Genetic alterations of triple negative breast cancer by targeted next-generation sequencing and correlation with tumor morphology.

Triple negative breast cancer represents a heterogeneous group of breast carcinomas, both at the histologic and genetic level. Although recent molecular studies have comprehensively characterized the genetic landscape of these tumors, few have integrated a detailed histologic examination into the analysis. In this study, we defined the genetic alterations in 39 triple negative breast cancers using a high-depth targeted massively parallel sequencing assay and correlated the findings with a detailed morphologic analysis. We obtained representative frozen tissue of primary triple negative breast cancers from patients treated at our institution between 2002 and 2010. We characterized tumors according to their histologic subtype and morphologic features. DNA was extracted from paired frozen primary tumor and normal tissue samples and was subjected to a targeted massively parallel sequencing platform comprising 229 cancer-associated genes common across all experiments. The average number of non-synonymous mutations was 3 (range 0-10) per case. The most frequent somatic alterations were mutations in TP53 (74%) and PIK3CA (10%) and MYC amplifications (26%). Triple negative breast cancers with apocrine differentiation less frequently harbored TP53 mutations (25%) and MYC gains (0%), and displayed a high mutation frequency in PIK3CA and other PI3K signaling pathway-related genes (75%). Using a targeted massively parallel sequencing platform, we identified the key somatic genetic alterations previously reported in triple negative breast cancers. Furthermore, our findings show that triple negative breast cancers with apocrine differentiation constitute a distinct subset, characterized by a high frequency of PI3K pathway alterations similar to luminal subtypes of breast cancer.

Pathological evaluation of nipple-sparing mastectomies with emphasis on occult nipple involvement: the Weill-Cornell experience with 325 cases.

Nipple-sparing mastectomy (NSM) is an increasingly utilized surgical option in managing breast carcinoma; however, data on malignant involvement of a separately submitted nipple margin are scant. Consecutive NSM, including those performed for therapeutic and prophylactic purposes, over a 4-year period (2007-2011), were studied. A separately submitted nipple margin was evaluated by permanent H&E preparations and via frozen section evaluation whenever requested. 325 consecutive NSM specimens, 208 (64%) therapeutic-NSM, and 117 (36%) prophylactic-NSM were studied. All nipples were clinically unremarkable. 86% (179/208) of nipple margins from therapeutic-NSM and 100% (117/117) from prophylactic-NSM showed no histopathologic abnormality. 14% (29/208) of nipple margins from therapeutic-NSM and no nipple margin from prophylactic-NSM showed malignancy. Frozen section evaluation was performed in 188/325 NSM (58%) with a sensitivity of 64% and specificity of 99%. Central tumor location and stage N2/N3 lymph node status were significantly associated with nipple margin positivity (χ(2) ≤ 0.05). Subsequent nipple resection was performed in 69% (20/29) of nipple margin-positive cases with residual malignancy found in 40% (8/20, including three cases of invasive carcinoma). In a mean follow-up of 33 months, one invasive carcinoma recurred in the "saved" nipple, 36 months after therapeutic-NSM. 14% (29/208) of nipple margins in therapeutic-NSM and no nipple margin (0/117) in prophylactic-NSM showed malignancy. Central tumor location and N2/N3 stage were significantly associated with nipple margin positivity (χ(2) ≤ 0.05).

Sentinel lymph node biopsy is a reliable method for lymph node evaluation in neoadjuvant chemotherapy-treated patients with breast cancer.

Sentinel lymph node (SLN) mapping in patients with breast cancer treated with neoadjuvant chemotherapy has been debated by surgeons as a result of potential compromise of lymphatic drainage. Whether clinicopathologic variables traditionally associated with SLN positivity differ in patients who have been treated with neoadjuvant chemotherapy has not been well studied. Patients diagnosed with breast carcinoma who underwent neoadjuvant chemotherapy, definitive breast surgery, sentinel node biopsy (SNB), and axillary lymph node dissection (ALND) were retrospectively identified over a 75-month period. Clinicopathologic parameters including age, clinical tumor and node stage, neoadjuvant chemotherapy regimen, pathological tumor and node stage, lymphovascular invasion (LVI), SLN and non-SLN involvement, and extranodal extension were recorded. Ninety-seven patients met inclusion criteria. Ninety-eight per cent had successful SLN mapping. Eight patients with negative SLNs had positive ALND (false-negative rate, 8.3%). Clinicopathological variables associated with SLN status included clinical axillary status (P = 0.038), pathologic tumor size, and nodal status and LVI (P < 0.001). Extranodal extension was significantly associated with non-SLN status (P = 0.004). In patients achieving a pathologic complete response (PCR), SNB remained feasible and accurate (false-negative rate, 11.6%). Successful SLN mapping in patients who have undergone neoadjuvant chemotherapy is highly accurate with a low false-negative rate even in patients who have a PCR.