Management of the Axilla in the Era of Breast Cancer Heterogeneity

Maïlys de Meric de Bellefon, Claire Lemanski, Angélique Ducteil, Pascal Fenoglietto, David Azria, Celine Bourgier, Maïlys de Meric de Bellefon, Claire Lemanski, Angélique Ducteil, Pascal Fenoglietto, David Azria, Celine Bourgier

Abstract

Systemic cancer therapies take into account breast cancer (BC) heterogeneity by targeting pathways specifically involved in some BC subtypes. On the other hand, BC intrinsic radiosensitivity is poorly understood and studied. Hence, radiotherapy personalization in BC is still "work in progress". In this review, we will summarize the existing data on the management of axillary lymph nodes in BC, the impact of BC radiotherapy on axillary management, the indications for axillary radiotherapy, and biomarkers to predict patients' outcome (tumor control and late toxicities) after axillary irradiation.

Keywords: axilla; breast cancer; heterogeneity; molecular subtypes; radiotherapy.

References

    1. Nowell PC. The clonal evolution of tumor cell populations. Science (1976) 194:23–8.10.1126/science.959840
    1. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature (2000) 406:747–52.10.1038/35021093
    1. Giuliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW, Blumencranz PW, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA (2011) 305:569–75.10.1001/jama.2011.90
    1. Donker M, van Tienhoven G, Straver ME, Meijnen P, van de Velde CJ, Mansel RE, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol (2014) 15:1303–10.10.1016/S1470-2045(14)70460-7
    1. Jagsi R, Chadha M, Moni J, Ballman K, Laurie F, Buchholz TA, et al. Radiation field design in the ACOSOG Z0011 (alliance) trial. J Clin Oncol (2014) 32:3600–6.10.1200/JCO.2014.56.5838
    1. TASoB S. Position Statement on Management of the Axilla in Patients With Invasive Breast Cancer. (2011). Available from:
    1. Dewar JA, Sarrazin D, Benhamou E, Petit JY, Benhamou S, Arriagada R, et al. Management of the axilla in conservatively treated breast cancer: 592 patients treated at institut Gustave-Roussy. Int J Radiat Oncol Biol Phys (1987) 13:475–81.10.1016/0360-3016(87)90060-5
    1. Louis-Sylvestre C, Clough K, Asselain B, Vilcoq JR, Salmon RJ, Campana F, et al. Axillary treatment in conservative management of operable breast cancer: dissection or radiotherapy? Results of a randomized study with 15 years of follow-up. J Clin Oncol (2004) 22:97–101.10.1200/JCO.2004.12.108
    1. Fisher B, Redmond C, Fisher ER, Bauer M, Wolmark N, Wickerham DL, et al. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med (1985) 312:674–81.10.1056/NEJM198503143121101
    1. Mahmoud O, Haffty BG. Regional nodal management in the light of the AMAROS trial. Ann Transl Med (2015) 3:88.10.3978/j.issn.2305-5839.2015.02.21
    1. Li S, Liu F, Chen K, Rao N, Xie Y, Su F, et al. The extent of axillary surgery is associated with breast cancer-specific survival in T1-2 breast cancer patients with 1 or 2 positive lymph nodes: a SEER-population study. Medicine (2016) 95:e3254.10.1097/MD.0000000000003254
    1. de Boer M, van Dijck JA, Bult P, Borm GF, Tjan-Heijnen VC. Breast cancer prognosis and occult lymph node metastases, isolated tumor cells, and micrometastases. J Natl Cancer Inst (2010) 102:410–25.10.1093/jnci/djq008
    1. Fisher B, Bauer M, Wickerham DL, Redmond CK, Fisher ER, Cruz AB, et al. Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer. An NSABP update. Cancer (1983) 52:1551–7.
    1. Reed J, Rosman M, Verbanac KM, Mannie A, Cheng Z, Tafra L. Prognostic implications of isolated tumor cells and micrometastases in sentinel nodes of patients with invasive breast cancer: 10-year analysis of patients enrolled in the prospective East Carolina university/Anne Arundel medical center sentinel node multicenter study. J Am Coll Surg (2009) 208:333–40.10.1016/j.jamcollsurg.2008.10.036
    1. Ban EJ, Lee JS, Koo JS, Park S, Kim SI, Park BW. How many sentinel lymph nodes are enough for accurate axillary staging in t1-2 breast cancer? J Breast Cancer (2011) 14:296–300.10.4048/jbc.2011.14.4.296
    1. Kim MK, Park HS, Kim JY, Kim S, Nam S, Park S, et al. The clinical implication of the number of lymph nodes harvested during sentinel lymph node biopsy and its effects on survival outcome in patients with node-negative breast cancer. Am J Surg (2017) 214:726–32.10.1016/j.amjsurg.2016.10.019
    1. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group) McGale P, Taylor C, Correa C, Cutter D, Duane F, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet (2014) 383:2127–35.10.1016/S0140-6736(14)60488-8
