INTRODUCTION

Breast cancer is the most commonly diagnosed cancer in females in Australia with an estimated 17,730 new cases in 2017.1 Breast cancer is the second most common cause of death from cancer in women, with an estimated 3114 deaths expected in 2017. Breast cancer is a heterogenous disease, with molecular subtyping based on the expression of several hormone receptors: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).2 Clinical and pathological features vary between the subgroups, as do survival outcomes. Triple negative breast cancer (TNBC) lacks all three receptors and accounts for approximately 15% of breast cancer cases.3–5 Patients with TNBC are often younger and there is considerable overlap with BRCA-1 related breast cancer mutation.6,7 Cancers are often more aggressive, with higher rates of local recurrence and poor survival.5,8

The choice of therapy and surgical approach largely depends on tumor characteristics.9 Therapeutic options for TNBC are limited to non-targeted therapies due to a lack of an identified molecular target.10 Breast conservation surgery is an option for early breast cancer followed by adjuvant radiation therapy; recent reviews suggest that, after adjusting for age at diagnosis, stage, histology and grade, survival was equal or better after breast conservation surgery than mastectomy.9,11


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Conventional radiation treatment involves whole-breast tangential irradiation over 5 weeks, with a subsequent boost to the tumor bed12 where indicated due to tumor and patient characteristics. Hypofractionation delivers fewer fractions with a higher daily radiation dose over a shorter period (usually 3–4 weeks) with similar efficacy13,14 and, equivalent toxicity.15,16 In Australia, hypofractionated regimens of whole breast radiation therapy have been variably administered in the adjuvant setting in early-stage, node-negative breast cancer.17 The possible benefits and drawbacks of hypofractionated regimens in TNBC are unknown.

The present quality assurance activity reviewed patients with TNBC undergoing radiation therapy as a component of their treatment. The aims were two-fold: to determine whether treatment regimens (radiation technique, fractionation protocols, type of surgery) were associated with survival outcomes in TNBC patients and secondly, whether patient characteristics (age, laterality, nodal status) were prognostic variables in these patients.

MATERIALS AND METHODS

This study was reviewed by the North Coast of New South Wales Human Research Ethics Committee (reference: QA220) and was considered to be a quality improvement project not requiring full ethical review.

A retrospective review of 2200 breast cancer patients on our electronic medical record (Mosaiq, Elekta, Crawley, United Kingdom) was undertaken; patients with TNBC treated with radiotherapy between 2006 and 2016 at the Mid-North Coast Cancer Institute and Northern New South Wales Cancer Institute were identified and their records collated. TNBC was defined by a lack of expression (or minimal expression) of estrogen receptor (ER) and progesterone receptor (PR) as well as an absence of human epidermal growth factor receptor 2 (HER2) overexpression.5 The review identified 214 patients who had all completed surgery, chemotherapy and radiation therapy and were staged M0. Staging followed the American Joint Committee on Cancer (AJCC) Cancer Staging System, version 7. TNBC patients were treated with anthracycline and taxane-based chemotherapy regimens as the standard of care (available at www.eviq.org.au).

Disease-free survival (DFS) and overall survival (OS) were determined according to nodal status, radiotherapy technique, fractionation protocol and type of surgery. Disease-free survival was defined as the time from diagnosis to first relapse (months); OS was defined as the time from diagnosis to death from any cause (months). Regarding radiotherapy technique, conventional radiotherapy (ie, 3D conformal radiation and tangential radiation) was compared to intensity modulated radiotherapy (IMRT, which included forward planned and inverse planned IMRT). For fractionation, conventionally fractionated delivery) was compared with hypofractionated delivery. Conventional fractionation delivered 2.0 Gray (Gy) per dose in 25 fractions (50Gy total), hypofractionation 2.67 Gy per dose in 15 fractions (40.05 Gy total radiation dose). Partial breast boost (generally 10 Gy) was delivered in selected cases. Finally, the effects of mastectomy or breast-conserving surgery on DFS and OS were evaluated. Information on subclassification of TNBC via genetic mutational analysis was not available for this QA project.

Statistical Analysis

Only deidentified patient data was subjected to statistical analysis. The clinical characteristics of the patient groups were compared using Student’s t-test (two-tailed) for normally distributed data. Proportions were compared using Fisher’s exact test (two-tailed). Corrections for multiple comparisons employed Sidak’s method. Overall survival and DFS times were analyzed using the Kaplan-Meier method; the Log rank test was used to detect significant differences in survival distribution. The mean survival time was estimated as the area under the survival curve in the interval 0 to tmax. As survival curves did not fall below 0.5, median times could not be computed. Multivariate Cox proportional hazard regression modelling was used to assess the significance of factors entered into the model. Statistical evaluations were undertaken using MedCalc v 16.8 (MedCalc Software bvba, Ostend, Belgium); a probability p <0.05 (two-tailed) was considered statistically significant.