Impact of NCI Socioeconomic Index on the Outcomes of Nonmetastatic Breast Cancer Patients: Analysis of SEER Census Tract–Level Socioeconomic Database

PurposeTo assess the impact of National Cancer Institute socioeconomic status (SES) index on breast cancer–specific survival (BCSS) of nonmetastatic breast cancer patients registered within the Surveillance, Epidemiology and End Results (SEER) census tract–level SES database.Patients and MethodsThe census tract–level SES index is a composite score integrating 7 parameters that assess different dimensions of SES. Women with a nonmetastatic breast cancer diagnosis (stage I-III) diagnosed during 2010-2015 and included in the SEER-SES specialized database were included in the current analysis. Multivariate Cox regression analysis was used to assess the impact of SES index on BCSS.ResultsA total of 296,100 women with nonmetastatic breast cancer were included in the current study. The impact of SES index on BCSS was evaluated in the overall cohort of patients through multivariate Cox regression analysis (adjusted for age at diagnosis, race, stage, and breast cancer subtype). Lower SES was associated with worse BCSS (hazard ratio for group 1 [lowest SES group] vs. group 3 [highest SES group]: 1.428; 95% confidence interval, 1.359-1.499; P < .001). Using additional interaction testing within Cox regression models, the impact of SES on BCSS seems to be modified by breast cancer subtype (P for interaction < .001), race (P for interaction = .001), and stage (P for interaction = .015).ConclusionLower SES index is associated with worse BCSS. Further efforts need to be directed to improving breast cancer outcomes among women with socioeconomically vulnerable attributes (poverty, lower education, and unemployment).     

Microcephalin is a new novel prognostic indicator in breast cancer associated with BRCA1 inactivation

The authors have investigated the expression of the microcephalin (MCPH1) protein to evaluate its prognostic importance in breast cancer. Microcephalin is a damage response protein involved in the regulation of BRCA1 and BRCA2. BRCA1 mutations are often associated with basal-like breast cancer, which are also often negative for oestrogen receptor (ER), progesterone receptor (PR) and HER2. MCPH1 immunohistochemistry was performed on 319 breast cancers prepared as tissue microarray and correlated with pathology, survival, ER, PR, HER2, EGFR, CK5/6, CK14 and BRCA1 expression. After performing continuous data analysis, mean microcephalin expression decreased with increasing grade (P < 0.006). Mean microcephalin expression was lower in ER/PR negative (P < 0.001) and triple negative cancers (P < 0.004). Conversely, an association with HER2-positive cancers was also identified (P < 0.034). Reduced microcephalin also correlated with reduced nuclear BRCA1 staining (P < 0.001). No association was identified with basal markers. After dichotomising the data into low and high microcephalin expression, reduced expression was identified in 29% (93/319) of breast cancers. An association with low expression was identified in invasive ductal carcinomas with breast cancer-specific survival (BCSS) (P = 0.052). Multivariate analysis of ductal carcinomas showed that microcephalin, together with lymph node involvement and tumour size were independent predictors of BCSS (P = 0.037). Microcephalin expression is reduced in 29% of breast cancers, particularly in higher grade tumours and BRCA1-negative cases. Microcephalin is an independent predictor of BCSS in invasive ductal breast cancer patients and may prove to be a useful biomarker for the identification of aggressive breast cancers.     

T1-2N0M0 Triple-Negative Breast Cancer Treated With Breast-Conserving Therapy Has Better Survival Compared to Mastectomy: A SEER Population-Based Retrospective Analysis

