.

397. Tutt ANJ, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, Gelber RD, de Azambuja E, Fielding A, Balmana J, Domcheck SM, Gelmon KA, Hollingsworth SJ, Korde LA, Linderholm B, Bandos H, Senkus E, Suga JM, Shao Z, Pippas AW, Nowecki Z, Huzarski T, Ganz PA, Lucas PC, Baker N, Loibl S, McConnell R, Piccart M, Schmutzler R, Steger GG, Costantino JP, Arahmani A, Wolmark N, McFadden E, Karantza V, Lakhani SR, Yothers G, Campbell C, Geyer CE Jr; for the OlympiA Clinical Trial Steering Committee and Investigators. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated Breast Cancer. N Engl J Med 2021. doi: 10.1056/NEJMoa2105215. Epub 2021 June 3. (IBCSG 50-14) (Journal Impact Factor 74.669).

In the OlympiA trial, a prospective, multicenter, multinational double-blind clinical trial, Dr. Tutt et al hypothesized that olaparib, a poly(adenosine diphosphate-ribose) polymerase inhibitor, would provide benefit as an adjuvant therapy for patients with germline BRCA1 or BRCA2 pathogenic or likely pathogenic variant-associated early breast cancer who have high risk of recurrence despite standard-of-care local and systemic therapy. Patients were randomly assigned (N=1836, including 6 men) to receive either olaparib or placebo for 1 year, after the completion of standard adjuvant or neoadjuvant chemotherapy and local therapy; stratified according to hormone-receptor status (positive or negative), timing of previous chemotherapy (neoadjuvant or adjuvant), and use of platinum chemotherapy for current breast cancer (yes or no). The primary end point was invasive disease-free survival. Results demonstrated that 1 year of adjuvant olaparib can meaningfully reduce recurrence risk and prevent progression to metastatic disease among patients with high-risk early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, with high adherence rates and primarily a low-grade toxicity profile. The results were presented at the 2021 ASCO Annual Meeting and concurrently published in the New England Journal of Medicine.

396. Moreno-Aspitia A, Holmes EM, Jackisch C, de Azambuja E, Boyle F, Hillman DW, Korde L, Fumagalli D, Izquierdo MA, McCullough AE, Wolff AC, Pritchard KI, Untch M, Guillaume S, Ewer MS, Shao Z, Sim SH, Aziz Z, Demetriou G, Mehta AO, Andersson M, Toi M, Lang I, Xu B, Smith IE, Barrios CH, Baselga J, Gelber RD, Piccart-Gebhart M, for the ALTTO Steering Committee and Investigators. Updated results from the International Phase III ALTTO Trial (BIG 2-06/Alliance N063D): Presented at the 2017 Annual Meeting of the American Society of Clinical Oncology. Eur J Cancer 2021;148:287-296. doi: 10.1016/j.ejca.2021.01.053. Epub 2021 March 22. (IBCSG 36-07) (Journal Impact Factor 7.275).

395.       Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer in the APHINITY Trial: 6 years' follow-up. J Clin Oncol 2021. doi: 10.1200/JCO.20.01204. Epub 2021 Feb 4. (IBCSG 39-11) (Journal Impact Factor 32.956).

In the APHINITY trial, Dr. Piccart et al demonstrated that pertuzumab, when added to adjuvant trastuzumab and chemotherapy, modestly but statistically significantly improved invasive disease-free survival (iDFS) among patients with HER2-positive, operable breast cancer. After surgery and central HER2-positive confirmation, patients (N=4805) with node-positive or high-risk node-negative breast cancer were randomly assigned (1:1) to either 1-year pertuzumab or placebo added to standard adjuvant chemotherapy and 1-year trastuzumab.  After 74 months median follow-up, fewer deaths were observed in the pertuzumab arm, however statistical significance was not reached at this second interim analysis. Updated iDFS results based on 508 events in the intent-to-treat population were: HR=0.76 [95% CI 0.64-0.91] with 6-year iDFS of 91% vs 88%. The node-positive cohort continues to derive clear benefit from the addition of pertuzumab compared with the node-negative cohort. No new cardiac safety concerns emerged. Results support the benefit of pertuzumab in HER2-positive early breast cancer, with the greatest benefit continuing to be observed in the node positive population. The results were presented at the 2019 SABCS Annual Meeting and concurrently published in the Journal of Clinical Oncology.

394.       Mayer EL, Dueck C, Martin M, Rubovszky G, Burstein HJ, Bellet-Ezquerra M, Miller KD, Zdenkowski N, Winer EP, Pfeiler G, Goetz M, Ruiz-Borrego M, Anderson D, Nowecki Z, Loibl S, Moulder S, Ring A, Fitzal F, Traina T, Chan A, Rugo HS, Lemieux J, Henao F, Lyss A, Antolin Novoa S, Wolff AC, Vetter M, Egle D, Morris PG, Mamounas EP, Gil-Gil MJ, Prat A, Fohler H, Metzger Filho O, Schwarz M, Dufrane C, Fumagalli D, Puyana Theall K, Lu DR, Huang Bartlett C, Koehler M, Fesl C, DeMichele A, Gnant M. Palbociblib with adjuvant endocrine therapy in early breast cancer (PALLAS): Interim analysis of a multicentre, open-label, randomized, phase 3 study. Lancet Oncol 2021;22(2):212-222. doi: 10.1016/S1470-2045(20)30642-2. Epub 2021 Jan 15. (IBCSG 52-15) (Journal Impact Factor 33.752).

In the PALLAS trial, a phase III open-label trial, Dr. Mayer et al found that addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy (ET) did not improve invasive disease-free survival (iDFS) compared with ET alone. Patients (n=5760) with stage II-III HR+ / HER2-negative early breast cancer were randomized to receive either 2 years of palbociclib with standard adjuvant ET, or standard ET alone; iDFS was the primary endpoint. When 67% of events were observed, the second interim analyses (IA2) were triggered. After a median follow-up of 23.7 months (351 events), iDFS was observed to be similar between the two arms, with 3-year iDFS of 88.2% for palbociclib and ET, and 88.5% for ET alone (HR 0.93, 95% CI 0.76-1.15), crossing a pre-specified futility boundary. No benefit from palbociclib was observed within clinicopathologic subgroups. At IA2, two years of adjuvant palbociclib with ET did not improve iDFS compared to ET alone. The results were presented at the 2020 European Society of Medical Oncology Congress Annual Meeting and published in the journal Lancet Oncology.


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