392.        Piccart MJ, Hilbers FS, Bliss JM, Caballero C, Frank ES, Renault P, Naït Kaoudjt R, Schumacher E, Spears PA, Regan MM, Gelber RD, Davidson NE, Norton L, Winer EP; BIG-NABCG Collaboration. Road Map to Safe and Well-Designed De-escalation Trials of Systemic Adjuvant Therapy for Solid Tumors. J Clin Oncol. 2020 Dec 1;38(34):4120-4129. doi: 10.1200/JCO.20.01382. Epub 2020 Oct 14. (Journal Impact Factor 32.956).


391.        Leone JP, Cole BF, Regan MM, Thürlimann B, Coates AS, Rabaglio M, Giobbie-Hurder A, Gelber RD, Ejlertsen B, Harvey VJ, Neven P, Láng I, Bonnefoi H, Wardley A, Goldhirsch A, Di Leo A, Colleoni M, Vaz-Luis I, Lin NU. Clinical behavior of recurrent hormone receptor-positive breast cancer by adjuvant endocrine therapy within the Breast International Group 1-98 Clinical Trial. Cancer 2020. doi: 10.1002/cncr.33318. Epub 2020 Dec 8. (BIG 1-98) (Journal Impact Factor 5.772).

Using data from the BIG 1-98 trial, which compared five years of adjuvant endocrine therapy with either tamoxifen (T), letrozole (L), or their sequences, TL or LT, in postmenopausal women with HR+ breast cancer, Dr. Leone et al conducted an observational analysis to investigate post-distant recurrence (DR) survival of patients. After 8.1 years median follow-up, 911 (T n=302, L n=285, TL n=170, LT n=154) of 8010 patients were identified to have DR as site of first recurrence. No difference in post-DR survival by adjuvant endocrine treatment arm was found (median post-DR survival: T 20.8, L 17.9, TL 17.3, LT 20.8 months; p=0.21). Older patients with tumors > 2cm, ≥ 4 positive nodes, PR-negative tumors and shorter disease-free survival (DFS) had significantly worse post-DR survival. This study reinforced the evidence that traditional high-risk features at diagnosis are prognostic even beyond the development of DR. The results have been published in the journal Cancer.


390.        Guerini-Rocco E, Gray KP, Fumagalli C, Reforgiato MR, Leone I, Raviele PR, Munzone E, Kammler R, Neven P, Hitre E, Jerusalem G, Simoncini EL, Gombos A, Deleu I, Karlsson P, Aebi S, Chirgwin J, Di Lauro V, Thompson AM, Grass M-P, Barber M, Fontaine C, Loibl S, Gavilá, Kuroi K,  Müller B, O’Reilly S, Di Leo A, Goldhirsch A, Viale G, Barberis M, Regan MM, Colleoni M. Genomic aberrations and late recurrence in postmenopausal women with hormone receptor-positive early breast cancer: Results from the SOLE trial. Clin Cancer Res 2020. doi: 10.1158/1078-0432.CCR-20-0126. Epub 2020 Oct 20. (IBCSG 35-07) (Journal Impact Factor 10.107).

Dr. Guerini-Rocco et al sought to identify tumor genomic aberrations associated with increased late recurrence risk. In a secondary analysis of the SOLE trial, 598 primary breast cancer cases underwent targeted next-generation sequencing (NGS) analysis of gene mutations and copy number gains (CNG). The most frequent alterations were PIK3CA mutations (42%) and CNGs of CCND1 (15%), ERBB2 (10%), FGFR1 (8%), and MYC (8%). Postmenopausal women with HR+ early breast cancer harboring FGFR1 CNG had an increased risk of late recurrence despite extended AI therapy, and may represent a useful prognostic biomarker for late recurrence and a therapeutic target. Results are published in the journal Clinical Cancer Research.


389.        Rabaglio M, Sun Z, Maibach R, Giobbie-Hurder A, Ejlertsen B, Harvey VJ, Neven P, Láng I, Bonnefoi H, Wardley A, Ruepp B, Castiglione M, Coates AS, Gelber RD, Goldhirsch A, Colleoni M, Thürlimann B, Regan MM. Cumulative incidence of cardiovascular events under tamoxifen and letrozole alone and in sequence: A report from the BIG 1-98 trial. Breast Cancer Res Treat 2020. doi: 10.1007/s10549-020-05981-z. Epub 2020 Nov 7. (BIG 1-98) (Journal Impact Factor 3.831).