BackgroundFor early-stage breast cancer, the two current mainstay treatments are breast-conserving therapy (BCT; lumpectomy followed by radiotherapy [RT] and BCT) and mastectomy. Generally, triple-negative breast cancer (TNBC) is more aggressive compared to hormone receptor–positive breast cancer. We sought to investigate the effect of BCT compared to mastectomy on overall survival (OS) and breast cancer–specific survival (BCSS) in T1-2N0M0 TNBC.Patients and MethodsA population-based retrospective analysis was performed using the Surveillance, Epidemiology, and End Results (SEER) database. Patients included in the analysis were divided into 3 groups according to surgical modality and RT: BCT, mastectomy alone, and mastectomy with RT. The survival end points were OS and BCSS, and survival analysis was performed by the Kaplan-Meier method and the log-rank test among treatment types.ResultsA total of 14,910 female subjects with T1-2N0M0 TNBC diagnosed between 2010 and 2014 were included. A total of 7381 patients had BCT; 6967 had mastectomy alone, and 562 had mastectomy with RT. Patients treated with BCT had better OS (log-rank P < .05) and BCSS (log-rank P < .05) than those receiving mastectomy with or without RT. The 5-year OS was 88.6% for BCT, 83.0% for mastectomy alone, and 79.6% for mastectomy with RT. The 5-year BCSS was 94.3% for BCT, 93.3% for mastectomy alone, and 83.7% for mastectomy with RT.ConclusionIn patients with T1-2N0M0 TNBC, BCT was associated with superior OS and BCSS compared to mastectomy with or without RT. After mastectomy, there was no evidence of survival benefit of RT.     

Second invasive breast cancers in patients treated with breast-conserving therapy

ObjectiveSecond breast cancers after breast-conserving therapy (BCT) include ipsilateral breast tumor recurrence (IBTR) and metachronous contralateral breast cancer (CBC). Each IBTR is further classified as true recurrence (TR) or new primary tumor (NP). We aim to compare survival outcomes of TR, NP and CBC, and explore the optimal treatments.Methods168,427 patients with primary breast cancer who underwent BCT between 1990 and 2005 were identified in the SEER database. The risks of IBTR and CBC were estimated by annual hazard rate. The breast cancer-specific survival (BCSS) were assessed using multivariable Cox regression analysis.ResultsWith median follow-up of 13 years after BCT, 5413 patients developed an IBTR and 4050 patients had a CBC. The risk of IBTR peaked between 10 and 15 years after BCT, while the risk of CBC distributed evenly. 45.9% of IBTRs were classified as a TR and 54.1% as an NP. The time interval from primary breast cancer to NP was longer than to TR and CBC (P < 0.001). Patients with TR had a poorer BCSS than NP (P = 0.003) and CBC (P = 0.002). There was no difference in BCSS between mastectomy and repeat BCT for treating TR (P = 0.584) or NP (P = 0.243). The BCSS of CBCs treated with BCT was better than mastectomy (P = 0.010). Chemotherapy didn't improve the survival of patients with TR (P = 0.058). However, TRs with grade III or negative hormone receptors benefited from chemotherapy significantly.ConclusionPatients with TR had a poorer BCSS than NP and CBC. Classifying IBTR may provide clinical significance for treatments.     

Geriatric Early-Stage Triple-Negative Breast Cancer Patients in Low-risk Population: Omitting Chemotherapy Based on Nomogram

BackgroundConsidering old age and comorbidities, the actual benefit of chemotherapy in older patients with early triple-negative breast cancer (TNBC) remains uncertain. We aimed to select appropriate patients who could avoid chemotherapy in this population.MethodsA total of 6482 patients more than 65 years old with T1-2N0-1M0 TNBC in 2010-2015 were extracted from SEER program. Multivariate logistic regression was performed to identify independent factors associated with chemotherapy usage. Survival analysis was performed using Kaplan-Meier plots and log-rank tests. Independent prognostic factors were identified by multivariate Cox analysis. A nomogram predicting breast cancer-specific survival (BCSS) and a risk stratification model were constructed.ResultsA total of 3379 (52.13%) patients received chemotherapy while 3103 (47.87%) did not. Age, married status, grade, T-stage, N-stage, radiation and breast-conserving surgery (BCS) were significantly associated with chemotherapy usage (all P < .05). Chemotherapy significantly improved OS (HR = 0.606, P < .001) and BCSS (HR = 0.763, P = .006) in the entire population. A nomogram was built by incorporating independent risk factors (age, T-stage, N-stage, grade and radiation). Based on the score of the nomogram, the risk stratification model demonstrated that chemotherapy improved OS (P < .001) and BCSS (P < .001) of patients in the high-risk group (score >180), but not in the low-risk group (score ≤75).ConclusionChemotherapy is beneficial for geriatric patients with T1-2N0-1M0 TNBC in this study, and the risk stratification model indicates the feasibility of sparing chemotherapy in low-risk subgroup without sacrificing survival, providing clinicians tools to weigh the risk–benefit of chemotherapy and customize the individualized treatment accordingly.     

