Xiaoxian Li

An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model

A nonsynonymous single-nucleotide polymorphism at codon 47 in TP53 exists in African-descent populations (P47S, rs1800371; referred to here as S47). Here we report that, in human cell lines and a mouse model, the S47 variant exhibits a modest decrease in apoptosis in response to most genotoxic stresses compared with wild-type p53 but exhibits a significant defect in cell death induced by cisplatin. We show that, compared with wild-type p53, S47 has nearly indistinguishable transcriptional function but shows impaired ability to transactivate a subset of p53 target genes, including two involved in metabolism:Gls2(glutaminase 2) and Sco2 We also show that human and mouse cells expressing the S47 variant are markedly resistant to cell death by agents that induce ferroptosis (iron-mediated nonapoptotic cell death). We show that mice expressing S47 in homozygous or heterozygous form are susceptible to spontaneous cancers of diverse histological types. Our data suggest that the S47 variant may contribute to increased cancer risk in individuals of African descent, and our findings highlight the need to assess the contribution of this variant to cancer risk in these populations. These data also confirm the potential relevance of metabolism and ferroptosis to tumor suppression by p53.

Stromal PD-L1 Expression Is Associated With Better Disease-Free Survival in Triple-Negative Breast Cancer

OBJECTIVES Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, and there is no approved targeted therapy. We studied the expression of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) in TNBC. METHODS Full-face sections from 136 TNBC cases without neoadjuvant therapy between 2004 and 2013 were stained and evaluated for immune cell PD-1 staining and stromal or tumoral PD-L1 staining using the H-score (staining percentage × intensity). Nottingham histologic grade, lymphovascular invasion (LVI), mitotic count, and tumor-infiltrating lymphocytes (TILs) were evaluated. Tumor size, lymph node status, Ki-67 score, metastasis, overall survival (OS), and disease-free survival (DFS) were retrieved from medical records. RESULTS Of the 136 TNBC cases, 69 (51%) had any PD-L1 staining and 35 (26%) had PD-L1 staining with an H-score of 5 or more; 117 (86%) had any PD-1 staining and 68 (50%) had PD-1 staining with an H-score of 5 or more. Tumor size and LVI were significantly associated with worse OS and DFS, and TILs and LVI were significantly associated with metastasis in univariate analysis. Stromal PD-L1 expression was significantly associated with better DFS in multivariate analysis. PD-1 expression was not associated with DFS, OS, or metastasis. CONCLUSIONS PD-L1 expression is seen in a high proportion of TNBCs and associated with better DFS.

Triple-negative breast cancer has worse overall survival and cause-specific survival than non-triple-negative breast cancer

PurposeThe current American Joint Committee on Cancer (AJCC) staging manual uses tumor size, lymph node, and metastatic status to stage breast cancer across different subtypes. We examined the prognosis of triple-negative breast cancer (TNBC) versus non-TNBC within the same stages and sub-stages to evaluate whether TNBC had worse prognosis than non-TNBC.MethodsWe reviewed the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) data and identified 158,358 patients diagnosed with breast cancer from 2010 to 2012. The overall survival (OS) time and breast cancer cause-specific survival time were compared between patients with TNBC and non-TNBC in each stage and sub-stages. The results were validated using a dataset of 2049 patients with longer follow-up from our institution.ResultsCompared with patients with non-TNBC, patients with TNBC had worse OS and breast cancer cause-specific survival time in every stage and sub-stage in univariate and multivariate analyses adjusting for age, race, tumor grade, and surgery and radiation treatments in the SEER data. The worse OS time in patients with TNBC was validated in our institutional dataset.ConclusionsPatients with TNBC have worse survival than patients with non-TNBC. The new AJCC staging manual should consider breast cancer biomarker information.

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.

New Developments in Breast Cancer and Their Impact on Daily Practice in Pathology

Advances in research have transformed our understanding of breast cancers and have altered the daily practice of pathology. Theranostic evaluations performed by pathologists are now critical in triaging the patients into appropriate treatment groups, as are new guidelines that were recently established for the evaluation of HER2/neu gene amplification. Emerging molecular classifications of breast cancers bring novel perspectives to the assessment of individual cases, and opportunities for better treatments. Molecular studies have particularly shed light on distinct biological subsets of triple-negative breast cancers, for which new targeted therapies are being developed. The prognostic and therapeutic utility of new histopathologic parameters, such as tumor-infiltrating lymphocytes, are also being elucidated, and new protocols have been devised for the pathologic evaluation of breast specimens that have undergone neoadjuvant treatment. Novel clinical practices, such as radioactive seed localization, also affect the way breast specimens are processed and evaluated. In this brief review, we highlight the developments that are most relevant to pathology and are changing or could potentially impact our daily practice.

Tumor-infiltrating lymphocytes are significantly associated with better overall survival and disease-free survival in triple-negative but not estrogen receptor–positive breast cancers ☆

