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In this study we evaluated local-regional recurrence (LRR) rates in 81 women with stage II-IIIA breast cancer who received neoadjuvant chemotherapy (NAC) followed by mastectomy and no postmastectomy radiation (PMRT). Pathologic complete response resulted in low LRR rates in all subtypes. Residual disease was predictive of high LRR in hormone receptor-positive HER2-positive women despite trastuzumab therapy. This information might guide decisions for PMRT after NAC.Downstaging with neoadjuvant chemotherapy (NAC) might obscure indications for postmastectomy radiation (PMRT). The degree of downstaging that results in local-regional recurrence (LRR) rates low enough to omit PMRT remains controversial. We examined the rate of LRR in women who received NAC who underwent mastectomy without PMRT.Between 2004 and 2013, 81 women with stage I to IIIA breast cancer had NAC and mastectomy; 48 patients (59%) were clinical N0 and 33 patients (41%) were clinical N1; median age was 45 years; 33 patients (41%) had hormone receptor-positive (HR+)HER2−, 21 patients (26%) HR+HER2+, 19 patients (23%) HR−HER2−, and 7 patients (9%) HR−HER2+ disease. We explored how LRR rates varied with age, BRCA status, Grade, receptor status, clinical N status, pathologic response, lymphovascular invasion, and mastectomy margins. Median follow-up was 4.9 years.After NAC, 35 patients (43%) had a pathologic complete response (pCR), 33 patients (41%) were ypN0, and 13 patients (16%) were ypN1-3+. There were 8 LRRs (6 chest wall, 1 axillary, 1 supraclavicular node). The 5-year cumulative incidence of LRR was 8% for all patients, 3% for pCR, 16% for ypN0, 10% for ypN1-3+, 6% for HR+HER2−, 25% for HR+HER2+, 0% for HR−HER2−, and 0% for HR−HER2+. LRR was 31% in the ypN0 and 33% in the ypN1-3+ HR+HER2+ women, and 12% in the ypN0 and 0% in the ypN1 to ypN3+ HR+HER2− patients.This study is unique. All HER2+ patients received trastuzumab and LRR was analyzed according to treatment response, clinicopathologic factors, and receptor status. pCR patients including young women and clinical stage IIIA had low LRR rates. However, ypN0 and ypN1-3+ HR+HER2+ patients had higher rates of LRR compared with other receptor subgroups and on the basis of limited data should be considered for PMRT.