Multifocality and multicentricity in breast cancer and survival outcomes

BackgroundThe clinicopathological characteristics and the prognostic significance of multifocal (MF) and multicentric (MC) breast cancers are not well established.Patients and MethodsMF and MC were defined as more than one lesion in the same quadrant or in separate quadrants, respectively. The Kaplan–Meier product limit was used to calculate recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS). Cox proportional hazards models were fit to determine independent associations of MF/MC disease with survival outcomes.ResultsOf 3924 patients, 942 (24%) had MF (n = 695) or MC (n = 247) disease. MF/MC disease was associated with higher T stages (T2: 26% versus 21.6%; T3: 7.4% versus 2.3%, P < 0.001), grade 3 disease (44% versus 38.2%, P < 0.001), lymphovascular invasion (26.2% versus 19.3%, P < 0.001), and lymph node metastases (43.1% versus 27.3%, P < 0.001). MC, but not MF, breast cancers were associated with a worse 5-year RFS (90% versus 95%, P = 0.02) and BCSS (95% versus 97%, P = 0.01). Multivariate analysis shows that MF or MC did not have an independent impact on RFS, BCSS, or OS.ConclusionsMF/MC breast cancers were associated with poor prognostic factors, but were not independent predictors of worse survival outcomes. Our findings support the current TNM staging system of using the diameter of the largest lesion to assign T stage.     

Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers

DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end-joining pathway required for the repair of DNA double-strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. We evaluated clinicopathological significance of DNA-PKcs protein expression in 1,161 tumours and DNA-PKcs mRNA expression in 1,950 tumours. We correlated DNA-PKcs to markers of aggressive phenotypes, DNA repair, apoptosis, cell cycle regulation and survival. Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps < 0.05). The absence of BRCA1, low XRCC1, low SMUG1, low APE1 and low Polβ was also more likely in low DNA-PKcs expressing tumours (ps < 0.05). Low DNA-PKcs protein expression was significantly associated with worse breast cancer-specific survival (BCSS) in univariate and multivariate analysis (ps < 0.01). At the mRNA level, similarly, low DNA-PKcs was associated with poor BCSS. In patients with ER-positive tumours who received endocrine therapy, low DNA-PKcs (protein and mRNA) was associated with poor survival. In ER-negative patients, low DNA-PKcs mRNA remains significantly associated with adverse outcome. Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers.     

Reproductive Factors and Subtypes of Breast Cancer Defined by Estrogen Receptor,Progesterone Receptor,and Human Epidermal Growth Factor Receptor 2: A Register-Based Study From Korea