    1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Darby S, McGale P, Correa C, Taylor C, Arriagada R, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet (2011) 378:1707–16.10.1016/S0140-6736(11)61629-2
    1. Whelan TJ, Olivotto IA, Levine MN. Regional nodal irradiation in early-stage breast cancer. N Engl J Med (2015) 373:1878–9.10.1056/NEJMoa1415340
    1. Poortmans PM, Collette S, Kirkove C, Van Limbergen E, Budach V, Struikmans H, et al. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med (2015) 373:317–27.10.1056/NEJMoa1415369
    1. Offersen BV, Boersma LJ, Kirkove C, Hol S, Aznar MC, Biete Sola A, et al. ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer. Radiother Oncol (2015) 114:3–10.10.1016/j.radonc.2014.11.030
    1. Belkacemi Y, Allab-Pan Q, Bigorie V, Khodari W, Beaussart P, Totobenazara JL, et al. The standard tangential fields used for breast irradiation do not allow optimal coverage and dose distribution in axillary levels I-II and the sentinel node area. Ann Oncol (2013) 24:2023–8.10.1093/annonc/mdt151
    1. van Wely BJ, Teerenstra S, Schinagl DA, Aufenacker TJ, de Wilt JH, Strobbe LJ. Systematic review of the effect of external beam radiation therapy to the breast on axillary recurrence after negative sentinel lymph node biopsy. Br J Surg (2011) 98:326–33.10.1002/bjs.7360
    1. Giuliano AE, Ballman K, McCall L, Beitsch P, Whitworth PW, Blumencranz P, et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: long-term follow-up from the American college of surgeons oncology group (alliance) ACOSOG Z0011 randomized trial. Ann Surg (2016) 264:413–20.10.1097/SLA.0000000000001863
    1. Haffty BG, Hunt KK, Harris JR, Buchholz TA. Positive sentinel nodes without axillary dissection: implications for the radiation oncologist. J Clin Oncol (2011) 29:4479–81.10.1200/JCO.2011.36.1667
    1. Fowble B, Solin LJ, Schultz DJ, Goodman RL. Frequency, sites of relapse, and outcome of regional node failures following conservative surgery and radiation for early breast cancer. Int J Radiat Oncol Biol Phys (1989) 17:703–10.10.1016/0360-3016(89)90055-2
    1. Fisher B, Wolmark N, Bauer M, Redmond C, Gebhardt M. The accuracy of clinical nodal staging and of limited axillary dissection as a determinant of histologic nodal status in carcinoma of the breast. Surg Gynecol Obstet (1981) 152:765–72.
    1. Gradishar WJ, Anderson BO, Balassanian R, Blair SL, Burstein HJ, Cyr A, et al. NCCN guidelines insights: breast cancer, version 1.2017. J Natl Compr Canc Netw (2017) 15:433–51.10.6004/jnccn.2017.0044
    1. Belkacémi Y, Fourquet A, Cutuli B, Bourgier C, Hery M, Ganem G, et al. Radiotherapy for invasive breast cancer: guidelines for clinical practice from the French expert review board of Nice/Saint-Paul de Vence. Crit Rev Oncol Hematol (2011) 79:91–102.10.1016/j.critrevonc.2010.06.002
    1. Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, et al. Tailoring therapies – improving the management of early breast cancer: St Gallen International expert consensus on the primary therapy of early breast cancer 2015. Ann Oncol (2015) 26:1533–46.10.1093/annonc/mdv221
    1. Mamounas EP, Anderson SJ, Dignam JJ, Bear HD, Julian TB, Geyer CE, Jr, et al. Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of National surgical adjuvant breast and bowel project B-18 and B-27. J Clin Oncol (2012) 30:3960–6.10.1200/JCO.2011.40.8369
    1. Pilewskie M, Morrow M. Axillary nodal management following neoadjuvant chemotherapy: a review. JAMA Oncol (2017) 3:549–55.10.1001/jamaoncol.2016.4163
    1. Lemanski C, Druet X, Riou O, Ducteil A, Azria D, Bourgier C. [Which node area should be irradiated after neoadjuvant chemotherapy in breast cancer?]. Cancer Radiother (2015) 19:271–5.10.1016/j.canrad.2015.02.011
    1. Rivera S, Louvel G, Rivin Del Campo E, Boros A, Oueslati H, Deutsch E. [Prophylactic axillary radiotherapy for breast cancer]. Cancer Radiother (2015) 19:253–60.10.1016/j.canrad.2015.05.001
    1. Bartlett JM, Christiansen J, Gustavson M, Rimm DL, Piper T, van de Velde CJ, et al. Validation of the IHC4 breast cancer prognostic algorithm using multiple approaches on the multinational TEAM clinical trial. Arch Pathol Lab Med (2016) 140:66–74.10.5858/arpa.2014-0599-OA
    1. Mittendorf EA, Hunt KK, Boughey JC, Bassett R, Degnim AC, Harrell R, et al. Incorporation of sentinel lymph node metastasis size into a nomogram predicting nonsentinel lymph node involvement in breast cancer patients with a positive sentinel lymph node. Ann Surg (2012) 255:109–15.10.1097/SLA.0b013e318238f461