Correlation between tumor-infiltrating lymphocytes (TILs) and complete pathological response (pCR) in breast cancers in neoadjuvant settings have been reported. In this study, we analyzed the association between TILs and diagnostic and prognostic parameters in estrogen receptor-positive (ER+) and triple-negative breast cancer (TNBC) without neoadjuvant treatments. Three hundred forty-four (344) patients who underwent mastectomy for breast cancer (187 ER+ and 157 TNBC) without neoadjuvant treatments were evaluated. Percentage of overall and peripheral TILs were correlated with lymphovascular invasion (LVI), Nottingham histologic grade (NHG, 1/2 versus 3), stage, lymph node status (LN), overall survival (OS), and disease-free survival (DFS). In TNBC, both peripheral and overall TILs were significantly associated with NHG 3 (P<.0001). Peripheral but not overall TILs were significantly associated with better OS (hazard ratio [HR]: 0.95; 95% confidence interval [CI]: 0.91-1.00; P=.0354) and DFS (HR: 0.95; 95% CI: 0.91-1.00; P=.0314) in univariate and multivariate analysis. In ER+ breast cancer, only peripheral TILs were associated with NHG 3 (P=.018) but not with OS or DFS (both P>.05). In ER+ breast cancer, there was a negative association between Oncotype DX recurrence score and both overall (P=.0007) and peripheral TILs (P=.0119). In conclusion, peripheral but not overall TILs correlate with better OS and DFS in TNBC, indicating the location of TILs may be important in TNBC. The negative association between TILs and Oncotype DX score in ER+ may indicate the possible prognostic value of TILs in ER+ breast cancer.

Hormone Receptor-Positive Breast Cancer Has a Worse Prognosis in Male Than in Female Patients

Introduction Male breast carcinoma (MBC) is treated similarly to female breast carcinoma (FBC), and similar survival rates for both have been assumed. We analyzed prognostic and clinicopathologic features of MBC to determine whether MBC subtypes differ from FBC subtypes. Patients and Methods We reviewed data for 172,847 FBC and 1442 MBC patients from 2010 to 2012 from the National Cancer Institute Surveillance, Epidemiology, and End Results database. Carcinomas were subtyped according to hormone receptor (HR) and HER2 status as HR‐positive (HR+)/HER2−, HR+/HER2+, HR−/HER2+, and HR−/HER2−. Results The overall incidence of MBC in all breast carcinoma cases was 0.8%. MBC was more frequently HR+/HER2− than was FBC (78.3% vs. 67.4%) and less frequently HR−/HER2− (2.1% vs. 10.9%). More MBC was staged as III or IV (24.9% vs. 17.2%). MBC had significantly worse overall survival (OS) than FBC (P < .0001). After adjustment for age, ethnicity, and tumor grade, stage I and II MBC had significantly worse OS time than stage‐matched FBC (P = .0011 for stage I, P = .0229 for stage II). When stage‐ and subtype‐matched patients were compared, MBC had significantly worse OS than FBC for stage I overall, for substages IA and IIB HR+/HER2− carcinoma, and for stage III HR+/HER2+ carcinoma. Furthermore, MBC patients with HR+/HER2− T1aN0 carcinomas had worse OS than did FBC patients. Conclusion Patients with MBC have worse survival than patients with FBC, especially for early‐stage HR+ breast cancers. More studies are needed optimize treatment for MBC. Micro‐Abstract Male breast carcinoma (MBC) has been thought to have similar survival as female breast carcinoma (FBC). We studies 172,847 FBC and 1442 MBC from the SEER data and found patients with MBC have worse survival than patients with FBC.

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.

High tumor budding count is associated with adverse clinicopathologic features and poor prognosis in breast carcinoma

This study is to address the significance of tumor budding (TB) in breast carcinoma. Totally 244 estrogen receptor-positive (ER+)/HER2-negative (HER2-) and 131 triple-negative breast carcinoma (TNBC) diagnosed from 2004 to 2014 were analyzed. TB (cluster of up to 5 tumor cells at the invasive front) was evaluated using five 200× high-power fields (HPF) at the hotspot. The highest TB (H-TB) in 1 HPF and average TB (A-TB) in 5 HPFs were correlated with lymph node and distant metastasis, lymphovascular invasion (LVI), local recurrence, overall survival (OS), and disease-free survival (DFS). In ER+/HER2- cancer, H-TB and A-TB were significantly associated with distant metastasis. In TNBC, H-TB was associated with distant metastasis by univariate but not multivariate analysis; H-TB and A-TB were associated with LVI and worse OS (all P < .05). TB is associated with poor prognosis in ER+/HER2- and TNBC cancer. Evaluation of H-TB may be sufficient in breast carcinoma.

Distinctions in Breast Tumor Recurrence Patterns Post-Therapy among Racially Distinct Populations

Background Clinical studies have revealed a higher risk of breast tumor recurrence in African-American (AA) patients compared to European-American (EA) patients, contributing to the alarming inequality in clinical outcomes among the ethnic groups. However, distinctions in recurrence patterns upon receiving hormone, radiation, and/or chemotherapy between the races remain poorly characterized. Methods We compared patterns and rates (per 1000 cancer patients per 1 year) of recurrence following each form of treatment between AA (n = 1850) and EA breast cancer patients (n = 7931) from a cohort of patients (n = 10504) treated between 2005–2015 at Northside Hospital in Atlanta, GA. Results Among patients who received any combination of adjuvant therapy, AA displayed higher overall rates of recurrence than EA (p = 0.015; HR: 1.699; CI: 1.108–2.606). Furthermore, recurrence rates were higher in AA than EA among stage I (p = 0.031; HR: 1.736; CI: 1.052–2.864) and T1 classified patients (p = 0.003; HR: 2.009; CI: 1.263–3.197). Interestingly, among patients who received neoadjuvant chemotherapy, AA displayed higher rates of local recurrence than EA (p = 0.024; HR: 7.134; CI: 1.295–39.313). Conclusion Our analysis revealed higher incidence rates of recurrence in AA compared to EA among patients that received any combination of adjuvant therapy. Moreover, our data demonstrates an increased risk of tumor recurrence in AA than EA among patients diagnosed with minimally invasive disease. This is the first clinical study to suggest that neoadjuvant chemotherapy improves breast cancer recurrence rates and patterns in AA.