BackgroundThe relationship between reproductive breast risk factors and breast cancer survival in patients with different breast cancer subtypes is not well known.MethodsWe examined a large-sized, retrospective study of 23,882 subjects from the Korean Breast Cancer Registry. The breast cancer subtype was determined by immunohistochemical staining for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). Information regarding reproductive factors, including breastfeeding, age at first birth (AFB), and parity, was gathered. Multivariate Cox regression analysis was used to estimate the association among breast cancer subtypes, such as luminal A, luminal B, Her-2/neu overexpressing, and triple negative breast cancer (TNBC), and breast cancer survival as dependent variables and adjusting for age and stage.ResultsHigh parity (≥ 5) increased the recurrence risk of luminal A and B breast cancer (hazard ratio [HR], 1.95; 95% confidence interval [CI], 0.96-3.97; P = .0055 and HR, 1.12; 95% CI, 0.42-3.02, respectively; P = .0073) in breast cancer–specific survival (BCSS), but 1 to 3 child births decreased the recurrence risk of luminal A breast cancer (HR, 0.56; 95% CI, 0.34-0.91; P = .0055) and luminal B breast cancer (HR, 0.32; 95% CI, 0.17-0.61; P = .0073) in BCSS. Early AFB (< 20 years) increased the recurrence risk of luminal A breast cancers (HR, 1.61; 95% CI, 0.62-4.26; P = .039) in BCSS and of TNBC (HR, 1.31; 95% CI, 0.78-2.21; P = .0006) in overall survival. Her-2/neu overexpressing breast cancer had no correlation with parity and AFB in breast cancer survival.ConclusionsHigh parity (≥ 5) and early AFB (< 20 years) were correlated with worse clinical outcomes in patients with luminal breast cancer, but not with other subtyped breast cancers.     

Clinicopathologic Factors Associated With Response to Neoadjuvant Anti-HER2–Directed Chemotherapy in HER2-Positive Breast Cancer

BackgroundHER2-targeted neoadjuvant therapy has high efficacy in treating HER2-positive breast cancer. Response to neoadjuvant therapy helps clinicians make treatment decisions and make estimates about prognosis. This study examined clinicopathologic features to determine which may be most predictive of response to neoadjuvant therapy in HER2⁺ breast cancer.Patients and MethodsPatients with HER2⁺ breast cancer (n = 173) who had an initial biopsy performed between 2010 and 2016 were identified at our institution. Tumor response was evaluated on excisional specimens using the MD Anderson residual cancer burden (RCB) classification. Tumors with pathologic complete response (defined as no residual invasive carcinoma in the breast and lymph nodes) and RCB-I were classified as having response and tumors with RCB-II and -III as having no response. Patient age, tumor size, nuclear grade (1/2 vs. 3), mitosis, Nottingham grade, HER2 immunohistochemistry (1/2+ vs. 3+), HER2/CEP17 (chromosome enumeration probe 17) ratio, HER2 copy number, estrogen receptor, progesterone receptor, Ki-67, and tumor-infiltrating lymphocytes (TIL) were evaluated and correlated with response. TILs were evaluated for an average and also for the hot spot/total tumor stromal ratio.ResultsSmall tumor size, low estrogen receptor and progesterone receptor expression, HER2 immunohistochemistry 3+, high Ki-67, high HER2/CEP17 ratio, and high HER2 copy number were significantly associated with response (all P < .05). TIL hot spot was associated with RCB in univariate (P < .05) but not multivariate analyses.ConclusionClinicopathologic features may help predict HER2⁺ breast cancer response to neoadjuvant therapy. Larger studies would be useful to confirm these associations, which may have relevance to clinical practice.     

Impact of Oncotype DX Recurrence Score in the Management of Breast Cancer Cases

BackgroundOncologists have used clinicopathologic features to guide treatment decisions for their breast cancer patients; however, more recently, results of multigene assays are also being considered. A popular assay, Oncotype DX (Genomic Health), stratifies node-negative breast cancer patients into groups that are at low, intermediate, or high risk for distant recurrence and guides decisions about adjuvant chemotherapy utilization.ObjectiveWe studied the impact of Oncotype DX recurrence score (ODxRS) compared with that of clinicopathologic features on adjuvant chemotherapy utilization in node-negative breast cancer patients and in node-positive breast cancer patients, and we evaluated whether clinicopathologic features impact the decision for adjuvant chemotherapy utilization in a subset of node-negative breast cancer patients with an intermediate-risk ODxRS.MethodsA retrospective study from a single academic institution was performed on 425 patients with invasive breast carcinoma.ResultsAdjuvant chemotherapy utilization most significantly correlated with a high-risk ODxRS (P < .0001) and, to a lesser degree, patient's age and tumor size. No statistically significant association was found between ODxRS and adjuvant chemotherapy utilization in a subset of patients. In the 156 node-negative breast cancer patients with intermediate-risk ODxRS, high tumor grade most significantly correlated with adjuvant chemotherapy utilization (P < .0001).ConclusionODxRS, if available, heavily impacts adjuvant chemotherapy utilization and more so than any clinicopathologic factor in node-negative breast cancer patients. Node-negative breast cancer patients in the intermediate-risk group whose tumors were high grade were more likely to receive adjuvant chemotherapy.     

