Low-grade adenosquamous carcinoma of the breast: a clinical, morphological and immunohistochemical analysis of 25 patients.

AIMS: Due to its rarity and non-specific clinical and pathological features, low-grade adenosquamous carcinoma (LGASC) of the breast continues to pose diagnostic challenges. Unlike other triple-negative breast carcinomas, LGASC tends to have an indolent clinical behaviour. It is essential to recognise this lesion for accurate diagnosis and appropriate management. METHODS AND RESULTS: Twenty-five cases of LGASC were identified in our archives and collaborating institutes. Cases of LGASC with dominant coexisting other type carcinomas were excluded. We studied the clinical presentation, morphological features, patterns of the commonly used immunohistochemical stains and follow-up. In our cohort, LGASC was commonly located at the outer aspect of the breast and associated with intraductal papilloma. The morphology of LGASC is characterised by infiltrating small glands and nests with variable squamous differentiation. We also found cuffing desmoplastic (fibrolamellar) stromal change in 75% of patients and peripheral lymphocytic aggregates in 87.5% of patients. P63 and smooth muscle myosin (SMM) were the most common myoepithelial markers used to assist in diagnosis. P63 often stained peripheral tumour cells surrounding invasive glands (circumferential staining in 80% of the cases), mimicking myoepithelial cells. It also stained the small nests with squamous differentiation. However, SMM was negative in 63% of the cases. The vast majority of our cases were triple-negative; only a few had focal and weak expressions of ER and PR. One patient who did not have excision developed lymph node metastasis. Most patients underwent excision or mastectomy with negative margins as surgical treatment; there were no recurrences or metastases in these patients with clinical follow-ups up to 108 months. CONCLUSIONS: LGASC has some unique, although not entirely specific, morphological features and immunohistochemical staining patterns. Fibrolamellar stromal change, peripheral lymphocytic aggregates and variable staining of p63 and SMM are valuable features to facilitate the diagnosis.

Combined HER3-EGFR score in triple-negative breast cancer provides prognostic and predictive significance superior to individual biomarkers.

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3) have been investigated as triple-negative breast cancer (TNBC) biomarkers. Reduced EGFR levels can be compensated by increases in HER3; thus, assaying EGFR and HER3 together may improve prognostic value. In a multi-institutional cohort of 510 TNBC patients, we analyzed the impact of HER3, EGFR, or combined HER3-EGFR protein expression in pre-treatment samples on breast cancer-specific and distant metastasis-free survival (BCSS and DMFS, respectively). A subset of 60 TNBC samples were RNA-sequenced using massive parallel sequencing. The combined HER3-EGFR score outperformed individual HER3 and EGFR scores, with high HER3-EGFR score independently predicting worse BCSS (Hazard Ratio [HR] = 2.30, p = 0.006) and DMFS (HR = 1.78, p = 0.041, respectively). TNBCs with high HER3-EGFR scores exhibited significantly suppressed ATM signaling and differential expression of a network predicted to be controlled by low TXN activity, resulting in activation of EGFR, PARP1, and caspases and inhibition of p53 and NFκB. Nuclear PARP1 protein levels were higher in HER3-EGFR-high TNBCs based on immunohistochemistry (p = 0.036). Assessing HER3 and EGFR protein expression in combination may identify which adjuvant chemotherapy-treated TNBC patients have a higher risk of treatment resistance and may benefit from a dual HER3-EGFR inhibitor and a PARP1 inhibitor.

Prognostic Role of Androgen Receptor in Triple Negative Breast Cancer: A Multi-Institutional Study.

