413. Ribi K, Pagan E, Sala I, Ruggeri M, Bianco N, Oreste Bucci E, Graffeo R, Borner M, Giordano M, Gianni L, Rabaglio M, Freschi A, Cretella E, Seles E, Farolfi A, Simoncini E, Ciccarese M, Rauch D, Favaretto A, Glaus A, Berardi R, Franzetti-Pellanda A, Bagnardi V, Gelber S, Partridge AH, Goldhirsch A, Olivia Pagani O. Employment trajectories of young women with breast cancer: An ongoing prospective cohort study in Italy and Switzerland. J Cancer Surviv 2022. doi: 10.1007/s11764-002-01222-y. Epub 2022 June 10. (IBCSG 43-09) (Journal Impact Factor 4.442).
Dr. Karin Ribi et al published the second manuscript based on the IBCSG’s 43-09 HOHO study.  HOHO (Helping Ourselves, Helping Others) is a European prospective multicenter cohort study which enrolled 300 young women (40 years) with newly diagnosed breast cancer. Women completed surveys at baseline and every 6 months for 3 years, then yearly for up to 10 years, to assess employment status, sociodemographic, medical and treatment data, among other variables. Symptoms were assessed by the Breast Cancer Prevention Trial symptom scales and single items from the Cancer Rehabilitation Evaluation System. Among the 245 women included in the analysis, 85% were employed at the last individual post-baseline assessment (1 to 10 years). Results suggest that most young breast cancer survivors remain employed in the long-term. Results were published in the Journal of Cancer Survivorship.
The manuscript is attached and the Journal of Cancer Survivorship link is here: https://link.springer.com/article/10.1007/s11764-022-01222-y
412. Goodwin PJ, Chen BE, Gelmon KA, Whelan TJ, Ennis M, Lemieux J, Ligibel JA, Hershman DL, Mayer IA, Hobday TJ, Bliss JM, Rastogi P, Rabaglio-Poretti M, Mukherjee SD, Mackey JR, Abramson VG, Oja C, Wesolowski R, Thompson AM, Rea DW, Stos PM, Shepherd LE, Stambolic V, Parulekar WR. Effect of metformin vs placebo on invasive disease-free survival in patients with breast cancer: The MA.32 randomized clinical trial. JAMA 2022;327(20):1963-1973. doi: 10.1001/jama.2022.6147. Epub 2022 24 May. (IBCSG 40-11) (Journal Impact Factor 56.272).
In the Canadian Cancer Trials Group (CCTG) MA.32 phase III randomized placebo-controlled trial, Dr. Goodwin et al studied whether metformin for 5 years improves outcomes in non-diabetic patients with moderate/high risk, early-stage breast cancer who were receiving standard therapy. Results for the hormone receptor-positive (HR+) cohort (n=2533) after 96 months median follow-up reported the addition of metformin to standard therapy did not improve invasive disease-free survival, overall survival or other breast cancer outcomes in women with moderate/high risk, early-stage HR+ breast cancer and do not support the use of metformin in this population. Results have been published in JAMA.
The manuscript is attached and the JAMA link is here: https://jamanetwork.com/journals/jama/fullarticle/2792615

411.  Pérez-Fidalgo JA, Criscitiello C, Carrasco E, Regan MM, Di Leo A, Ribi K, Adam V, Bedard PL. A phase 3 trial of alpelisib+trastuzumab+/-fulvestrant vs trastuzumab+chemotherapy in HER2+ PIK3CA-mutated breast cancer. Future Oncol 2022;18(19):2339-2349. doi: 10.2217/fon-2022-0045. Epub 2022 Apr 25. (Special article / review) (IBCSG 62-20) (Journal Impact Factor 3.404).

410. Malorni L, Tyekucheva S, Hilbers FS, Ignatiadis M, Neven P, Colleoni M, Henry S, Ballestrero A, Bonetti A, Jerusalem G, Papadimitriou K, Bernardo A, Seles E, Duhoux FP, MacPherson IR, Thomson A, Davies DM, Bergqvist M, Migliaccio I, Gebhart G, Zoppoli G, Bliss JM, Benelli M, McCartney A, Kammler R, DeSwert H, Ruepp B, Fumagalli D, Maibach R, Cameron D, Loi S, Piccart* M, Regan* MM. Serum thymidine kinase activity in patients with hormone receptor positive and HER2-negative metastatic breast cancer treated with palbociclib and fulvestrant. *Co-last authors. Eur J Cancer 2022;164:39-51. doi: 10.1016/j.ejca.2021.12.030. Epub 2022 Feb 13. (IBCSG 53-14) (Journal Impact Factor 9.162). 