The Role of CXCL13 and CXCL9 in Early Breast Cancer

BackgroundChemokines, cytokines in the immune microenvironment of tumors, may be associated with patient outcome. We assessed the impact of CXCL13 and CXCL9 on disease-free (DFS) and overall survival (OS), in an attempt to retrospectively evaluate both T and B cell function in the microenvironment of primary tumors from patients with breast cancer.Materials and MethodsFormalin-fixed paraffin-embedded tissue blocks from patients with intermediate/high-risk, early breast cancer, treated with sequential adjuvant epirubicin, paclitaxel, and cyclophosphamide methotrexate fluorouracil within a randomized trial, were tested for CXCL13 and CXCL9 messenger RNA expression; 557 patients with adequate tissue were eligible for the analysis.ResultsCXCL13 was correlated with CXCL9 (rho = 0.52; P < .001). High-expressing CXL13 and CXCL9 tumors had higher Ki67 and tumor infiltrating lymphocyte density (P-values < .001). High CXCL9 expression was an unfavorable prognosticator for OS among all patients (hazard ratio [HR], 1.73; P = .021), whereas it showed favorable significance for both DFS and OS in patients with triple negative disease (HR, 0.29; P = .027 and HR, 0.32; P = .045). High CXCL13 conferred longer DFS and OS among patients with luminal-human epidermal growth factor receptor 2 disease (HR, 0.31; P = .013 and HR, 0.25; P = .005). Patients with low CXCL13 and high CXCL9 expression had shorter DFS and OS compared with those with high expression of both chemokines (HR, 1.63; P = .006 and HR, 1.61; P = .016).ConclusionsBoth biomarkers were associated with poor prognosis characteristics and with tumor infiltrating lymphocyte density. High CXCL9 conferred an improved prognosis in the triple negative subtype, whereas high CXCL13 was associated with improved outcome in the luminal-human epidermal growth factor receptor 2 subtype. Chemokines can be associated with breast cancer subtype and outcome. These data should be evaluated prospectively.     

Low expression of Mel-18 predicts poor prognosis in patients with breast cancer

BackgroundOur previous study suggested that melanoma nuclear protein 18 (Mel-18) acted as a tumor suppressor in human breast cancer. This study was designed to investigate the clinical and prognostic significance of Mel-18 in breast cancer patients.Patients and methodsMel-18 was detected by immunohistochemistry in paraffin-embedded tissues from 287 breast cancer patients, of which 287 were from primary cancer sites, 63 from matched adjacent noncancerous sites, and 35 from metastatic lymph nodes. Differences in Mel-18 expression and clinical characteristics were compared by χ² test. Prognostic outcomes correlated with Mel-18 were examined using Kaplan–Meier analysis and Cox proportional hazards model.ResultsThe decreased Mel-18 expression is incremental depending upon the magnitude of cancer progression (P < 0.001). Mel-18 was conversely correlated with the pathological classifications (P < 0.001 for T, N, and M classifications, respectively), clinical staging (P < 0.001), and progesterone receptor (P = 0.030). Furthermore, patients with higher level of Mel-18 showed prolonged overall survivals (P < 0.001). The diminished Mel-18 expression may be a risk factor for the patients’ survival (P < 0.001).ConclusionsLower Mel-18 expression is correlated with advanced clinicopathologic classifications and a poor overall survival in breast cancer patients. These findings suggest that Mel-18 may serve as a useful marker in prognostic evaluation for patients.     

