Radiotherapy After Mastectomy for Breast Cancer Patients at Increased Risk of Local Recurrence

STUDY DESCRIPTION: This is a single-arm study to assess the feasibility, toxicity and cosmetic outcome of partial radiotherapy of the chest wall in breast cancer patients at increased risk of local relapse submitted to nipple-areola complex (NAC) sparing mastectomy and immediate implant-based reconstruction Inclusion criteria Histologically confirmed diagnosis of in situ ductal carcinoma (pTis) or invasive breast carcinoma (pT1 and pT2), submitted to NAC sparing mastectomy with prosthetic-based breast reconstruction (expander or prosthesis) and: Group A) Negative sentinel node dissection or axillary clearance (pN0) and all the following risk factors: Close (less than 1 mm) or positive (ink on tumor margin) surgical margin in a single breast quadrant Tumor diameter \>2 cm Age ≤50 years Group B) Positive sentinel dissection (pN1a) followed by axillary clearance (or primary axillary clearance) with only 1 positive node and any of the following risk factors: Close (less than 1 mm) or positive (ink on tumor margin) surgical margin in a single breast quadrant Age ≤50 years Tumor diameter \>2 cm Grade 3 histology Lymphovascular invasion HER-2 overexpression/amplification Triple negativity Treatment - Radioterapy The tumor bed is defined by the area at risk (skin and the pectoralis muscles) delineated by surgical clips and 3D-MRI reconstruction for a precise localization of the tumor excised. The clinical target volume (CTV) is defined as the tumor bed with a 1.5 cm margin limited by skin contour. A dose of 40 Gy is delivered in 16 fractions (2.5 Gy per fraction). For conventional post-mastectomy radiotherapy this moderately hypofractionated schedule is considered feasible and safe (31). Even more so, this schedule should be feasible and safe for a smaller irradiated volume as in the current protocol. Regional nodal irradiation is not considered at our Institution for patients fulfilling the entry criteria of the protocol. OUTCOME MEASURES Primary To assess feasibility of PCWRT via VMAT-IGRT linac-based or helical Tomotherapy To assess the safety of PCWRT via VMAT-IGRT linac-based or helical Tomotherapy To assess the surgical complication of implant-based breast reconstruction after PCWRT Secondary To assess the cosmetic outcome of implant-based breast reconstruction after PCWRT To assess patients' satisfaction of implant-based breast reconstruction after PCWRT

Sex

Female

Minimum age

18 Years

Maximum age

80 Years

Inclusion Criteria:

* Histologically confirmed diagnosis of in situ ductal carcinoma (pTis) or invasive breast carcinoma (pT1 and pT2), submitted to NAC sparing mastectomy with prosthetic-based breast reconstruction (expander or prosthesis) and:
* Group A)

Negative sentinel node dissection or axillary clearance (pN0) and all the following risk factors:

* Close (less than 1 mm) or positive (ink on tumor margin) surgical margin in a single breast quadrant
* Tumor diameter \>2 cm
* Age ≤50 years
* Grade 3 histology

  * Group B)

Positive sentinel dissection (pN1a) followed by axillary clearance (or primary axillary clearance) with only 1 positive node and any of the following risk factors:

* Close (less than 1 mm) or positive (ink on tumor margin) surgical margins in a single breast quadrant
* Age ≤50 years
* Tumor diameter \>2 cm
* Grade 3 histology
* Lymphovascular invasion
* HER-2 overexpression/amplification
* Triple negativity

  * Patients must be older than 18 and less than 81 years of age
  * WHO (ECOG) Performance Status of 0-2
  * Patients must consent to return for scheduled treatments and follow up
  * Written informed consent document signed

Exclusion Criteria:

* Stages IIIB, IIIC and IV (any T4, any N3 or M1)
* Pathological metastasis in ≥2 axillary lymph nodes, clinically apparent metastasis in internal mammary and/or supraclavicular lymph nodes
* Close (less than 1 mm) or positive (ink on tumor margin) surgical margin in multiple breast quadrants
* Patients submitted to neoadjuvant chemotherapy
* Recurrence of breast cancer following mastectomy and/or adjuvant chemotherapy.
* Concomitant primary cancer in the contralateral breast
* History of other malignancy except carcinoma in situ of the cervix or non-melanoma skin cancer
* Pregnant or breast-feeding
* Other severe concomitant disease that could impact upon the ability to deliver treatment or increase the risk of toxicity (such as uncompensated congestive heart failure, unstable coronary heart disease, uncompensated chronic obstructive pulmonary disease, collagen vascular diseases including systemic lupus erythematosus, systemic sclerosis, dermatomyositis, and ataxia telangiectasia)
* Contraindications to radiation therapy (such as previous irradiation of the breast or chest wall)
* Severe psychiatric disorder that may interfere with the process of informed consent and/or treatment or follow-up compliance

• BACKGROUNDRecht A, Edge SB, Solin LJ, Robinson DS, Estabrook A, Fine RE, Fleming GF, Formenti S, Hudis C, Kirshner JJ, Krause DA, Kuske RR, Langer AS, Sledge GW Jr, Whelan TJ, Pfister DG; American Society of Clinical Oncology. Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001 Mar 1;19(5):1539-69. doi: 10.1200/JCO.2001.19.5.1539. PMID 11230499
• BACKGROUNDEBCTCG (Early Breast Cancer Trialists' Collaborative Group); McGale P, Taylor C, Correa C, Cutter D, Duane F, Ewertz M, Gray R, Mannu G, Peto R, Whelan T, Wang Y, Wang Z, Darby S. 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 Jun 21;383(9935):2127-35. doi: 10.1016/S0140-6736(14)60488-8. Epub 2014 Mar 19. PMID 24656685
• BACKGROUNDNordenskjold AE, Fohlin H, Albertsson P, Arnesson LG, Chamalidou C, Einbeigi Z, Holmberg E, Nordenskjold B, Karlsson P. 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 Jun;26(6):1149-1154. doi: 10.1093/annonc/mdv159. Epub 2015 Apr 3. PMID 25839671
• BACKGROUNDKarlsson P, Cole BF, Chua BH, Price KN, Lindtner J, Collins JP, Kovacs A, Thurlimann B, Crivellari D, Castiglione-Gertsch M, Forbes JF, Gelber RD, Goldhirsch A, Gruber G; International Breast Cancer Study Group. Patterns and risk factors for locoregional failures after mastectomy for breast cancer: an International Breast Cancer Study Group report. Ann Oncol. 2012 Nov;23(11):2852-2858. doi: 10.1093/annonc/mds118. Epub 2012 Jul 9. PMID 22776708
• BACKGROUNDHuo D, Hou N, Jaskowiak N, Winchester DJ, Winchester DP, Yao K. Use of Postmastectomy Radiotherapy and Survival Rates for Breast Cancer Patients with T1-T2 and One to Three Positive Lymph Nodes. Ann Surg Oncol. 2015 Dec;22(13):4295-304. doi: 10.1245/s10434-015-4528-x. Epub 2015 Mar 28. PMID 25820998