Dr. Rabaglio et al investigated cardiovascular disease outcomes of postmenopausal women with HR+ early breast cancer treated with adjuvant endocrine therapy. Based on patients enrolled during the 4-arm randomization (N = 6,182) to tamoxifen, letrozole, or sequential use of the agents over 5 years, from the IBCSG 18-98/ BIG 1-98 trial, cardiovascular events occurring during study treatment until 30 days after cessation were considered. Results indicated that letrozole monotherapy was associated with higher risk of grade 1-5 ischemic heart disease compared with tamoxifen monotherapy, while patients assigned sequential therapy showed a lesser degree of risk elevation. Patients assigned to tamoxifen-containing regimens had significantly higher risk of grade 1-5 thromboembolic events as compared with patients assigned letrozole alone. The study suggests that when initiating or switching between adjuvant endocrine treatments in postmenopausal patients, age and medical history, with special attention to prior cardiovascular events, should be balanced with expected benefit of the treatment. The results have been published in the journal Breast Cancer Research and Treatment.


388. Luen SJ, Asher R, Lee CK, Savas P, Kammler R, Dell’Orto P, Biasi M, Demanse D, Hackl W, Thürlimann B, Viale G, Di Leo A, Colleoni M, Regan* MM, Loi* S. Identifying oncogenic drivers associated with increased risk of late distant recurrence in post-menopausal, estrogen receptor-positive, HER2-negative early breast cancer: results from the BIG 1-98 study. *Co-last authors. Ann Oncol 2020. doi: 10.1016/j.annonc.2020.06.024 Epub 2020 July 8. (BIG 1-98) (Journal Impact Factor 18.274).

Dr. Luen et al sought to identify genomic driver alterations associated with late distant recurrence of luminal breast cancer based on a subset of 538 postmenopausal ER+/HER2- patients from the IBCSG 18-98 / BIG 1-98 randomized trial. In this subset, 88 early and 52 late (beyond 5 years) distant recurrence events occurred after a median follow-up of 8.1 years. Results showed that among ER+/HER2- postmenopausal early breast cancer, PIK3CA mutations were associated with reduced risk of late distant recurrence, whereas amplifications on 8p11 and BRCA2 mutations were associated with increased risk of late distant recurrence. This study shows the significance of characterizing oncogenic driver alterations as they may aid in refining treatment choices in the late disease setting and help identify potential drug targets for testing in future trials. The results have been published in the Annals of Oncology.

The manuscript is attached and Annals of Oncology link is here:  https://www.sciencedirect.com/science/article/pii/S0923753420399348 
387. Sun Z, Niman SM, Pagani O, Partridge AH, Azim HA, Peccatori FA, Ruggeri M, Di Leo A, Colleoni M, Gelber RD, Regan MM; POSITIVE Steering Committee and Investigators. Estimation of Historical Control Rate for a Single Arm De-escalation Study – Application to the POSITIVE Trial. Breast 2020;53:1-7. doi: 10.1016/j.breast.2020.05.012 Epub 2020 Jun 2. (IBCSG 48-14/ BIG 8-13/ Alliance A221405) (Journal Impact Factor 3.494).
The prospective, single-arm POSITIVE study in young, pregnancy-seeking women with HR+ early breast cancer is designed to assess whether temporarily interrupting adjuvant endocrine therapy to attempt pregnancy increases the risk of a breast cancer event. In preparation for placing the results of the POSITIVE study into context, Sun et al. investigated two methods to estimate a standard-of-care external control breast cancer event rate (at 3 years since enrolment in the POSITIVE trial and interruption of endocrine therapy). Method I used a SOFT/TEXT cohort, meeting POSITIVE eligibility criteria. Method II used the SOFT/TEXT cohort to group-match SOFT/TEXT patients to POSITIVE patients who actually enrolled. Results showed that the estimated 3-year breast cancer event rates were 9.5% (95% CI: 7.9%,11.1%) for Method I and 9.4% (95% CI: 7.8%,10.9%) for Method II, compared with 5.8% initially assumed when POSITIVE was designed. Results have been published in The Breast.
The manuscript is attached and the The Breast link is here: https://www.thebreastonline.com/article/S0960-9776(20)30119-3/pdf 

