Restricted Axillary Staging in Clinically and Sonographically Node-Negative Early Invasive Breast Cancer (c/iT1–2) in the Context of Breast Conserving Therapy: First Results Following Commencement of the Intergroup-Sentinel-Mamma (INSEMA) Trial

Abstract

Axillary lymph node status remains an important prognostic factor in early breast cancer. It is regarded as an indicator for (neo)adjuvant systemic treatment and postoperative radiotherapy of the regional lymphatics. Commenced in September 2015, the INSEMA trial is investigating whether operative determination of nodal status as part of breast conserving therapy (BCT) for early stage breast cancer (c/iT1–2 c/iN0) can be avoided without reducing oncological safety. After inclusion of 1001 patients there was general acceptance of the complex study design by patients and study doctors so that recruitment for the first randomisation (axillary sentinel lymph node biopsy [SLNB]: yes or no) achieved predicted case numbers. The second randomisation however (SLNB alone versus complete axillary dissection when one or two macrometastases are present at SLNB) recruited fewer cases than expected for the following three reasons: a) the 13 % rate of one or two macrometastases after SLNB in the INSEMA trial collective was lower than expected; b) around 20 % of patients refused the second randomisation; c) there was delayed inclusion of the Austrian study centres, which only recruited for the second randomisation. Lack of knowledge of nodal status when SLNB is avoided represents a new challenge for the postoperative tumour board. In particular decisions on chemotherapy for luminal-like tumours and irradiation of the lymphatics (excluding axilla) must be guided by tumour biological parameters. The INSEMA trial does not provide answers to some important questions, e.g. it remains unclear whether patients without SLNB can be offered partial breast irradiation alone in low-risk situations and whether SLNB can also be avoided in patients with stage T1–2 tumours who have a mastectomy indication.

Key words

breast cancer - INSEMA trial - nodal status - sentinel lymph node biopsy - radiotherapy