Effect of Breast Conservation Therapy vs Mastectomy on Overall Survival and Breast Cancer-Specific Survival Among Men With Stage I-II Breast Cancer: Analysis of SEER, 2000-2018

BackgroundMale breast cancer is a rare malignant tumor, and outcomes of breast conservation therapy (BCT) are currently lacking.MethodThe retrospective, population-based cohort study included 1369 stage I-II (T1–2 N0–1 M0) male breast cancer patients from the SEER database (2000-2018). The patients were grouped in two groups: BCT group and mastectomy group, according to surgical and radiation therapy. Kaplan-Meier method and univariable Cox proportional hazard analysis were used to compare overall survival (OS) and breast cancer-specific survival (BCSS) between two treatment groups. Propensity score matching (PSM) was performed to balance the confounding factors.ResultsOf the 1369 men, 97 (7%) patients received BCT, 1272 (93%) received mastectomy alone. The 5- and 10-year OS rates were 92.3% and 80.7% for BCT group compared with 80.4% and 61.4% for mastectomy group. The 5- and 10-year BCSS rates were 96.5% and 93.9% for patients undergoing BCT, as compared with 93.1% and 84.4% for patients undergoing mastectomy. Compared with mastectomy group, BCT group showed improved OS (hazard ratio [HR], 0.294; 95% CI 0.138-0.623, P = .002) and BCSS (hazard ratio [HR], 0.182; 95% CI 0.040-0.820, P = .027). Of the 791 patients with T1 stage, BCT showed insignificant association with OS (hazard ratio [HR], 0.555; 95% CI 0.207-1.488, P = .242) and BCSS (hazard ratio [HR], 1.217; 95% CI 0.171-8.675, P = .844).ConclusionThe results of this cohort study suggest that BCT is at least equivalent to mastectomy in male breast cancer patients. The underlying mechanism of this association needs further research.     

A nomogram to predict individual prognosis in node-negative breast carcinoma

BackgroundCurrently, the benefit of chemotherapy (CT) in node-negative breast carcinoma (NNBC) is discussed. The evaluation of classical clinical and histological factors is limited to assess individual outcome. A statistical model was developed to improve the prognostic accuracy of NNBC.MethodsA total of 305 node-negative breast carcinomas who underwent surgery (+/– radiotherapy) but no adjuvant treatment were selected. Putative prognosis factors including age, tumour size, oestrogen receptor (ER), progesterone receptor (PgR), Scarff–Bloom–Richardon (SBR) grading, urokinase plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1) and thymidine kinase (TK) were evaluated. The developed model was internally validated using Harrell’s concordance index. A prognosis index (PI) was proposed and compared with Adjuvant! Online program.ResultsAge (p < 0.001), pathological tumour size (pT) (p < 0.001), PgR (p = 0.02), and PAI-1 (p ⩽ 0.001) were included in the Cox regression model predicting Breast cancer specific survival (BCSS) at 5-years. Internal validation revealed a concordance index of 0.71. A PI score was derived from our nomogram. The PI score was significantly associated with BCSS (hazard ratio (HR): 4.1 for intermediate, p = 0.02, HR: 8.8, p < 0.001 for high group) as compared to Adjuvant! Online score (HR: 1.4, p = 0.14).ConclusionA nomogram can be used to predict probability survival curves for individual breast cancer patients.     

