416.  Pagani* O, Walley* BA, Francis GF, Colleoni M, Láng I, Gomez Hl, Tondini C, Burstein HJ, Goetz MP, Ciruelos EM, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Chini C, Puglisi F, Spazzapan S, Ruhstaller T, Winder EP, Ruepp B, Loi S, Coates AS, Gelber RD, Goldhirsch A, Regan** MM, Francis** PA, for the SOFT and TEXT Investigators and the International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer: long-term follow-up of the combined TEXT and SOFT trials. *Co-lead authors. **Co-last authors. J Clin Oncol 2022. (IBCSG 24-02 and 25-02) (Journal Impact Factor 50.717).
 
Drs Pagani and Walley et al reported the combined analysis of SOFT-TEXT compared outcomes in 4690 premenopausal women with Estrogen/Progesterone-receptor-positive (ER/PgR+) early breast cancer randomized to 5 years exemestane+ovarian function suppression (OFS) versus tamoxifen+OFS. After 9 years median follow-up (MFU), exemestane+OFS significantly improved disease-free survival (DFS) and distant recurrence-free interval (DRFI), but not overall survival, compared to tamoxifen+OFS. With 13-years MFU, a reduction not only in recurrences but also in mortality emerged for exemestane+OFS versus tamoxifen+OFS in women with HER2-negative disease, most clinically-meaningful for those at higher-risk of relapse. No overall survival benefit with exemestane+OFS was evident in women at lower risk of relapse not receiving chemotherapy. Annual follow-up for SOFT and TEXT will continue until 2025. Results are reported in the Journal of Clinical Oncology.
 
The manuscript is freely available from The Journal of Clinical Oncology at:  https://ascopubs.org/doi/abs/10.1200/JCO.22.01064
 
415. Francis* PA, Fleming* GF, Láng I, Ciruelos EM, Bonnefoi HR, Bellet M, Bernardo A, Climent MA, Martino S, Bermejo B, Burstein HJ, Davidson NE, Geyer CE Jr, Walley BA, Ingle, JN, Coleman RE, Müller B, Le Du F, Loibl S, Winer EP, Ruepp B, Loi S, Colleoni M, Coates AS, Gelber RD, Goldhirsch A, Regan MM, for the SOFT Investigators and the International Breast Cancer Study Group. Adjuvant endocrine therapy in premenopausal breast cancer: 12-year results from SOFT. *Co-lead authors. J Clin Oncol 2022. doi: 10.1200/JCO.22.01065. Epub 2022 Dec 9. (IBCSG 24-02) (Journal Impact Factor 50.717).

Drs. Francis and Fleming et al reported outcomes after 12-years median follow-up in the SOFT trial which randomized premenopausal women with hormone receptor-positive breast cancer to 5 years of adjuvant tamoxifen, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. The primary analysis compared disease-free survival (DFS) between tamoxifen plus OFS versus tamoxifen alone. After 8 years, SOFT reported a significant reduction in recurrence and improved overall survival with adjuvant tamoxifen plus OFS versus tamoxifen alone. After 12 years, SOFT showed a sustained significant reduction in the risk of recurrence with the addition of OFS to adjuvant tamoxifen. Further reduction of recurrence was observed with exemestane plus OFS. Moreover, a benefit in overall survival with exemestane plus OFS, that was not evident in the first five years, emerged in subsequent years. After 12 years, there remains a benefit from including OFS in adjuvant endocrine therapy, with an absolute improvement in overall survival more apparent with higher baseline risk of recurrence. Patients who did not receive chemotherapy and were assigned tamoxifen alone continue to have very high rates of freedom from distant recurrence and overall survival, although distant recurrences have continued to occur. Annual follow-up for SOFT will continue until 2025. Results are reported in the Journal of Clinical Oncology. The manuscript is freely available from The Journal of Clinical Oncology at: https://ascopubs.org/doi/10.1200/JCO.22.01065

414.  Chua BH, Link EK, Kunkler IH, Whelan TJ, Westenberg AH, Gruber G, Bryant G, Ahern V, Purohit K, Graham PH, Akra M, McArdle O, O'Brien P, Harvey JA, Kirkove C, Maduro JH, Campbell ID, Delaney GP, Martin JD, Vu T TT, Muanza TM, Neal A, Olivotto IA, BIG 3–07/TROG 07.01 trial investigators. Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3-07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study. Lancet 2022;400(10350):431-440. doi: 10.1016/S0140-6736(22)01246-6. Epub 2022 Aug 6. (IBCSG 38-10) (Journal Impact Factor 202.731).

Dr. Chua et al investigated whether a tumor bed boost after whole breast irradiation (WBI) improved decreased local recurrence, and examined radiation dose fractionation sensitivity for non-low-risk ductal carcinoma in situ (DCIS) in an international, randomized, unmasked, phase 3 trial. Eligible patients were women, aged 18 years or older, with unilateral, histologically proven, non-low-risk DCIS treated by breast-conserving surgery with at least 1 mm of clear radial resection margins. Patients were assigned to one of four groups (1:1:1:1) of no tumor bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after each participating center prespecified conventional or hypofractionated WBI. The primary endpoint was time to local recurrence. Median follow-up was 6.6 years. Results demonstrated that a tumor bed boost after WBI reduced local recurrence with an increase in grade 2 or greater toxicity in patients with resected non-low-risk DCIS. Results were published in the Lancet.The Lancet article is here: https://thelancet.com/journals/lancet/article/PIIS0140-6736(22)01246-6/fulltext

 
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.

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