386.       King MT, Link ET, Whelan TJ, Olivotto LA, Kunkler I, Westenberg AH, Gruber G, Schofield P, Chua BH, on behalf of BIG 3-07/TROG 07.01 trial investigators. Quality of life after breast-conserving therapy and adjuvant radiotherapy for non-low-risk ductal carcinoma in situ (BIG 3-07/TROG 07.01): 2-year results of a randomised, controlled, phase 3 trial. Lancet Oncol 2020;21(5):685-698. doi: 10.1016/S1470-2045(20)30085-1 Epub 2020 Mar 20. (IBCSG 38-10) (Journal Impact Factor 35.386),

In this health-related quality of life (HRQOL) substudy of the randomized, controlled, phase 3 BIG 3-07/TROG 07.01 trial evaluating tumor bed boost and whole breast RT dose fractionation schedules for women with non-low risk DCIS treated with breast-conserving therapy, Prof. King et al provide patients’ perspectives to complement the primary endpoint, time to local recurrence (to be reported when participants have completed 5 years of follow-up). All patients (n=1208) were followed up at 2 years for the analysis of 8 HRQOL dimensions. Results showed that cosmetic status and arm and shoulder function were worse with tumor bed boost than with no boost across all timepoints. Results have been published in The Lancet Oncology.


385.       Ribi K, Luo W, Walley BA, Burstein HJ, Chirgwin J, Ansari RH, Salim M, van der Westhuizen A, Abdi E, Francis PA, Chia S, Harvey VJ, Giobbie-Hurder A, Fleming GF, Pagani O, Di Leo A, Colleoni M, Gelber RD, Goldhirsch A, Coates AS, Regan MM, Bernhard J. Treatment-induced symptoms, depression and age as predictors of sexual problems in premenopausal women with early breast cancer receiving adjuvant endocrine therapy. Breast Cancer Res Treat 2020;181(2):347-359. doi: 10.1007/s10549-020-05622-5 Epub 2020 Apr 9. (IBCSG 24-02 and 25-02) (Journal Impact Factor 3.471)

Dr. Ribi et al investigated predictors of sexual problems in premenopausal women with early breast cancer enrolled in IBCSG’s SOFT and TEXT randomized controlled trials. A subset of these women (N=2287) completed global and symptom-specific quality-of-life indicators, CES-Depression and MOS-Sexual Problems scales at baseline, six, 12 and 24 months. Results showed that sexual problems increased by 6 months and persisted at this level during the first two years. Depression scores were significantly associated with sexual problems in the short-term. Results have been published in Breast Cancer Research and Treatment


384.       Fackler MJ, Cho S, Cope L, Gabrielson E, Visvanathan K, Wilsbach K, Meir-Levi D, Lynch CF, Marks J, Geradts J, Regan MM, Viale G, Wolff AC, Sukumar S, Umbricht CB. DNA methylation markers predict recurrence-free interval in triple-negative breast cancer. NPJ Breast Cancer 2020;6(1):1-6. doi: 10.1038/s41523-020-0145-3 Epub 2020 Jan 31. PMCID: PMC6994477 (IBCSG VIII and IX) (Journal Impact Factor 6.230) 

Dr. Fackler et al investigated whether DNA methylation markers have the potential to be used as a prognostic tool to differentiate between breast cancers with a favorable natural history and those with a high risk of recurrence. Data were analyzed from available samples from IBCSG Trials VIII and IX and samples of node-negative triple-negative breast cancer (TNBC) tumors archived at three U.S. academic institutions. Results showed a repeated association between methylation patterns and long-term outcome. Results have been published in NPJ (Nature Partner Journals) Breast Cancer.


383.       Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo M. Survival outcomes of the NeoALTTO study (BIG 1–06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer Eur J Cancer 2019;118:169-177. doi: 10.1016/j.ejca.2019.04.038. (IBCSG 37-07) (Journal Impact Factor 6.680).


