407. Gnant M, Dueck AC, Frantal S, Martin M, Burstein HJ, Greil R, Fox P, Wolff AC, Chan A, Winer EP, Pfeiler G, Miller KD, Colleoni M, Suga JM, Rubovsky G, Bliss JM, Mayer IA, Singer CF, Nowecki Z, Hahn O, Thomson J, Wolmark N, Amillano K, Rugo HS, Steger GG, Hernando Fernández de Aránguiz B, Haddad TC, Perelló A, Bellet M, Fohler H, Metzger Filho O, Jallitsch-Halper A, Solomon K, Schurmans C, Theall KP, Lu DR, Tenner K, Fesl C, DeMichele A, Mayer EL, PALLAS groups and investigators. Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol 2021;JCO2102554. doi: 10.1200/JCO.21.02554. Epub 2021 Dec 7. (IBCSG 52-15) (Journal Impact Factor 44.544).

Professor Gnant et al reported the final results of the PALLAS (PALbociclib CoLlaborative Adjuvant Study) trial, a phase III open-label trial, designed to determine whether the addition of palbociclib to standard adjuvant endocrine therapy (ET) improves outcomes compared with ET therapy alone. Of the 5,761 patients with early hormone receptor-positive breast cancer included in the intention-to-treat population, 2,884 were randomly assigned to receive Palbociclib plus ET and 2,877 to receive ET alone. The primary endpoint of invasive disease-free survival (iDFS) was not found to be significantly different in patients receiving palbociclib and ET versus those receiving ET alone. Differences in secondary endpoints (invasive breast cancer–free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival) also were not observed between the two treatment groups. The results were published in the Journal of Clinical Oncology.

The paper is attached and the Journal of Clinical Oncology link is here: https://ascopubs.org/doi/10.1200/JCO.21.02554

406. Turner NC, Balmaña J, Poncet C, Goulioti T, Tryfonidis K, Honkoop AH, Zoppoli G, Razis E, Johannsson OT, Colleoni M, Tutt AN, Audeh W, Ignatiadis M, Mailliez A, Trédan O, Musolino A, Vuylsteke P, Juan-Fita MJ, Macpherson IRJ, Kaufman B, Manso L, Goldstein LJ, Ellard SL, Láng I, Jen KY, Adam V, Litière S, Erban J, Cameron DA; BRAVO Steering Committee and the BRAVO Investigators. Niraparib for Advanced Breast Cancer with Germline BRCA1 and BRCA2 Mutations: the EORTC 1307-BCG/BIG 5-13/TESARO PR-30-50-10-C BRAVO Study. Clin Cancer Res 2021;27(20):5482-5491. doi: 10.1158/1078-0432.CCR-21-0310. Epub 2021 Jul 22. (IBCSG 47-14) (Journal Impact Factor 12.531).

Professor Turner et al reported on the final analysis of the BRAVO trial, a randomized, open-label phase III trial, designed to compare the progression-free survival (PFS) of patients treated with either niraparib, a potent oral selective poly(ADP-ribose) polymerase, PARP inhibitor, monotherapy or commonly used mono-chemotherapy regimens. Eligible patients had confirmed HER2-negative locally advanced or metastatic breast cancer and were germline-mutated BRCA 1/2 (gBRCAm)-carriers, irrespective of the tumor hormonal status. The full intention to treat (ITT) population comprised all 215 randomized patients with a centrally confirmed gBRCAm. After review of a planned interim efficacy analysis, enrollment was terminated early due to the PFS analysis results crossing the pre-defined boundary and informative censoring in the control arm. Despite the futility determination, the objective response rate of 35% in the niraparib arm confirmed the drug’s activity in patients with advanced breast cancer and germline BRCA 1 and BRCA2 mutations, supporting the role of PARP inhibitors in the treatment of breast cancer. The results are published in Clinical Cancer Research.

405. Aftimos P, Oliveira M, Irrthum A, Fumagalli D, Sotiriou C, Nili Gal-Yam E, Robson ME, Ndozeng J, Di Leo A, Ciruelos EM, de Azambuja E, Viale G, Scheepers E, Curigliano G, Bliss JM, Reis-Filho JS, Colleoni M, Balic M, Cardoso F, Albanell J, Duhem C, Marreaud S, Romagnoli D, Rojas B, Gombos A, Wildiers H, Guerrero-Zotano A, Hall P, Bonetti A, Larsson KF, Degiorgis M, Khodaverdi S, Greil R, Sverrisdottir A, Paoli M, Seyll E, Loibl S, Linderholm B, Zoppoli G, Davidson NE, Johannsson OT, Bedard PL, Loi S, Knox S, Cameron DA, Harbeck N, Montoya ML, Brandão M, Vingiani A, Caballero C, Hilbers FS, Yates LR, Benelli M, Venet D, Piccart MJ. Genomic and transcriptomic analyses of breast cancer primaries and matched metastases in AURORA, the Breast International Group (BIG) molecular screening initiative. Cancer Discov 2021;11(11):2796-2811. doi: 10.1158/2159-8290.CD-20-1647. Online first 2021 June 28. Epub 2021 Oct 11. (IBCSG 51-14) (Journal Impact Factor 39.397).

