Isolated ipsilateral local recurrence of breast cancer: predictive factors and prognostic impact
Tumour features associated with isolated invasive breast cancer (BC) ipsilateral local recurrence (ILR) after breast conservative treatment (BCT) and consequences on overall survival (OS) are still debated. Our objective was to investigate these points.
Patients were retrospectively identified from a cohort of patients who underwent BCT for invasive BC in 16 cancer centres. End-points were ILR rate and OS. The impact of ILR on OS was assessed by multivariate analysis (MVA) for all patients and according to endocrine receptors (ERs) and grade or tumour subtypes.
Of 15,570 patients, ILR rate was 3.1%. Cumulative ILR rates differed according to ERs/grade (ERs+/Grade2: HR 1.42, p = 0.010; ERs+/Grade3: HR 1.41, p = 0.067; ERs−: HR 2.14, p < 0.0001), endocrine therapy (HR 2.05, p < 0.0001) and age < 40-years old (HR 2.28, p = 0.005) in MVA. When MVA was adjusted on tumour subtype, the latter was the only independent factor. OS-after-ILR was significantly different according to ILR-free intervals (HR 4.96 for ILR-free interval between 2 and 5-years and HR 9.00 when < 2-years, in comparison with ≥ 5-years).
ERs/Grade status, lack of endocrine therapy and tumour subtypes predict isolated ILR risk in patients treated with BCT. Short ILR-free-intervals represent a strong pejorative factor for OS. These results may help selecting initial treatment as well as tailoring ILR systemic chemotherapy.
KeywordsIpsilateral Local recurrence Breast cancer Survival Prognosis
Axillary LN dissection
Breast conservative treatment
Human epidermal growth factor 2
Ipsilateral local recurrence
Ipsilateral local recurrence-free survival
Pathological node status
Regional nodal irradiation
Sentinel lymph node biopsy
Triple negative breast cancer
Study concepts: GH, AN, MC, AG and EL. Study design: GH, AN, MC, AG and EL. Data acquisition: GH, AN, MC, JMC, FR, CM, NC, AM, ED, CC, PEC, PG, MPC, PA, RR, CTL, XM, AA, AG and EL. Quality control of data and algorithms: GH, AN, MC, JMC, FR, CM, NC, AM, ED, CC, PEC, PG, MPC, PA, RR, CTL, XM, AA, AG and EL. Data analysis and interpretation: GH, AN, MC, JMC, FR, CM, NC, AM, ED, CC, PEC, PG, MPC, PA, RR, CTL, XM, AA, AG and EL. Statistical analysis: GH and EL. Manuscript preparation: GH, AN, MC, AG and EL. Manuscript editing: GH, AN, MC, AG and EL. Manuscript review: GH, AN, MC, JMC, FR, CM, NC, AM, ED, CC, PEC, PG, MPC, PA, RR, CTL, XM, AA, AG and EL.
This research did not receive any specific grant from funding agencies in the public. commercial. or not-for-profit sectors.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest to disclose.
This work was approved by our institutional review board (IPC—Comité d’Orientation Stratégique). All procedures performed in this study involving human participants were done in accordance with the French ethical standards and with the 2008 Helsinki declaration.
All included patients provided written informed consent before surgery.
- 1.Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER et al (2002) Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347(16):1233–1241Google Scholar
- 2.Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A et al (2002) Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347(16):1227–1232Google Scholar
- 3.Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V et al (2005) Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet Lond Engl 366(9503):2087–2106Google Scholar
- 4.Maaren MC van, Munck L de, Bock GH de, Jobsen JJ, Dalen T van, Linn SC et al (2016) 10 year survival after breast-conserving surgery plus radiotherapy compared with mastectomy in early breast cancer in the Netherlands: a population-based study. Lancet Oncol 17(8):1158–1170Google Scholar
- 5.Wapnir IL, Anderson SJ, Mamounas EP, Geyer CE, Jeong J-H, Tan-Chiu E et al (2006) Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in five National Surgical Adjuvant Breast and Bowel Project node-positive adjuvant breast cancer trials. J Clin 24(13):2028–2037Google Scholar
- 6.Sanghani M, Truong PT, Raad RA, Niemierko A, Lesperance M, Olivotto IA et al (2010) Validation of a Web-based predictive nomogram for ipsilateral breast tumor recurrence after breast conserving therapy. J Clin Oncol 28(5):718–722Google Scholar
