420.  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, Bjelic-Radisic V, Susnjar S, Cardoso F, Smith KL, Ferreiro T, Ribi K, Ruddy K, Kammler R, El-Abed S, Viale G, Piccart M, Korde LA, Goldhirsch A, Gelber RD, Pagani O, for the International Breast Cancer Study Group and the POSITIVE Trial Consortium, Steering Committee and Investigators. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med 2023;388:1645-1656. doi: 10.1056/NEJMoa2212856. (IBCSG 48-14) (Journal Impact Factor 176.079).

Dr. Partridge et al. evaluated temporary interruption of adjuvant endocrine therapy for pregnancy in young breast cancer survivors in POSITIVE, a single-arm trial. Eligible women <42 years with stage I-III disease, received 18-30 months of prior adjuvant endocrine therapy and desired pregnancy. The primary endpoint was breast-cancer-free interval (BCFI, time from enrollment to first breast cancer event). The primary analysis planned 1600 patient-years follow-up, with >46 BCFI events as safety threshold. To supplement the primary analysis, BCFI and distant-recurrence outcomes were compared to an external control from the SOFT/TEXT trials using Bootstrapped Matching Method. Of 518 women enrolled, the median age was 37 years. Median time from diagnosis to enrollment was 29 months, 93.4% had stage I-II disease. Of 497 women followed for pregnancy status, 368 (74.0%) had at least one pregnancy, 317 (63.8%) at least one live birth (365 babies born). At 1638 patient-years (median follow-up, 41 months), 44 participants experienced a BCFI event, not exceeding the safety threshold. Results suggest that for select young women with early hormone-receptor-positive breast cancer, temporary interruption of endocrine therapy to attempt pregnancy does not confer greater short-term risk of recurrence than a modern control group. Further follow-up data will be critical to inform longer-term safety. Results have been published in New England Journal of Medicine.

The manuscript is attached, and N Engl J Med link is here: https://www.nejm.org/doi/full/10.1056/NEJMoa2212856?query=featured_home 

419. Luen SJ, Viale G, Nik-Zainal S, Savas P, Kammler R, Dell’Orto P, Biasi O, Degasperi A, Brown LC, Láng I, MacGrogan G, Tondini C, Bellet M, Villa F, Bernardo A, Ciruelos E, Karlsson P, Neven P, Climent M, Müller B, Joshum W, Bonnefoi H, Martino S, Davidson NE, Geyer CE Jr, Walley BA, Ingle JN, Coleman R, Solbach C, Thürlimann B, Colleoni M, Coates AS, Goldhirsch A, Fleming GF, Francis PA, Speed TP, Regan MM, Loi S. Genomic charicterisation of hormone receptor-positive breast cancer arising in young women. Ann Oncol 2022;S0923-7534(23)00047-9. doi: 10.1016/j.annonc.2023.01.009. Epub 2023 Jan 25. (IBCSG 24-02) (Journal Impact Factor 51.769). 

Using tumour samples obtained from patients enrolled in the SOFT clinical trial, Dr. Luen et al aimed to explore genomic features that may be enriched in young premenopausal women diagnosed with hormone receptor-positive, HER2-negative (HR+/HER2-) early breast cancer. Genomic drivers enriched in young premenopausal women were determined using genomic sequencing. Genomic alterations were characterised using next-generation sequencing from a subset of 1276 patients (deep targeted sequencing, N=1258; whole-exome sequencing in a young-age, case-control subsample, N=82). Copy number was defined in subgroups and assessed for features suggestive of homologous recombination deficiency. Genomic alteration frequencies were compared between young premenopausal women (<40 years) and older premenopausal women (≥40 years), and assessed for associations with distant recurrence-free interval (DRFI), and overall survival. Results demonstrated age-related differences in genomic profiles with enrichment of genomic features associated with poor prognosis in younger premenopausal women compared with older women premenopausal and postmenopausal women. Younger women (<40) had the poorest outcomes (8-year DRFI and overall survival). Results are reported in Annals of Oncology.