BACKGROUND: The androgen receptor (AR) has emerged as a potential therapeutic target for AR-positive triple-negative breast cancer (TNBC). However, conflicting reports regarding AR's prognostic role in TNBC are putting its usefulness in question. Some studies conclude that AR positivity indicates a good prognosis in TNBC, whereas others suggest the opposite, and some show that AR status has no significant bearing on the patients' prognosis. METHODS: We evaluated the prognostic value of AR in resected primary tumors from TNBC patients from six international cohorts {US (n = 420), UK (n = 239), Norway (n = 104), Ireland (n = 222), Nigeria (n = 180), and India (n = 242); total n = 1407}. All TNBC samples were stained with the same anti-AR antibody using the same immunohistochemistry protocol, and samples with ≥1% of AR-positive nuclei were deemed AR-positive TNBCs. RESULTS: AR status shows population-specific patterns of association with patients' overall survival after controlling for age, grade, population, and chemotherapy. We found AR-positive status to be a marker of good prognosis in US and Nigerian cohorts, a marker of poor prognosis in Norway, Ireland and Indian cohorts, and neutral in UK cohort. CONCLUSION: AR status, on its own, is not a reliable prognostic marker. More research to investigate molecular subtype composition among the different cohorts is warranted.

Magee Equation Recurrence Score Is Associated With Distal Metastatic Risk in Male Breast Carcinomas: Experience From Two Institutions.

OBJECTIVES: To conduct a clinicopathologic study of male breast carcinoma with Magee equation recurrence score (RS). METHODS: Seventy-four cases of male invasive breast cancers (MBCs) were studied, including 63 hormone receptor (HR)-positive, 10 human epidermal growth factor receptor 2-positive, and one triple-negative breast cancers. RESULTS: Among 63 HR-positive MBC patients, nine patients developed distal metastasis. Statistical analysis demonstrated distal metastasis was significantly associated with positive lymph node, high Nottingham grade, and increased Magee equation RS. All HR-positive MBCs were further stratified into two categories (low RS <18; intermediate/high RS ≥18). There was a significantly increased risk for distal metastasis in MBCs with intermediate/high Magee equation RS, but no increased risk for lymph node metastasis. CONCLUSIONS: Our data suggest Magee equation RS may be useful to predict distal metastatic risk in MBC patients.

Multi-institutional study of nuclear KIFC1 as a biomarker of poor prognosis in African American women with triple-negative breast cancer.

Nuclear KIFC1 (nKIFC1) predicts worse outcomes in breast cancer, but its prognostic value within racially distinct triple-negative breast cancer (TNBC) patients is unknown. Thus, nKIFC1 expression was assessed by immunohistochemistry in 163 African American (AA) and 144 White TNBC tissue microarrays (TMAs) pooled from four hospitals. nKIFC1 correlated significantly with Ki67 in White TNBCs but not in AA TNBCs, suggesting that nKIFC1 is not merely a surrogate for proliferation in AA TNBCs. High nKIFC1 weighted index (WI) was associated with significantly worse overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) (Hazard Ratios [HRs] = 3.5, 3.1, and 3.8, respectively; P = 0.01, 0.009, and 0.007, respectively) in multivariable Cox models in AA TNBCs but not White TNBCs. Furthermore, KIFC1 knockdown more severely impaired migration in AA TNBC cells than White TNBC cells. Collectively, these data suggest that nKIFC1 WI an independent biomarker of poor prognosis in AA TNBC patients, potentially due to the necessity of KIFC1 for migration in AA TNBC cells.

Biomarkers Predicting Pathologic Complete Response to Neoadjuvant Chemotherapy in Breast Cancer.

OBJECTIVES: Recent studies have shown strong correlation of pathologic complete response (pCR) to neoadjuvant chemotherapy with survival and prognosis in breast cancers. METHODS: Clinical data from 237 breast cancer patients who received neoadjuvant chemotherapy between 2012 and 2014 were reviewed. Correlations were sought between pCR and estrogen receptor (ER), progesterone receptor (PR), and HER2 status; Nottingham and nuclear grades; tumor tubule formation; mitotic score; Ki67 index; and tumoral and stromal lymphocytic infiltration (TLI and SLI, respectively). RESULTS: Of the 237 cases, 104 (43.9%) achieved pCR. The HER2+ and triple negative breast cancer (TNBC) subtypes had higher pCR rates compared with the luminal subtype (ER+ or PR+ and HER2-). ER and PR negativity, HER2 positivity, Nottingham grade 3, increased TLI and SLI, high mitotic count and Ki67 score correlated significantly with pCR in the overall cohort. TLI and SLI correlated significantly with pCR in the HER2+ and TNBC subtypes in multivariate analysis, whereas no biomarkers correlated with pCR in the luminal subtype. CONCLUSIONS: In addition to the pathologic parameters and biomarkers already routinely assessed, evaluation of TLI and SLI may help to better select patients with HER2+ and TNBC for neoadjuvant chemotherapy.