The AURORA trial is a study aiming to understand the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients, Dr. Aftimos et al found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA and RB1 mutations; MDM4, MYC amplifications; and ARID1A deletions. An increase in clonality was observed in driver genes like ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. The most prevalent point mutations in primary and/or metastases were found in TP53 followed by PIK3CA, ESR1, CDHI, and GATA3. Luminal A/B to HER2-Enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune permissive cells. High tumor mutational burden (TMB) correlated to shorter time to relapse in HR+/HER2- breast cancers. The results are published in Cancer Discovery.

 The paper is attached and the Cancer Discovery link is here: https://cancerdiscovery.aacrjournals.org/content/early/2021/06/29/2159-8290.CD-20-1647

404. Weber WP, Matrai Z, Hayoz S, Tausch C, Henke G, Zwahlen DR, Gruber G, Zimmermann F, Seiler S, Maddox C, Ruhstaller T, Muenst S, Ackerknecht M, Kuemmel S, Bjelic-Radisic V, Kurzeder C, Újhelyi M, Vrieling C, Satler R, Meyer I, Becciolini C, Bucher S, Simonson C, Fehr PM, Gabriel N, Maraz R, Sarlos D, Dedes KJ, Leo C, Berclaz G, Dubsky P, Exner R, Fansa H, Hager C, Reisenberger K, Singer CF, Reitsamer R, Reinisch M, Winkler J, Thanh Lam G, Fehr MK, Naydina T, Kohilk M, Clerc K, Ostapenko V, Fitzal F, Nussbaumer R, Maggi N, Schulz A, Markellou P, Lelièvre L, Egle D, Heil J, Knauer M. Tailored axillary surgery in patients with clinically node-positive breast cancer: Pre-planned feasibility substudy of TAXIS (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101). Breast 2021;60:98-110. doi: 10.1016/j.breast.2021.09.004. Epub 2021 Sept 8. (IBCSG 57-18) (Journal Impact Factor 4.380). 

Dr. Weber et al aimed to quantify the extent of tumor load reduction achieved by tailored axillary surgery (TAS) in a prospective substudy of TAXIS, a phase-III non-inferiority, randomized trial designed to examine whether TAS in combination with regional nodal irradiation is oncologically non-inferior and associated with improved quality of life compared to axillary lymph node dissection (ALND). A total of 296 patients with clinically node-positive breast cancer were included. Results demonstrated that TAS selectively reduced the tumor load in the axilla and remained much less radical than ALND. The results are published in The Breast.