The paper is attached and the Annals Oncology link is here: https://www.annalsofoncology.org/article/S0923-7534(23)00047-9/fulltext

418. Nuciforo P, Townend J, Piccart MJ, Fielding S, Gkolfi P, El-Abed S, de Azambuza E, Werutsky G, Bliss J, Moebus V, Colleoni M, Moreno Aspitia A, Gomez H, Gombos A, Coccia-Portugal MA, Tseng LM, Kunz G, Lerzo G, Sohn J, Semiglazov V, Saura C, Kroep J, Ferro A, Cameron D, Gelber R, Huober J, Di Cosimo S. Ten-year survival of neoadjuvant dual HER2 blockade in patients with HER2-positive breast cancer. Eur J Cancer 2022;181:92-101. doi: 10.1016/j.ejca.2022.12.020. Epub 2022 Dec 27. (IBCSG 37-07) (Journal Impact Factor 10.002).

The NeoALTTO trial, a multicenter phase III neoadjuvant clinical trial, sought to understand the benefit of lapatinib and trastuzumab, in combination with paclitaxel, for women with HER2+ early breast cancer. 455 women randomly received laptinib, trastuzumab, or both for 6 weeks, followed by 12 weeks of the assigned anti-HER2 treatment combined with paclitaxel weekly. The primary endpoint was pathologic complete response (pCR); secondary endpoints were event-free survival (EFS) and overall survival (OS). At 6.7 years MFU, women who received both lapatinib and trastuzumab had higher EFS and OS rates; subsequently, women with pCR had a significantly higher EFS and OS rates. Primary results for NeoALTTO showed achieving a pCR is important in HER2+ disease. At 9.7 MFU, patients with a pCR had significantly higher EFS and OS than those who did not. Final analysis results showed women with pCR had significantly better outcomes than patients without pCR. Results are reported 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(22)01831-7/fulltext

417. Geyer CE Jr, Garber J, Gelber RD, Yothers G, Taboada M, Ross L, Rastogi P, Cui KY, Arahmani A, Aktan G, Armstrong AC, Arnedos M, Balmana J, Bergh J, Bliss J, Delaloge S, Domchek SM, Eisen A, Elsafy F, Fein LE, Fielding A, Ford JM, Friedman S, Gelmon KA, Gianni L, Gnant M, Hollingsworth SJ, Im S-A, Jager A, Johannsson OP, Lakhani SR, Janni W, Linderholm B, Liu T-W, Loman N, Korde L, Loibl S, Lucas PC, Marme F, Martinez de Duenas E, McConnell R, Phillips K-A, Piccart M, Rossi G, Schmutzler R, Senkus E, Shao Z, Sharma P, Singer CF, Spanic T, Stickeler E, Toi M, Traina TA, Viale G, Zoppoli G, Park YH, Yerushalmi R, Yang H, Pang D, Jung KH, Mailliez A, Fan Z, Tennevet I, Zhang J, Nagy T, Sonke GS, Sun Q, Parton M, Colleoni MA, Schmidt M, Brufsky AM, Razaq W, Kaufman B, Cameron D, Campbell C, Tutt AN; Olympia Clinical Trial Steering Committee and Investigators. Overall survival in the OlympiA phase III trial of adjuvant Olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer. Ann Oncol 2022;33(12):1250-1268. doi: 10.1016/j.annonc.2022.09.159. Epub 2022 Oct 10. (IBCSG 50-14) (Journal Impact Factor 51.769).

The OlympiA trial is a prospective, multicenter, multinational double-blind clinical trial that assessed whether olaparib, a poly(adenosine diphosphate-ribose) polymerase inhibitor, would confer benefit as an adjuvant therapy for patients with germline BRCA1 or BRCA2 pathogenic or likely pathogenic variant-associated early breast cancer with high risk of recurrence despite standard-of-care local and systemic therapy. Patients were randomly assigned (N=1836) 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 (IDFS). In the first interim analysis (IA), results at 1-year demonstrated that 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. With a median follow-up of 3.5 years, the pre-specified second IA of OlympiA, results demonstrated a statistically significant improvement in overall survival with olaparib compared to placebo and maintenance of clinically meaningful absolute improvements in the previously reported (at 1 year) statistically significant primary endpoint of IDFS and the secondary endpoint of distant disease-free survival. No new safety signals were observed. The results were published in the Annals of Oncology.

The paper is attached and the Annals Oncology link is here: https://www.annalsofoncology.org/article/S0923-7534(22)04165-5/fulltext

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