In PYTHIA (Palbociclib in molecularly characterized ER-positive/HER2-negative metastatic breast cancer), a biomarker discovery phase II trial, Dr. Malorni et al prospectively investigated serum thymidine kinase activity (sTka) as a potential prognostic and monitoring marker for post-menopausal women treated with palbociclib + fulvestrant. Serum samples were collected pre-treatment, at day 15 of cycle 1, during the one week-off palbociclib before initiating cycle 2, and at end of treatment. The primary study endpoint was progression-free survival, assessed for its association with pre- and on-treatment sTka. 124 women were enrolled. Data from 122 women were analyzed. Results showed that palbociclib + fulvestrant saliently suppressed sTKa levels at day 15. At each timepoint, higher sTKa was associated with shorter progression-free survival. High pre-treatment TKa and its incomplete suppression during treatment may identify patients with poor prognosis and primary resistance to Palbociclib + fulvestrant. Results warrant validation in prospective comparative trials. PYTHIA first results were published in European Journal of Cancer.
The paper is attached and the European Journal of Cancer link is here:  https://www.ejcancer.com/article/S0959-8049 
409. Bradley R, Braybrooke J, Gray R, Hills R, Liu Z, Pan H, Peto R, Dodwell D, McGale P, Taylor C, Bergh J, Swain S, Francis PA, Gnant M, Perrone F, Regan MM, for the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: Patient level meta-analysis of 7,030 women in four randomised trials. Lancet Oncol 2022. doi: 10.org/10.1016/S1470-2045(21)00758-0. Epub 2022 Feb 3. (IBCSG 24-02 and 25-02) (Journal Impact Factor 41.316). 
As part of the EBCTCG (Early Breast Cancer Trialists’ Collaborative Group), Bradley et al performed a patient-level meta-analysis of four trials (ABCSG XII, SOFT, TEXT and HOBOE) of 7030 pre-menopausal women with early-stage, hormone receptor-positive breast cancer. Median follow-up was 8.0 years. The main benefit was observed in years 0-4. Results suggest that using an aromatase inhibitor rather than tamoxifen in addition to ovarian function suppression for pre-menopausal women reduced recurrence risk but did not lead to better overall survival. To assess any impact on breast cancer mortality, longer follow-up is recommended. The authors suggest that quality of life should also be carefully considered alongside the expected improvement in disease outcomes observed in this meta-analysis. Results were published in Lancet Oncology.
The paper is attached and the Lancet Oncology link is here:  https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045
408. Loi S, Salgado R, Adams S, Pruneri G, Francis PA, Lacroix-Triki M, Joensuu H, Vittoria Dieci M, Badve S, Demaria S, Gray R, Munzone E, Drubay D, Lemonnier J, Sotiriou C, Kellokumpu-Lehtinen PL, Vingiani A, Gray K, André F, Denkert C, Piccart M, Roblin E, Michiels S. Tumor infiltrating lymphocyte stratification of prognostic staging of early-stage triple negative breast cancer (Brief communication). npj Breast Cancer 2022;8(1):3. doi: 10.1038/s41523-021-00362-1. Epub 2022 Jan 11. (IBCSG 22-00). (Journal Impact Factor 6.923). 
In a follow-up analysis, Professor Loi et al performed a pooled analysis of 2148 patients with early-stage triple-negative breast cancer (TNBC), enrolled onto eight prospective clinical trials, as well as one large institutional cohort, in the adjuvant setting. The findings heighten the evidence supporting tumor infiltrating lymphocytes (TILs) as a biologic biomarker, improving discernment over prognostic pathological and clinical staging for early-stage TNBC. Results indicate that TILs, in addition to TNM stage, should be considered in clinical and research studies on TNBC as patients with stage II TNBC and high TILs were shown to have a better outcome than patients with stage I and low TILs. Histological grade was not found to be prognostic in this pooled analysis. Results were published in npj Breast Cancer.
The paper is attached and the npj Breast Cancer link is here:  https://www.nature.com/articles/s41523-021-00362-1

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).

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