medicina Article Does Surgical Margin Width Remain a Challenge for Triple-Negative Breast Cancer? A Retrospective Analysis 1,2 1,2 2 2 Eduard-Alexandru Bonci ,S, tefan T, ît, u , Alexandru Marius Petrus, an , Claudiu Hossu , Vlad Alexandru Gâta 1,2, Morvarid Talaeian Ghomi 1, Paul Milan Kubelac 1,3,* , Teodora Irina Bonci 1, 1,3 1,3 1 1,4 Andra Piciu , Maria Cosnarovici , Liviu Hît, u , Alexandra Timea Kirsch-Mangu , 1,4 1,2, 1,2 1,5 Diana Cristina Pop , Ioan Cosmin Lisencu *, Patriciu Achimas, -Cadariu , Doina Piciu , Hank Schmidt 6,7 and Bogdan Fetica 1,8 1 11th Department of Oncological Surgery and Gynecological Oncology, “Iuliu Hat, ieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; [email protected] (E.-A.B.); [email protected] (S, .T, .); [email protected] (V.A.G.); [email protected] (M.T.G.); [email protected] (T.I.B.); [email protected] (A.P.); [email protected] (M.C.); [email protected] (L.H.); [email protected] (A.T.K.-M.); [email protected] (D.C.P.); [email protected] (P.A.-C.); [email protected] (D.P.); [email protected] (B.F.) 2 Department of Surgical Oncology, “Prof. Dr. Ion Chiricut, ă” Institute of Oncology, 400015 Cluj-Napoca, Romania; [email protected] (A.M.P.); [email protected] (C.H.) 3 Department of Medical Oncology, “Prof. Dr. Ion Chiricut, ă” Institute of Oncology, 400015 Cluj-Napoca, Romania 4 Department of Radiotherapy, “Prof. Dr. Ion Chiricut, ă” Institute of Oncology, 400015 Cluj-Napoca, Romania 5 Department of Nuclear Medicine, “Prof. Dr. Ion Chiricut, ă” Institute of Oncology, 400015 Cluj-Napoca, Romania 6 Citation: Bonci, E.-A.; T, ît,u, S, .; Division of Breast Surgery, Tisch Cancer Institute, Mount Sinai Health System, New York, NY 10029, USA; Petrus, an, A.M.; Hossu, C.; Gâta, V.A.; [email protected] 7 Ghomi, M.T.; Kubelac, P.M.; Bonci, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 8 T.I.; Piciu, A.; Cosnarovici, M.; et al. Department of Anatomical Pathology, “Prof. Dr. Ion Chiricut, ă” Institute of Oncology, 400015 Cluj-Napoca, Romania Does Surgical Margin Width Remain * Correspondence: [email protected] (P.M.K.); [email protected] (I.C.L.) a Challenge for Triple-Negative Breast Cancer? A Retrospective Analysis. Medicina 2021, 57, 203. Abstract: Background and Objectives: Local and distant relapse (LR, DR) in breast cancer vary according https://doi.org/10.3390/ to its molecular subtypes, with triple-negative breast cancer (TNBC) being the most aggressive. The medicina57030203 surgical resection margin width (SRMW) for breast-conserving surgery (BCS) has been intensely debated, especially for the aforementioned subtype. The aim of this study was to examine the Academic Editor: Tithi Biswas impact of SRMW on LR following BCS in TNBC patients. Materials and Methods: We conducted a retrospective study including all patients with TNBC for whom BCS was performed between 2005 Received: 29 January 2021 and 2014. Results: Final analysis included a total of 92 patients, with a median tumor size of 2.5 cm Accepted: 23 February 2021 (range 0–5 cm) and no distant metastasis at the time of diagnosis. A total of 87 patients had received Published: 26 February 2021 neoadjuvant and/or adjuvant chemotherapy, and all patients had received adjuvant whole-breast radiotherapy. After a median follow-up of 110.7 months (95% CI, 95.23–126.166), there were 5 local Publisher’s Note: MDPI stays neutral recurrences and 8 regional/distant recurrences with an overall LR rate of 5.4%. The risk of LR and with regard to jurisdictional claims in DR was similar between groups of patients with several SRMW cut-off values. Conclusions: Our published maps and institutional affil- study supports a safe “no ink on tumor” approach for TNBC patients treated with BCS. iations. Keywords: triple-negative breast cancer; breast-conserving surgery; local recurrence; surgical margin width; no ink on tumor Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article 1. Introduction distributed under the terms and conditions of the Creative Commons Globally, breast cancer is the second leading type of diagnosed malignancy, accounting Attribution (CC BY) license (https:// for over two million cases per year [1]. Of these, approximately 10–20% belong to the creativecommons.org/licenses/by/ triple-negative breastcancer (TNBC) subtype [2–5]. TNBC is characterized by the lack of 4.0/). expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal Medicina 2021, 57, 203. https://doi.org/10.3390/medicina57030203 https://www.mdpi.com/journal/medicina Medicina 2021, 57, 203 2 of 10 growth factor 2 (HER 2) [6]. The main treatment armamentarium for nonmetastatic TNBC includes surgery, systemic therapy, and radiotherapy. The last few decades of medical research demonstrated that breast-conserving surgery (BCS) with radiotherapy attains equivalent local control and survival as radical mastec- tomy does [7–11]. The aim of BCS is to decrease the amount of unnecessary and healthy