Estrogen Receptor and Cytokeratin 5 Are Reliable Markers to Separate Usual Ductal Hyperplasia From Atypical Ductal Hyperplasia and Low-Grade Ductal Carcinoma In Situ.

CONTEXT: -High-molecular weight cytokeratins, such as cytokeratin 5 (CK5), are helpful to distinguish usual ductal hyperplasia (UDH) from atypical ductal hyperplasia (ADH) or low-grade ductal carcinoma in situ (DCIS). Few studies have looked at combining CK5 with estrogen receptor (ER) to differentiate UDH from ADH. OBJECTIVE: -To evaluate the expression pattern of CK5 and ER as single or combined markers to separate UDH from ADH and low-grade DCIS. DESIGN: -A total of 23 ADH, 10 low-grade DCIS, and 32 UDH whole-tissue slides were stained for ER, CK5, progesterone receptor (PR), and Bcl-2. Nuclear staining of ER and PR was scored as diffuse (>80%), focal (10%-80%), or negative (<10%). Cytoplasmic staining of CK5 and Bcl-2 was scored as diffuse (>60%), focal (10%-60%), or negative (<10%). Differences in staining patterns were evaluated. RESULTS: -For ER staining: 94% of ADH/DCIS cases showed a diffuse staining pattern, whereas none of the 32 UDH cases showed diffuse staining. For CK5 staining: 96% of ADH/DCIS cases were negative or focally positive, whereas all 32 UDH cases had diffuse staining. The combination of ER and CK5 increased the sensitivity (94% to 97%). For PR staining: 11 of 23 ADH cases (48%), 6 of 10 DCIS cases (60%), and 4 of 32 UDH cases (13%) showed diffuse staining. Bcl-2 staining showed no statistical significance (P = .73). CONCLUSIONS: -Although morphology remains the gold standard, ER and CK5 are useful makers to differentiate UDH from ADH. Progesterone receptor staining may have limited value, and Bcl-2 staining is not useful.

GATA-3 and FOXA1 expression is useful to differentiate breast carcinoma from other carcinomas.

GATA-3, a member of the GATA family of zinc-finger DNA binding proteins, and FOXA1, a member of the forkhead transcription factor family, are both associated with estrogen receptor expression. Both GATA-3 and FOXA1 are useful markers for breast carcinoma, but their expression in the different breast cancer subtypes and other neoplasms has not been thoroughly evaluated. We examined the expression of GATA-3 and FOXA1 in estrogen receptor-positive, Her2/neu-positive, and triple-negative breast carcinomas as well as in 10 other common carcinomas, including hepatocellular, colonic, pancreatic, gastric, endometrial (endometrioid), lung, prostatic, renal cell, urothelial, and ovarian serous carcinomas. Primary and metastatic melanomas and mesotheliomas were also evaluated. GATA-3 and FOXA1 staining of estrogen receptor-positive breast carcinomas was seen in 96.6% and 96.2%, respectively. In triple-negative breast carcinomas, GATA-3 and FOXA1 staining was seen in 21.6% and 15.9%, respectively. Among the other tumors, GATA-3 staining was only seen in urothelial carcinoma (70.9%) and FOXA1 staining was only seen in prostatic (87.5%), urothelial (5.1%) carcinomas, and mesotheliomas (40.0%). In conclusion, GATA-3 and FOXA1 are excellent breast carcinoma markers; however, their utility is limited in the triple-negative subtype. The utility of FOXA1 in diagnosing prostatic carcinoma and mesothelioma warrants further investigation.