• References/Literatur

• 1 Giuliano AE, McCall L, Beitsch P. et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: the American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg 2010; 252: 426-432
• 2 Gerber B, Heintze K, Stubert J. et al. Axillary lymph node dissection in early-stage invasive breast cancer: is it still standard today?. Breast Cancer Res Treat 2011; 128: 613-624
• 3 Reimer T, Hartmann S, Stachs A. et al. Local treatment of the axilla in early breast cancer: concepts from the national surgical adjuvant breast and bowel project B-04 to the planned intergroup sentinel mamma trial. Breast Care (Basel) 2014; 9: 87-95
• 4 Gentilini O, Botteri E, Dadda P. et al. Physical function of the upper limb after breast cancer surgery. Results from the SOUND (Sentinel node vs. Observation after axillary Ultra-souND) trial. Eur J Surg Oncol 2016; 42: 685-689
• 5 Lyman GH, Temin S, Edge SB. et al. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2014; 32: 1365-1383
• 6 Galimberti V, Manika A, Maisonneuve P. et al. Long-term follow-up of 5262 breast cancer patients with negative sentinel node and no axillary dissection confirms low rate of axillary disease. Eur J Surg Oncol 2014; 40: 1203-1208
• 7 Galimberti V, Cole BF, Zurrida S. et al. Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol 2013; 14: 297-305
• 8 Goldhirsch A, Winer EP, Coates AS. et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 2013; 24: 2206-2223
• 9 Giuliano AE, Ballman K, McCall L. 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: 413-420
• 10 Goyal A, Dodwell D. POSNOC: a randomised trial looking at axillary treatment in women with one or two sentinel nodes with macrometastases. Clin Oncol (R Coll Radiol) 2015; 27: 692-695
• 11 Senomac. 2016 Online: http://www.senomac.se last access: 20.09.2016
• 12 van Roozendaal LM, de Wilt JH, van Dalen T. et al. The value of completion axillary treatment in sentinel node positive breast cancer patients undergoing a mastectomy: a Dutch randomized controlled multicentre trial (BOOG 2013-07). BMC Cancer 2015; 15: 610
• 13 Tinterri C, Canavese G, Bruzzi P. et al. SINODAR ONE, an ongoing randomized clinical trial to assess the role of axillary surgery in breast cancer patients with one or two macrometastatic sentinel nodes. Breast 2016; 30: 197-200
• 14 Caretta-Weyer H, Greenberg CG, Wilke LG. et al. Impact of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial on clinical management of the axilla in older breast cancer patients: a SEER-medicare analysis. Ann Surg Oncol 2013; 20: 4145-4152
• 15 AGO. Diagnostic and treatment of early and metastatic breast cancer. 2016 Online: http://www.ago-online.org last access: 20.09.2016
• 16 Giuliano AE, Hunt KK, Ballman KV. 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: 569-575
• 17 Jagsi R, Chadha M, Moni J. et al. Radiation field design in the ACOSOG Z0011 (Alliance) Trial. J Clin Oncol 2014; 32: 3600-3606
• 18 Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller DG, Morrow M. eds. AMERICAN JOINT COMMITTEE ON CANCER: Cancer Staging Manual. 6th ed. New York: Springer; 2002
• 19 Fleming ID, Henson DE. AJCC Cancer Staging Manual. Philadelphia, PA: Lippincott-Raven; 1997
• 20 Nottegar A, Veronese N, Senthil M. 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: 919-925
• 21 Choi AH, Blount S, Perez MN. et al. Size of extranodal extension on sentinel lymph node dissection in the American College of Surgeons Oncology Group Z0011 trial era. JAMA Surg 2015; 150: 1141-1148
• 22 Gooch J, King TA, Eaton A. et al. The extent of extracapsular extension may influence the need for axillary lymph node dissection in patients with T1-T2 breast cancer. Ann Surg Oncol 2014; 21: 2897-2903
• 23 Mittendorf EA, Hunt KK, Boughey JC. 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: 109-115
• 24 Caudle AS, Kuerer HM, Le-Petross HT. et al. Predicting the extent of nodal disease in early-stage breast cancer. Ann Surg Oncol 2014; 21: 3440-3447
• 25 Dengel LC, King TA. The presence and extent of extracapsular extension (ECE) and the need for axillary lymph node dissection (ALND) in patients who meet ACOSOG Z11 eligibility criteria. J Clin Oncol 2013; 31 (Suppl.) Abstr. 1019
• 26 Whelan TJ, Olivotto IA, Parulekar WR. et al. Regional nodal irradiation in early-stage breast cancer. N Engl J Med 2015; 373: 307-316
• 27 Poortmans PM, Collette S, Kirkove C. et al. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med 2015; 373: 317-327
• 28 Hennequin C, Bossard N, Servagi-Vernat S. et al. Ten-year survival results of a randomized trial of irradiation of internal mammary nodes after mastectomy. Int J Radiat Oncol Biol Phys 2013; 86: 860-866
• 29 Thorsen LB, Offersen BV, Dano H. et al. DBCG-IMN: a population-based cohort study on the effect of internal mammary node irradiation in early node-positive breast cancer. J Clin Oncol 2016; 34: 314-320