- 7.Bouganim N, Tsvetkova E, Clemons M, Amir E (2013) Evolution of sites of recurrence after early breast cancer over the last 20 years: implications for patient care and future research. Breast Cancer Res Treat 139(2):603–606Google Scholar
- 8.Gosset M, Hamy A-S, Mallon P, Delomenie M, Mouttet D, Pierga J-Y et al (2016) Prognostic impact of time to ipsilateral breast tumor recurrence after breast conserving surgery. PLOS ONE 11(8):e0159888Google Scholar
- 9.Braunstein LZ, Taghian AG, Niemierko A, Salama L, Capuco A, Bellon JR et al (2017) Breast-cancer subtype, age, and lymph node status as predictors of local recurrence following breast-conserving therapy. Breast Cancer Res Treat 161(1):173–179Google Scholar
- 10.Witteveen A, Kwast ABG, Sonke GS, IJzerman MJ, Siesling S (2015) Survival after locoregional recurrence or second primary breast cancer: impact of the disease-free interval. PLOS ONE 10(4):e0120832Google Scholar
- 11.Geurts YM, Witteveen A, Bretveld R, Poortmans PM, Sonke GS, Strobbe LJA et al (2017) Patterns and predictors of first and subsequent recurrence in women with early breast cancer. Breast Cancer Res Treat 165(3):709–720Google Scholar
- 12.Penault-Llorca F, Balaton A, Sabourin J-C, Le Doussal V (2002) Groupe d’évaluation des facteurs pronostiques par immunohistochimie dans les cancers du sein (GEFPICS). [Immunochemistry evaluation of HER2 status in infiltration breast cancer: technical protocol and interpretation guidelines]. Ann Pathol 22(2):150–157Google Scholar
- 13.von Minckwitz G, Untch M, Blohmer J-U, Costa SD, Eidtmann H, Fasching PA et al (2012) Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 30(15):1796–1804Google Scholar
- 14.Moossdorff M, van Roozendaal LM, Strobbe LJA, Aebi S, Cameron DA, Dixon JM et al. Maastricht Delphi consensus on event definitions for classification of recurrence in breast cancer research. J Natl Cancer Inst. 2014;106(12)Google Scholar
- 15.Vandenbroucke JP, von Elm E, Altman DG, Gøtzsche PC, Mulrow CD, Pocock SJ et al (2007) Strengthening the Reporting of observational studies in epidemiology (STROBE): explanation and elaboration. PLoS Med 4(10):e297Google Scholar
- 16.Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874Google Scholar
- 17.Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K et al (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295(21):2492–2502Google Scholar
- 18.Gonzalez-Angulo AM, Litton JK, Broglio KR, Meric-Bernstam F, Rakkhit R, Cardoso F et al (2009) High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol 27(34):5700–5706Google Scholar
- 19.Caudle AS, Yu T-K, Tucker SL, Bedrosian I, Litton JK, Gonzalez-Angulo AM et al (2012) Local-regional control according to surrogate markers of breast cancer subtypes and response to neoadjuvant chemotherapy in breast cancer patients undergoing breast conserving therapy. Breast Cancer Res BCR 14(3):R83Google Scholar
- 20.Swisher SK, Vila J, Tucker SL, Bedrosian I, Shaitelman SF, Litton JK et al (2016) Locoregional control according to breast cancer subtype and response to neoadjuvant chemotherapy in breast cancer patients undergoing breast-conserving therapy. Ann Surg Oncol 23(3):749–756Google Scholar
- 21.de Nonneville A, Gonçalves A, Zemmour C, Classe JM, Cohen M, Lambaudie E et al (2017) Benefit of adjuvant chemotherapy with or without trastuzumab in pT1ab node-negative human epidermal growth factor receptor 2-positive breast carcinomas: results of a national multi-institutional study. Breast Cancer Res Treat. https://doi.org/10.1007/s10549-017-4136-5 Google Scholar
- 22.Mihalcik SA, Rawal B, Braunstein LZ, Capuco A, Wong JS, Punglia RS et al (2017) The impact of reexcision and residual disease on local recurrence following breast-conserving therapy. Ann Surg Oncol 24(7):1868–1873Google Scholar
- 23.Millar EKA, Graham PH, O’Toole SA, McNeil CM, Browne L, Morey AL et al (2009) Prediction of local recurrence, distant metastases, and death after breast-conserving therapy in early-stage invasive breast cancer using a five-biomarker panel. J Clin Oncol 27(28):4701–4708Google Scholar
- 24.Sanpaolo P, Barbieri V, Genovesi D (2011) Prognostic value of breast cancer subtypes on breast cancer specific survival, distant metastases and local relapse rates in conservatively managed early stage breast cancer: a retrospective clinical study. Eur J Surg Oncol 37(10):876–882Google Scholar
- 25.Nguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL et al (2008) Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol 26(14):2373–2378Google Scholar