403. Jerusalem G, Farah S, Courtois A, Chirgwin J, Aebi S, Karlsson P, Neven P, Hitre E, Graas MP, Simoncini E, Abdi E, Kamby C, Thompson A, Loibl S, Gavilá J, Kuroi K, Marth C, Müller B, O’Reilly S, Gombos A, Ruhstaller T, Burstein HJ, Rabaglio M, Ruepp B, Ribi K, Viale G, Gelber RD, Coates AS, Loi S, Goldhirsch A, Regan* MM, Colleoni* M. on behalf of the SOLE Investigators. Continuous vs intermittent extended adjuvant letrozole for breast cancer: Final results of randomized phase 3 SOLE (Study of Letrozole Extension) and SOLE Estrogen Substudy. *Co-last authors. Ann Oncol 2021;32(10):1256-1266. doi: 10.1016/j.annonc.2021.07.017. Epub 2021 Aug 10. (IBCSG 35-07) (Journal Impact Factor 32.976).
Dr. Jerusalem et al present the final analysis of the Study of Letrozole Extension (SOLE), a phase 3 randomized, open-label trial examining the effect of extended intermittent letrozole treatment in comparison with continuous letrozole and the results of the SOLE estrogen sub-study (SOLE-EST) which was conducted to document changes of circulating estrogen levels before and during the initial three-month treatment interruption and its relationship with some baseline clinical factors, quality of life and grip strength. SOLE enrolled 4884 postmenopausal women with hormone receptor-positive, lymph node-positive, operable breast cancer between December 2007 and October 2012 and, among them, 104 patients were enrolled in SOLE-EST. Patients were randomized between continuous letrozole and intermittent letrozole treatment. After a median follow-up of 84 months, 7-year disease-free survival was observed to be similar between the treatment groups as were reported adverse events. Circulating estrogen recovery was demonstrated within 6 weeks after the stop of letrozole treatment. These results along with previously reported quality-of-life advantages suggest intermittent extended treatment offers a valid option for patients who need or prefer to interrupt extended therapy. Results are published in Annals of Oncology.
402. Partridge AH, Niman SM, Ruggeri M, Peccatori FA, Azim HA Jr, Colleoni M, Saura C, Shimizu C, Saetersdal AB, Kroep JR, Mailliez A, Warner E, Borges VF, Amant F, Gombos A, Kataoka A, Rousset-Jablonski C, Borstnar S, Takei J, Lee JE, Walshe JM, Borrego MR, Moore HCF, Saunders C, Cardoso F, Susnjar S, Bjelic-Radisic V, Smith KL, Piccart M, Korde LA, Goldhirsch A, Gelber RD, Pagani O. Who are the women who enrolled in the POSITIVE Trial: a global study to support young hormone receptor positive breast cancer survivors desiring pregnancy? Breast 2021;59:327-338. doi: 10.1016/j.breast.2021.07.021. 2021 Aug 3. (IBCSG 48-14) (Journal Impact Factor 4.380).
Dr. Partridge et al. describe sociodemographic, disease and treatment characteristics as well as regional variations of women enrolled in POSITIVE, the prospective, single-arm study in young, pregnancy-seeking women with HR+ early breast cancer designed to assess whether temporarily interrupting adjuvant endocrine therapy (ET) to attempt pregnancy increases the risk of a breast cancer event. Treatment interruption for up to 2 years was permitted to allow pregnancy, delivery, and breastfeeding, followed by ET resumption to complete the planned duration. From 12/2014 to 12/2019, 518 women were enrolled at 116 institutions/ 20 countries/ 4 continents. Results indicated that, overall, patients enrolled had a relatively high median age (37 years) and low-risk disease. Also observed were geographical variations, for example, differences in treatment strategies. Results have been published in The Breast.
401. Goodwin PJ, Dowling RJO, Ennis M, Chen BE, Parulekar WR, Shepherd LE, Gelmon KA, Whelan TJ, Ligibel JA, Hershman DL, Mayer IA, Hobday TJ, Rastogi P, Rabaglio-Porettti M, Lemieux J, Thompson AM, Rea DW, Stambolic V. Cancer antigen 15-3/mucin 1 levels in CCTG MA.32: A breast cancer randomized trial of metformin vs placebo. JNCI Cancer Spectr 2021;5(5):pkab066. doi: 10.1093/jncics/pkab066. Epub 2021 July 28. (IBCSG 40-11).
Dr. Goodwin et al explored the effect of metformin (vs placebo) on levels of cancer antigen (CA) 15-3, a tumor marker and regulator of cellular metabolism, at baseline and 6 months, in the Canadian Cancer Trials Group (CCTG) MA.32, a phase III randomized adjuvant trial of the effect of metformin vs placebo on invasive disease-free survival (IDFS) in women with high-risk, operable breast cancer. A total of 3649 non-diabetic patients with T1-3, N0-3, M0 breast cancer were randomly assigned to receive metformin or an identical placebo for 5 years; pretreatment and 6-month on-treatment fasting plasma were centrally assayed for CA 15-3. Genomic DNA was analyzed for the rs11212617 single nucleotide polymorphism. Absolute and relative change of CA 15-3 (metformin vs placebo) were compared using Wilcoxon rank and t tests. Regression models were adjusted for baseline differences and assessed for key interactions. Results demonstrated that CA 15-3 was statistically significantly reduced, at 6 months, in metformin vs placebo arms. This reduction was independent of tumor characteristics, perioperative systemic therapy, baseline body mass index, insulin, and the single nucleotide polymorphism status (all Ps > .11). Results have been published in JNCI Cancer Spectrum.
400. Burstein HJ, Curigliano G, Thürlimann B, Weber WP, Poortmans P, Regan MM, Senn HJ, Winer EP, Gnant M, Panelists of the St. Gallen Consensus Conference. Customizing local and systemic therapies for women with early breast cancer: The St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. Ann Oncol 2021;S0923-7531(21):02104-9. doi: 10.1016/j.annonc.2021.06.023. Epub 2021 July 6. (Special article) (Jounal Impact Factor 32.976).

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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