382. Pagani O, Francis PA, Fleming GF, Walley BA, Viale G, Colleoni M, Lang I, Gomez HL, Tondini C, Pinotti G, Di Leo A, Coates AS, Goldhirsch A, Gelber RD, Regan MM. Absolute improvements in freedom from distant recurrence to tailor adjuvant endocrine therapies for premenopausal women: Results from TEXT and SOFT. J Clin Oncol. doi: 10.1200/JCO.18.01967. 2019 Oct 16. [Epub ahead of print] (IBCSG 24-02, 25-02) (Journal Impact Factor 26.303).

The manuscript is attached and The Journal of Clinical Oncology link is here: https://ascopubs.org/doi/abs/10.1200/JCO.18.01967


381.  Pagani O, Francis PA, Fleming GF, Walley BA, Viale G, Colleoni M, Lang I, Gomez HL, Tondini C, Pinotti G, Di Leo A, Coates AS, Goldhirsch A, Gelber RD, Regan MM. Absolute improvements in freedom from distant recurrence to tailor adjuvant endocrine therapies for premenopausal women: Results from TEXT and SOFT. J Clin Oncol 2020 Apr 20;38(12):1293-1303. doi: 10.1200/JCO.18.01967. Epub 2019 Oct 16. (IBCSG 24-02, 25-02) (Journal Impact Factor 26.303).

Dr. Pagani et al investigated absolute improvement in freedom from distance recurrence for premenopausal women with hormone receptor-positive, HER2-negative breast cancer in the TEXT and SOFT trials according to Composite Risk. Results showed that women with low recurrence risk have minimal potential benefit in escalating endocrine therapy, while women with high recurrence risk may experience a 10-15% absolute improvement in 8-year freedom from distant recurrence with exemestane+OFS versus tamoxifen+OFS or tamoxifen alone. 

Along with the 20 April 2020 print version of the manuscript in the Journal of Clinical Oncology, we are pleased to announce the availability of a Composite Risk web application to better illustrate, for an individual set of characteristics, how similar patients in SOFT and TEXT have fared: https://rconnect.dfci.harvard.edu/CompositeRiskSTEPP/.


380. Denkert C, Budczies J, Regan MM, Loibl S, Dell'Orto P, von Minckwitz G, Mastropasqua MG, Solbach C, Thürlimann B, Mehta K, Blohmer JU, Colleoni M, Müller V, Klauschen F, Ataseven B, Engels K, Kammler R, Pfitzner BM, Dietel M, Fasching PA, Viale G. Clinical and analytical validation of Ki-67 in 9069 patients from IBCSG VIII + IX, BIG1-98 and GeparTrio trial: systematic modulation of interobserver variance in a comprehensive in silico ring trial. Breast Cancer Res Treat 2019 Aug;176(3:557-568. doi: 10.1007/s10549-018-05112-9. Epub 2019 May 7. (IBCSG VIII + IX, BIG1-98) (Impact Journal Factor 3.471).

379. Saura C, Hlauschek D, Oliveira M, Zardavas D, Jallitsch-Halper A, de la Peña L, Nuciforo P, Ballestrero A, Dubsky P, Lombard JM, Vuylsteke P, Castaneda CA, Colleoni M, Santos Borges G, Ciruelos E, Fornier M, Boer K, Bardia A, Wilson TP, Stout TJ, Hsu JY, Shi Y, Piccart M, Gnant M, Baselga J, de Azambuja E. Neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with oestrogen receptor-positive, HER2-negative, early-stage breast cancer (LORELEI): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2019 Sep 1;20(9):1226-1238. doi: 10.1016/S1470-2045(19)30334-1. Epub 2019 Aug 8. (IBCSG 46-13) (Journal Impact Factor 59.102).

378. Buechler S, Gray KP, Gökmen-Polar Y, Willis S, Thürlimann B, Kammler R, Viale G, Leyland-Jones B, Badve* SS, Regan* MM. *Co-last authors. Independent validation of EarlyR gene signature in BIG 1-98: A randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer. JNCI Cancer Spectr. doi: 10.1093/jncics/pkz051. Epub 2019 Aug 16. (BIG 1-98).

The manuscript is attached and JNCI Cancer Spectrum link is here: https://academic.oup.com/jncics/advance-article/doi/10.1093/jncics/pkz051/5550648.

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