- 26.Cheang MCU, Chia SK, Voduc D, Gao D, Leung S, Snider J et al (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101(10):736–750Google Scholar
- 27.Voduc KD, Cheang MCU, Tyldesley S, Gelmon K, Nielsen TO, Kennecke H (2010) Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol 28(10):1684–1691Google Scholar
- 28.Liu F-F, Shi W, Done SJ, Miller N, Pintilie M, Voduc D et al (2015) Identification of a Low-risk luminal A breast cancer cohort that may not benefit from breast radiotherapy. J Clin Oncol Off J Am Soc Clin Oncol 33(18):2035––40Google Scholar
- 29.Houvenaeghel G, Lambaudie E, Classe J-M et al. (2018) Lymph node positivity in different early breast carcinoma phenotypes: a predictive model. Under submissionGoogle Scholar
- 30.Turashvili G, Chou JF, Brogi E, Morrow M, Dickler M, Norton L et al (2017) 21-Gene recurrence score and locoregional recurrence in lymph node-negative, estrogen receptor-positive breast cancer. Breast Cancer Res Treat 166(1):69–76Google Scholar
- 32.Fisher B, Anderson S, Fisher ER, Redmond C, Wickerham DL, Wolmark N et al (1991) Significance of ipsilateral breast tumour recurrence after lumpectomy. Lancet Lond Engl 338(8763):327–331Google Scholar
- 33.Nottage MK, Kopciuk KA, Tzontcheva A, Andrulis IL, Bull SB, Blackstein ME (2006) Analysis of incidence and prognostic factors for ipsilateral breast tumour recurrence and its impact on disease-specific survival of women with node-negative breast cancer: a prospective cohort study. Breast Cancer Res BCR 8(4):R44Google Scholar
- 34.van der Sangen MJC, van de Poll-Franse LV, Roumen RMH, Rutten HJT, Coebergh JWW, Vreugdenhil G et al (2006) The prognosis of patients with local recurrence more than five years after breast conservation therapy for invasive breast carcinoma. Eur J Surg Oncol 32(1):34–38Google Scholar
- 35.Fodor J, Major T, Polgár C, Orosz Z, Sulyok Z, Kásler M (2008) Prognosis of patients with local recurrence after mastectomy or conservative surgery for early-stage invasive breast cancer. The Breast 17(3):302–308Google Scholar
- 36.Anderson SJ, Wapnir I, Dignam JJ, Fisher B, Mamounas EP, Jeong J-H et al (2009) Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in patients treated by breast-conserving therapy in five National Surgical Adjuvant Breast and Bowel Project protocols of node-negative breast cancer. J Clin Oncol 27(15):2466–2473Google Scholar
- 37.Gentilini O, Botteri E, Veronesi P, Sangalli C, Del Castillo A, Ballardini B et al (2012) Repeating conservative surgery after ipsilateral breast tumor reappearance: criteria for selecting the best candidates. Ann Surg Oncol 19(12):3771–3776Google Scholar
- 38.Lee JH, Lee SK, Park SM, Ryu JM, Paik HJ, Yi HW et al (2015) Independent prognostic factors for overall survival after salvage operation for ipsilateral breast tumor recurrence following breast-conserving surgery. J Breast Cancer 18(4):386–393Google Scholar
- 39.Melvin JC, Purushotham AD, Garmo H, Pinder SE, Fentiman IS, Gillett C et al (2016) Progression of breast cancer following locoregional ipsilateral recurrence: importance of interval time. Br J Cancer 114(1):88–95Google Scholar
- 40.Houvenaeghel G, Classe JM, Garbay J-R, Giard S, Cohen M, Faure C et al (2016) Survival impact and predictive factors of axillary recurrence after sentinel biopsy. Eur J Cancer Oxf Engl 1990 58:73–82Google Scholar
- 41.Aebi S, Gelber S, Anderson SJ, Láng I, Robidoux A, Martín M et al (2014) Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial. Lancet Oncol 15(2):156–163Google Scholar
- 42.Houvenaeghel G, Boher JM, Michel V, Bannier M, Minsat M, Tallet A et al (2017) Survival after breast cancer local recurrence according to therapeutic strategies. Eur J Surg Oncol 43(8):1409–1414Google Scholar
- 43.Buchholz TA, Somerfield MR, Griggs JJ, El-Eid S, Hammond MEH, Lyman GH et al (2014) Margins for breast-conserving surgery with whole-breast irradiation in stage I and II invasive breast cancer: American Society of Clinical Oncology endorsement of the Society of Surgical Oncology/American Society for Radiation Oncology consensus guideline. J Clin Oncol 32(14):1502–1506Google Scholar
- 44.Colleoni M, Sun Z, Price KN, Karlsson P, Forbes JF, Thürlimann B et al (2016) Annual hazard rates of recurrence for breast cancer during 24 years of follow-up: results from the International Breast Cancer Study Group Trials I to V. J Clin Oncol 34(9):927–935Google Scholar