Published online Jan 24, 2020. doi: 10.5306/wjco.v11.i1.20
Peer-review started: March 26, 2019
First decision: August 2, 2015
Revised: October 21, 2015
Accepted: November 6, 2019
Article in press: November 6, 2019
Published online: January 24, 2020
Patients with an in-breast tumor recurrence (IBTR) after breast conserving therapy have a high risk of distant metastasis and disease-related mortality. The management of patients with IBTR represents a complicated clinical challenge. Local therapy after an IBTR in the setting of prior radiation has evolved in the modern era from standard salvage mastectomy with axillary dissection. Recent literature supports salvage lumpectomy and partial breast irradiation for patients with small tumor recurrences that have favorable tumor biology. The role of chemotherapy is guided by the biomarkers of the tumor.
One controversy that complicates the decision on how to manage recurrences is whether the disease event represents a true recurrence or a new primary. Distinguishing these processes based on clinical features alone remains a challenge given the dearth of data with regard to outcomes after the first recurrence.
The purpose of our study was to identify patients treated with BCS and whole breast irradiation who experienced an IBTR. We aimed to characterize the features of the primary tumor and the recurrence and determine the factors that increase the risk for IBTR. The study also aimed to better define the relationship between the primary tumor and the ipsilateral breast recurrence with respect to location of recurrence in the breast and the biologic subtype based on histopathology markers. Lastly, the study investigated the disease outcomes in these patients and elucidated whether any primary disease characteristics or IBTR characteristics influence outcomes after the first recurrence.
Patients were identified from institutional databases of patients treated from 2003-2017 at our institution. All women in the cohort were > 18 years diagnosed with pathological stage 0-II in situ and invasive breast cancer treated with lumpectomy and adjuvant radiation. Histopathological and tumor information for the primary tumor and the ipsilateral breast recurrence were obtained through review of pathology reports. We classififed each IBTR as receptor discordant if the IBTR hormone status was estrogen receptor/progesterone receptor (ER/PR) negative, while the original primary tumor was ER/PR positive; or when the IBTR hormone status was ER/PR positive, while the original primary tumor was ER/PR negative. The tumor quadrant in the breast was determined based on mammography and/or magnetic resonance imaging prior to BCS at initial presentation and at recurrence. IBTRs that recurred in the same quadrant of the breast were considered concordant; skin recurrences and recurrences outside the original quadrant were considered discordant. Overall survival (OS), disease-free survival, and local recurrence-free survival (LRFS) were estimated using the Kaplan Meier method. We identified patients who experienced an isolated IBTR. Concordance of hormone receptor status and location of tumor from primary to recurrence were evaluated using the Chi-square test. The effect of clinical and treatment parameters on disease outcomes was evaluated using a univariate Cox proportional-hazards model. All statistical tests were two-sided with alpha = 0.05.
We identified 2164 patients who met the eligibility criteria. The median follow-up for all patients was 3.73 [Interquartile range (IQR) 2.27-6.07] years. Five-year OS was 97.7% (95%CI: 96.8%-98.6%) with 28 deaths; 5-year LRFS was 98.0% (97.2-98.8) with 31 IBTRs. We identified 37 patients with isolated IBTR, 19 (51.4%) as ductal carcinoma in situ and 18 (48.6%) as invasive disease, of whom 83.3% had an in situ component. Median time from initial diagnosis to IBTR was 1.97 (IQR: 1.03-3.5) years. Radiotherapy information was available for 30 of 37 patients. Median whole-breast dose was 40.5 Gy and 23 patients received a boost to the tumor bed. Twenty-five of thirty-two (78.1%) patients had concordant hormone receptor status, HER-2 receptor status, and ER (P = 0.006) and PR (P = 0.001) receptor status from primary to IBTR were significantly associated. There were no observed changes in HER-2 status from primary to IBTR. The concordance between quadrant of primary to IBTR was 10/19 [(62.2%), P = 0.008]. Tumor size greater than 1.5 cm [HR = 0.44, 95%CI: 0.22-0.90, P < 0.05), and endocrine therapy decreased the risk of IBTR (HR = 0.36, 95%CI: 0.18-0.73, P < 0.05) with a median interval to IBTR of 54 wk in patients with tumors < 1.5 cm (vs 119 wk in patients with tumor greater than or equal to 1.5 cm) and a median time to IBTR of 54.5 wk in patients who did not receive endocrine therapy (vs 138.1 wk in patients treated with endocrine therapy). The primary tumor grade, chemotherapy up-front, margins, ER, PR, and patient age were not associated with time interval to IBTR. Among patients with invasive primary tumors, HER-2 receptor status, lymphovascular invasion, and Ki-67 were not associated with a shorter time interval to IBTR. The presence of an in situ component at the time of invasive recurrence was not associated with time interval to IBTR.
The OS rate in our entire cohort compares favorably with the outcomes of modern trials with early stage breast cancer patients. Among patients with early stage breast cancer who had BCS treated with adjuvant RT, ER/PR status and quadrant were highly concordant from primary to IBTR. Tumor size greater than 1.5 cm and use of adjuvant endocrine therapy were significantly associated with decreased risk of IBTR. We did not find an association between disease outcomes after IBTR and quadrant concordance, biomarker concordance or the presence of in situ component, although our numbers were small.
In order to further classify IBTRs, studies have attempted to distinguish between new primaries and true recurrence with the idea that new primaries will have improved outcomes compared to true recurrences. Early vs late IBTR, biomarker and quadrant concordance may serve as useful classifiers; however, more evidence is necessary to accurately classify IBTRs in a way that is prognostic of outcomes. In an era where options for the management of IBTRs often represent a complex clinical challenge, a better understanding of what is a recurrence and what may represent a new primary will refine our treatment paradigms. These questions should be further investigated in larger multi-institutional prospective clinical studies with the statistical power to determine associations between the characteristics of primary tumor and IBTRs, treatment and disease outcomes.