    1. Van Zee KJ, Manasseh DM, Bevilacqua JL, Boolbol SK, Fey JV, Tan LK, et al. A nomogram for predicting the likelihood of additional nodal metastases in breast cancer patients with a positive sentinel node biopsy. Ann Surg Oncol (2003) 10:1140–51.10.1245/ASO.2003.03.015
    1. Bi X, Wang Y, Li M, Chen P, Zhou Z, Liu Y, et al. Validation of the memorial sloan kettering cancer center nomogram for predicting non-sentinel lymph node metastasis in sentinel lymph node-positive breast-cancer patients. Onco Targets Ther (2015) 8:487–93.10.2147/OTT.S78903
    1. Rakha EA, Martin S, Lee AH, Morgan D, Pharoah PD, Hodi Z, et al. The prognostic significance of lymphovascular invasion in invasive breast carcinoma. Cancer (2012) 118:3670–80.10.1002/cncr.26711
    1. Nottegar A, Veronese N, Senthil M, Roumen RM, Stubbs B, Choi AH, et al. Extra-nodal extension of sentinel lymph node metastasis is a marker of poor prognosis in breast cancer patients: a systematic review and an exploratory meta-analysis. Eur J Surg Oncol (2016) 42:919–25.10.1016/j.ejso.2016.02.259
    1. Liu YH, Wang OC, Chen ED, Cai YF, Pan CM, Yang F, et al. Unexpected features of breast cancer subtype. World J Surg Oncol (2015) 13:249.10.1186/s12957-015-0665-8
    1. Shriver CD, Hueman MT, Ellsworth RE. Molecular signatures of lymph node status by intrinsic subtype: gene expression analysis of primary breast tumors from patients with and without metastatic lymph nodes. J Exp Clin Cancer Res (2014) 33:116.10.1186/s13046-014-0116-3
    1. Jones T, Neboori H, Wu H, Yang Q, Haffty BG, Evans S, et al. Are breast cancer subtypes prognostic for nodal involvement and associated with clinicopathologic features at presentation in early-stage breast cancer? Ann Surg Oncol (2013) 20:2866–72.10.1245/s10434-013-2994-6
    1. Feng Y, Sun B, Li X, Zhang L, Niu Y, Xiao C, et al. Differentially expressed genes between primary cancer and paired lymph node metastases predict clinical outcome of node-positive breast cancer patients. Breast Cancer Res Treat (2007) 103:319–29.10.1007/s10549-006-9385-7
    1. Paula LM, De Moraes LH, Do Canto AL, Dos Santos L, Martin AA, Rogatto SR, et al. Analysis of molecular markers as predictive factors of lymph node involvement in breast carcinoma. Oncol Lett (2017) 13:488–96.10.3892/ol.2016.5438
    1. Mamounas EP, Liu Q, Paik S, Baehner FL, Tang G, Jeong JH, et al. 21-Gene recurrence score and locoregional recurrence in node-positive/ER-positive breast cancer treated with chemo-endocrine therapy. J Natl Cancer Inst (2017) 109(4):djw259.10.1093/jnci/djw259
    1. Veronesi U, Paganelli G, Viale G, Luini A, Zurrida S, Galimberti V, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med (2003) 349:546–53.10.1056/NEJMoa012782
    1. Fleissig A, Fallowfield LJ, Langridge CI, Johnson L, Newcombe RG, Dixon JM, et al. Post-operative arm morbidity and quality of life. Results of the ALMANAC randomised trial comparing sentinel node biopsy with standard axillary treatment in the management of patients with early breast cancer. Breast Cancer Res Treat (2006) 95:279–93.10.1007/s10549-005-9025-7
    1. Land SR, Kopec JA, Julian TB, Brown AM, Anderson SJ, Krag DN, et al. Patient-reported outcomes in sentinel node-negative adjuvant breast cancer patients receiving sentinel-node biopsy or axillary dissection: National surgical adjuvant breast and bowel project phase III protocol B-32. J Clin Oncol (2010) 28:3929–36.10.1200/JCO.2010.28.2491
    1. Deutsch M, Land S, Begovic M, Sharif S. The incidence of arm edema in women with breast cancer randomized on the National surgical adjuvant breast and bowel project study B-04 to radical mastectomy versus total mastectomy and radiotherapy versus total mastectomy alone. Int J Radiat Oncol Biol Phys (2008) 70:1020–4.10.1016/j.ijrobp.2007.07.2376
    1. Lee TS, Kilbreath SL, Refshauge KM, Herbert RD, Beith JM. Prognosis of the upper limb following surgery and radiation for breast cancer. Breast Cancer Res Treat (2008) 110:19–37.10.1186/bcr1865
    1. Norman SA, Localio AR, Potashnik SL, Simoes Torpey HA, Kallan MJ, Weber AL, et al. Lymphedema in breast cancer survivors: incidence, degree, time course, treatment, and symptoms. J Clin Oncol (2009) 27:390–7.10.1200/JCO.2008.17.9291
    1. Newman B, Lose F, Kedda MA, Francois M, Ferguson K, Janda M, et al. Possible genetic predisposition to lymphedema after breast cancer. Lymphat Res Biol (2012) 10:2–13.10.1089/lrb.2011.0024

Source: PubMed

3
Suscribir