• 30 Budach W, Bölke E, Kammers K. et al. Adjuvant radiation therapy of regional lymph nodes in breast cancer - a meta-analysis of randomized trials- an update. Radiat Oncol 2015; 10: 258
• 31 Nordenskjold AE, Fohlin H, Albertsson P. et al. No clear effect of postoperative radiotherapy on survival of breast cancer patients with one to three positive nodes: a population-based study. Ann Oncol 2015; 26: 1149-1154
• 32 Speers C, Pierce LJ. Postoperative radiotherapy after breast-conserving surgery for early-stage breast cancer: a review. JAMA Oncology 2016; 2: 1075-1082
• 33 van Wely BJ, Teerenstra S, Schinagl DA. et al. 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: 326-333
• 34 Belkacemi Y, Allab-Pan Q, Bigorie V. 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: 2023-2028
• 35 Veronesi U, Orecchia R, Maisonneuve P. et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol 2013; 14: 1269-1277
• 36 Vaidya JS, Wenz F, Bulsara M. et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet 2014; 383: 603-613
• 37 Strnad V, Ott OJ, Hildebrandt G. et al. 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial. Lancet 2016; 387: 229-238
• 38 Marta GN, Macedo CR, Carvalho Hde A. et al. Accelerated partial irradiation for breast cancer: systematic review and meta-analysis of 8653 women in eight randomized trials. Radiother Oncol 2015; 114: 42-49
• 39 Sorlie T, Perou CM, Tibshirani R. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001; 98: 10869-10874
• 40 Anampa J, Makower D, Sparano JA. Progress in adjuvant chemotherapy for breast cancer: an overview. BMC Med 2015; 13: 195
• 41 Freedman OC, Fletcher GG, Gandhi S. et al. Adjuvant endocrine therapy for early breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline. Curr Oncol 2015; 22: S95-S113
• 42 Gandhi S, Fletcher GG, Eisen A. et al. Adjuvant chemotherapy for early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline. Curr Oncol 2015; 22: S82-S94
• 43 Gradishar WJ, Anderson BO, Balassanian R. et al. NCCN Guidelines Insights Breast Cancer, Version 1.2016. J Natl Compr Canc Netw 2015; 13: 1475-1485
• 44 Henry NL, Somerfield MR, Abramson VG. et al. Role of patient and disease factors in adjuvant systemic therapy decision making for early-stage, operable breast cancer: American Society of Clinical Oncology Endorsement of Cancer Care Ontario Guideline Recommendations. J Clin Oncol 2016; 34: 2303-2311
• 45 Mates M, Fletcher GG, Freedman OC. et al. Systemic targeted therapy for HER2-positive early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline. Curr Oncol 2015; 22: S114-S122
• 46 Coates AS, Winer EP, Goldhirsch A. 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: 1533-1546
• 47 Gnant M, Filipts M, Greil R. et al. Predicting distant recurrences in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 risk of recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann Oncol 2014; 25: 339-345
• 48 Straver ME, Meijnen P, van Tienhoven G. et al. Role of axillary clearance after a tumor-positive sentinel node in the administration of adjuvant therapy in early breast cancer. J Clin Oncol 2010; 28: 731-737
• 49 Burstein HJ, Morrow M. Nodal irradiation after breast-cancer surgery in the era of effective adjuvant therapy. N Engl J Med 2015; 373: 379-381
• 50 Fisher B, Anderson S, Bryant J. et al. 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 2002; 347: 1233-1241
• 51 Intra M, Trifiro G, Viale G. et al. Second biopsy of axillary sentinel lymph node for reappearing breast cancer after previous sentinel lymph node biopsy. Ann Surg Oncol 2005; 12: 895-899
• 52 Rudenstam CM, Zahrieh D, Forbes JF. et al. Randomized trial comparing axillary clearance versus no axillary clearance in older patients with breast cancer: first results of International Breast Cancer Study Group Trial 10-93. J Clin Oncol 2006; 24: 337-344
• 53 Martelli G, Boracchi P, Orenti A. et al. Axillary dissection versus no axillary dissection in older T1N0 breast cancer patients: 15-year results of trial and out-trial patients. Eur J Surg Oncol 2014; 40: 805-812
• 54 Agresti R, Martelli G, Sandri M. et al. Axillary lymph node dissection versus no dissection in patients with T1N0 breast cancer: a randomized clinical trial (INT09/98). Cancer 2014; 120: 885-893
• 55 Dodwell DJ, Dyker K, Brown J. et al. A randomised study of whole-breast vs. tumour-bed irradiation after local excision and axillary dissection for early breast cancer. Clin Oncol (R Coll Radiol) 2005; 17: 618-622
• 56 Rodriguez N, Sanz X, Dengra J. et al. Five-year outcomes, cosmesis, and toxicity with 3-dimensional conformal external beam radiation therapy to deliver accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys 2013; 87: 1051-1057
• 57 Straver ME, Meijnen P, van Tienhoven G. et al. Sentinel node identification rate and nodal involvement in the EORTC 10981-22023 AMAROS trial. Ann Surg Oncol 2010; 17: 1854-1861