Original Research Article|Articles in Press

Delayed adjuvant endocrine therapy is associated with decreased recurrence-free survival following neoadjuvant chemotherapy for breast cancer

Published:February 24, 2023DOI:


      • In high-risk breast cancer, longer time from surgery to endocrine therapy was associated with worse recurrence-free survival.
      • High-risk patients may benefit from early systemic endocrine therapy, and delays may have negative oncologic consequences.
      • Delaying endocrine therapy in patients receiving radiotherapy should be carefully considered, weighing patient risk factors



      In hormone receptor-positive breast cancer (HRPBC), endocrine therapy is often initiated after adjuvant radiotherapy given concerns of radiation fibrosis. No studies have investigated how this may impact outcomes in high-risk patients undergoing neoadjuvant chemotherapy (NAC).


      Females with nonmetastatic HRPBC receiving NAC from 2011 to 2017 were identified from our multi-institutional database. Interval from surgery to endocrine therapy (ISET) was calculated in weeks. Recurrence-free survival (RFS) and overall survival (OS) were evaluated with Kaplan-Meier and Cox proportional hazards modeling.


      Of 280 patients, 179 (64%) received adjuvant radiotherapy; all deaths (n = 25) and 90% (n = 27) of recurrences occurred in this group, which was the focus of subsequent analysis.
      Median follow-up was 49 months. Recurrences were predominantly distant metastases (n = 21, 81%). Median ISET was 12 weeks (range 0–55 weeks). On multivariable analysis, ISET >14 weeks was independently associated with worse RFS (HR 3.20, 95% C.I. 1.22–8.40, P = 0.02) but not OS (HR 2.15, 95% C.I. 0.75–6.15, P = 0.15).


      In patients with HRPBC treated with NAC and adjuvant radiation, increasing ISET is associated with adverse oncologic outcomes.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The American Journal of Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Burstein H.J.
        • Lacchetti C.
        • Anderson H.
        • et al.
        Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: Asco clinical practice guideline focused update.
        J Clin Oncol. 2019 Feb 10; 37: 423-438
        • Burstein H.J.
        • Lacchetti C.
        • Anderson H.
        • et al.
        Adjuvant endocrine therapy for women with hormone receptor–positive breast cancer: Asco clinical practice guideline focused update.
        J Clin Oncol. 2019; 37: 423-438
        • Paulsen G.H.
        • Strickert T.
        • Marthinsen A.B.
        • Lundgren S.
        Changes in radiation sensitivity and steroid receptor content induced by hormonal Agents and ionizing radiation in breast cancer cells in vitro.
        Acta Oncol. 1996; 35: 1011-1019
        • Wazer D.E.
        • Tercilla O.F.
        • Lin P.S.
        • Schmidt-Ullrich R.
        Modulation in the radiosensitivity of Mcf-7 human breast carcinoma cells by 17b-estradiol and tamoxifen.
        Br J Radiol. 1989 Dec; 62: 1079-1083
        • Villalobos M.
        • Becerra D.
        • Nunez M.I.
        • et al.
        Radiosensitivity of human breast cancer cell lines of different hormonal responsiveness. Modulatory effects of oestradiol.
        Int J Radiat Biol. 1996 Aug; 70: 161-169
        • Azria D.
        • Larbouret C.
        • Cunat S.
        • et al.
        Letrozole sensitizes breast cancer cells to ionizing radiation.
        Breast Cancer Res. 2005; 7: R156-R163
        • Zeng Z.J.
        • Li J.H.
        • Zhang Y.J.
        • Zhao S.T.
        Optimal combination of radiotherapy and endocrine drugs in breast cancer treatment.
        Cancer Radiother. 2013 Jun; 17: 208-214
        • Pierce L.J.
        • Hutchins L.F.
        • Green S.R.
        • et al.
        Sequencing of tamoxifen and radiotherapy after breast-conserving surgery in early-stage breast cancer.
        J Clin Oncol. 2005 Jan 1; 23: 24-29
        • Harris E.E.
        • Christensen V.J.
        • Hwang W.T.
        • et al.
        Impact of concurrent versus sequential tamoxifen with radiation therapy in early-stage breast cancer patients undergoing breast conservation treatment.
        J Clin Oncol. 2005 Jan 1; 23: 11-16
        • Ishitobi M.
        • Komoike Y.
        • Motomura K.
        • et al.
        Retrospective analysis of concurrent vs. Sequential Administration of radiotherapy and hormone therapy using Aromatase inhibitor for hormone receptor-positive postmenopausal breast cancer.
        Anticancer Res. 2009 Nov; 29: 4791-4794
        • Ishitobi M.
        • Shiba M.
        • Nakayama T.
        • et al.
        Treatment sequence of Aromatase inhibitors and radiotherapy and long-term outcomes of breast cancer patients.
        Anticancer Res. 2014 Aug; 34: 4311-4314
        • Valakh V.
        • Trombetta M.G.
        • Werts E.D.
        • et al.
        Influence of concurrent anastrozole on Acute and late side effects of whole breast radiotherapy.
        Am J Clin Oncol. 2011 Jun; 34: 245-248
        • Ahn P.H.
        • Vu H.T.
        • Lannin D.
        • et al.
        Sequence of radiotherapy with tamoxifen in conservatively Managed breast cancer does not affect local relapse rates.
        J Clin Oncol. 2005 Jan 1; 23: 17-23
        • Bentzen S.M.
        • Skoczylas J.Z.
        • Overgaard M.
        • Overgaard J.
        Radiotherapy-related lung fibrosis enhanced by tamoxifen.
        J Natl Cancer Inst. 1996 Jul 3; 88: 918-922
        • Koc M.
        • Polat P.
        • Suma S.
        Effects of tamoxifen on pulmonary fibrosis after cobalt-60 radiotherapy in breast cancer patients.
        Radiother Oncol. 2002 Aug; 64: 171-175
        • Varga Z.
        • Cserhati A.
        • Kelemen G.
        • et al.
        Role of systemic therapy in the development of lung sequelae after conformal radiotherapy in breast cancer patients.
        Int J Radiat Oncol Biol Phys. 2011 Jul 15; 80: 1109-1116
        • Bese N.S.
        • Umay C.
        • Yildirim S.
        • et al.
        The effects of tamoxifen on radiation-induced pulmonary fibrosis in Wistar Albino rats: results of an experimental study.
        Breast. 2006 Jun; 15: 456-460
        • Yavas G.
        • Yavas C.
        • Acar H.
        • et al.
        Comparison of the effects of Aromatase inhibitors and tamoxifen on radiation-induced lung toxicity: results of an experimental study.
        Support Care Cancer. 2013 Mar; 21: 811-817
        • Munshi A.
        • Gupta D.
        Concurrent versus sequential radiotherapy and tamoxifen in breast cancer - the conset trial is launched.
        Acta Oncol. 2011 Jan; 50: 154-155
        • Symmans W.F.
        • Peintinger F.
        • Hatzis C.
        • et al.
        Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy.
        J Clin Oncol. 2007 Oct 1; 25: 4414-4422
        • Cox J.D.
        • Stetz J.
        • Pajak T.F.
        Toxicity criteria of the radiation therapy oncology group (Rtog) and the European organization for research and treatment of cancer (Eortc).
        Int J Radiat Oncol Biol Phys. 1995 Mar 30; 31: 1341-1346