Human Papillomavirus (HPV) Detection by Chromogenic In Situ Hybridization (CISH) and p16 Immunohistochemistry (IHC) in Breast Intraductal Papilloma and Breast Carcinoma

PurposeThis study explored human papillomavirus (HPV) amplification in breast benign and malignant lesions by chromogenic in situ hybridization (CISH) and the concordance of p16 expression by immunohistochemistry.Patients and MethodsThe presence of HPV6/11 and HPV16/18 in 33 cases of intraductal papilloma, 34 cases of ductal carcinoma in situ (DCIS), and 56 cases of invasive breast carcinoma (IBC) was evaluated using matched-background breast parenchyma and breast reduction as control groups. Association with clinicopathologic factors including prognosis was assessed.ResultsHPV 6/11 was observed in 0 cases (0%) of breast reduction, one case (3%) of intraductal papilloma, 11 cases (32.4%) of DCIS, and eight cases (14.3%) of IBC. HPV 16/18 was detected in three cases of (9.1%) breast reduction, six cases (18.8%) of intraductal papillomas, 14 cases (41.2%) of DCIS, and 25 cases (44.6%) of IBC. There was no difference in the HPV status between intraductal papilloma and breast reduction. HPV amplification in intraductal papilloma did not associate with developing atypia or carcinoma after long-term follow-up. However, HPV 6/11 and HPV 16/18 amplification was significantly higher in both DCIS and IBC when compared with breast reduction (P < .05). Compared with background breast parenchyma, HPV 16/18 amplification was significantly higher in both DCIS and IBC (P = .003 and P = .013, respectively). No correlation between p16 immunohistochemical staining and either of the HPV CISH testing was found (P > .05).ConclusionHPV infection was detected in both breast lesions and background parenchyma. HPV infection may play a role in the pathogenesis of breast cancer but is not associated with intraductal papilloma. Immunohistochemical stain for p16 is not a good surrogate marker for HPV infection in breast lesions.     

Divergent effects of insulin-like growth factor-1 receptor expression on prognosis of estrogen receptor positive versus triple negative invasive ductal breast carcinoma

The insulin-like growth factor type 1 receptor (IGF1R) is involved in progression of breast cancer and resistance to systemic treatment. Targeting IGF1R signaling may, therefore, be beneficial in systemic treatment. We report the effect of IGF1R expression on prognosis in invasive ductal breast carcinoma (IDC), the most common type of breast cancer. Immunohistochemistry was performed on tumor tissue of a consecutive cohort of 429 female patients treated for operable primary IDC. Associations between IGF1R expression with clinicopathological parameters, disease free survival (DFS) and breast cancer specific survival (BCSS) were evaluated by multivariate analyses focusing on ER-positive and triple negative IDC (TN-IDC). To enlarge the TN-IDCs cohort, we analyzed a combined dataset of 51 TN-IDC tumors from our series with 64 TN-IDCs with similar clinicopathological parameters. Patients with tumors expressing cytoplasmic IGF1R have a longer DFS and BCSS (DFS: HR 0.46, 95% CI 0.27–0.49, P = 0.005, BCSS: HR 0.38, 95% CI 0.19–0.74, P = 0.005). This effect was most prominent in ER-positive tumors. However, in a combined series of 105 TN-IDCs cytoplasmic IGF1R expression was associated with a shorter DFS (HR = 2.29, 95% CI 1.08–4.84, P = 0.03), also when combined in a multivariate model, including well-known prognostic factors (HR 2.06; 95% CI 0.95–4.47; P = 0.07). IGF1R expression in ER-positive IDC is strongly related to a favorable DFS and BCSS, but to a shorter DFS in TN-IDC tumors. This divergent effect of IGF1R expression in subgroups of IDC may affect selection of patients for IGF1R targeted therapy.     

Clinicopathological significance of KU70/KU80, a key DNA damage repair protein in breast cancer