resected breast tissue, and to increase the quality of life in breastcancer patients. Numerous groups showed that the satisfaction and psychosocial well-being of breastcancer patients is higher among women treated with BCS. Furthermore, postoperative complications are fewer in these patients [12–16]. However, the continuous decrease in size of surgical mar- gin width for BCS has been a source of debate for many years [17,18], with controversy still existing [19,20] in spite of a “no ink on tumor” definition proposed and adopted as the standard surgical margin width (SSO-ASTRO Consensus Guideline on Margins for Breast-Conserving Surgery with Whole-Breast Irradiation in Stage I and II Invasive Breast Cancer) [18]. Major concerns have been raised, especially for TNBC patients due to its higher local recurrence rate (LRR) and distant metastases compared to other molecular subtypes [21–23]. Avoiding local recurrence (LR) in breastcancer patients is essential according to a meta- analysis performed by the Early Breast Cancer Trialists’ Collaborative Group. In the aforementioned study, the authors showed that one death could be avoided for every four local recurrences [7]. The “wider is better” belief comes from a series of retrospective studies showing better results for increased surgical margins [24–28]. Nevertheless, the meta-analysis conducted by Houssami et al. [29] on 21 retrospective studies led to the adoption of a “no ink on tumor” consensus for surgical margin width in BCS [18]. Although the authors showed that positive and close margins were significantly associated with a higher LRR, a truly convincing and specific minimal value could not be established to separate a negative margin from a close margin. Furthermore, the meta-analysis did not include subanalyses for each breast molecular subtype. A lack of international consensus for surgical margin width in patients treated with neoadjuvant chemotherapy (NACT) also deepens the aforementioned debate. To date, only one retrospective study specifically investigated the relationship between surgical margin width and LRR in TNBC patients in the “no ink on tumor” era [30]. Although the study included a large number of patients treated with primary BCS, the authors chose a cut-off value of 2 mm for the surgical margin width and did not provide a detailed analysis for multiple cut-off values. The main objective of our study was to determine the impact of surgical resection margin width on LR following BCS in patients diagnosed with TNBC in our tertiary-cancer center. Our second objective was to perform subgroup analysis for TNBC patients treated with NACT and BCS. Our data revealed that a “no ink on tumor” consensus [18] seems to be appropriate for TNBC patients treated in our tertiary-cancer center. 2. Materials and Methods 2.1. Study Population A retrospective observational study was conducted at ”Prof. Dr. Ion Chiricut, ă” Institute of Oncology from Cluj-Napoca, Romania (IOCN). This study was approved by the IOCN Ethics Committee (approval number 175 from 22 April 2020) and conducted abiding by the principles stated in the Declaration of Helsinki. The research included all patients with breast cancer for whom surgery was performed in our institute between 1 January 2005 and 31 December 2014. The patients were identified by searching in the electronic database of histopathological examination results, and were selected if TNBC and BCS were identified. 2.2. Definitions (TNBC, Positive Surgical Resection Margin) TNBC was defined as ductal invasive breast cancer with estrogen receptors (ER) and progesterone receptors (PR) equal to 0%, and HER2 negative (0 or 1+) by immuno- Medicina 2021, 57, 203 3 of 10 histochemistry. If HER2 was 2+, patients with no amplification on fluorescence in situ hybridization (FISH) testing were included in the study. As our objective was to determine the effect of surgical margin width on LR in the “no ink on tumor” era, the margin was considered positive if “ink on tumor” was present, and patients were excluded from final analysis. Furthermore, to improve the quality of our analysis, several cut-off values for surgical resection margin width were used (2, 3, 4, 5, and 10 mm). 2.3. Clinicopathologic and Treatment Variables The selection of patients was made using the electronic database and medical records from our cancer center. After all patients with TNBC treated with BCS had been identified, we reviewed all medical records with regard to the following aspects: histopathological report of tumor biopsy and surgical specimen, neoadjuvant/adjuvant chemotherapy and radiotherapy records, and follow-up records. After excluding multifocal/multicentric disease, male patients, patients without follow-up data after surgery, patients without whole-breast radiation therapy (WBRT), and those with local recurrence before planned WBRT, we identified 92 patients eligible for final analysis.