Although the role of BRCA1 and the homologous recombination (HR) pathway in breast cancer (BC) has been extensively studied, the alternative repair pathway for DNA double-strand breaks (DSBs), non-homologous end-joining (NHEJ) remains to be defined. Ku proteins bind to DNA DSB ends and play a key role in NHEJ. In this study we aimed to assess the expression and biological significance of the KU70/KU80 heterodimer in the different molecular classes of BC. The expression of KU70/KU80 was assessed immunohistochemically in a well-characterised and annotated series of 1302 unselected invasive BC cases with a long-term follow-up together with 25 cases with known BRCA1 mutations. The results were correlated with clinicopathological parameters, other DNA repair proteins and patient outcome. The expression of KU70/KU80 protein was further evaluated in various BC cell lines using western blotting and reverse-phase protein microarray (RPPA). Nuclear KU70/KU80 expression was correlated with features of poor prognosis including higher histological grade, lymphovascular invasion, negative oestrogen receptor expression, basal-like phenotype, P53 and CHK1 positivity. KU70/KU80 was expressed in all BRCA1-associated tumours and showed an inverse correlation with nuclear BRCA1 protein and aberrant cytoplasmic RAD51 expression. RPPA confirmed these results and showed higher expression of KU70/KU80 in BRCA1-deficient cell line compared to BRCA1-proficient cell line. KU70/KU80 expression showed an association with disease-free interval; however, it was not an independent predictor of outcome. As a conclusion, KU70/KU80 may play a role in DNA DSBs repair in HR-deficient tumours. Further study of other NHEJ markers in sporadic BC is warranted.     

The prevalence of luminal B subtype is higher in older postmenopausal women with ER+/HER2- breast cancer and is associated with inferior outcomes

ObjectivesTo establish whether clinicopathologic and genomic characteristics may explain the poor prognosis associated with advanced age in ER+/HER2- breast cancer.Materials and MethodsThe cohort included 271 consecutive post-menopausal patients with ER+/HER2- invasive breast cancer ages 55 years and older. Patients were categorized as “younger” (ages 55- < 75) and “older” (ages ≥75). The Kaplan-Meier method was used to estimate locoregional recurrence (LRR), recurrence-free interval (RFi), and overall survival (OS). Gene expression of tumor samples was assessed with Affymetrix Rosetta/Merck Human RSTA microarray platform. Differential gene expression analysis of tumor samples was performed using R package Limma.Results271 breast cancer patients were identified, including 186 younger and 85 older patients. Older patients had higher rates of Luminal B subtype (53% vs 34%) and lower rates of Luminal A subtype (42% vs 58%, p = 0.02). Older patients were less likely to receive chemotherapy (9% vs 40%, p < 0.001) and hormone therapy (71% vs 89%, p < 0.001). For cases of grade 1–2 disease, older patients had a higher proportion of the luminal B subtype (49% vs. 30%, p = 0.014). Age ≥ 75 predicted for inferior OS (HR = 3.06, p < 0.001). The luminal B subtype predicted for inferior OS (HR = 2.12, p = 0.014), RFi (HR 5.02, p < 0.001), and LRR (HR = 3.12, p = 0.045). There were no significant differences in individual gene expression between the two groups.ConclusionWomen with ER+/HER2- breast cancer ≥75 years old had higher rates of the more aggressive luminal B subtype and inferior outcomes. Genomic testing of these patients should be strongly considered, and treatment should be intensified when appropriate.     

Clinical Characteristics and Outcomes of Single Versus Double Hormone Receptor–Positive Breast Cancer in 2 Large Databases

PurposeTo identify biologic and outcome differences between double hormone receptor (HR)-positive (dHR⁺, estrogen receptor (ER)⁺/progesterone receptor [PgR⁺]) and single HR-positive (sHR⁺, either ER⁺/PgR⁻ or ER⁻/PgR⁺) breast cancer; and to explore whether hormone therapy (HT) response in HER2-negative breast cancer correlates with HR status.Patients and MethodsThis retrospective study was conducted by using 2 large breast cancer databases: the Surveillance, Epidemiology, and End Results (SEER) database and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) clinical data set. Cox regression analysis was used to estimate overall survival (OS) and breast cancer–specific survival (BCSS) among sHR⁺ and dHR⁺ patients.ResultsIn the SEER database, dHR⁺ patients had significantly longer OS and BCSS than ER⁺/PgR⁻ patients in short-term follow-up (OS: hazard ratio = 0.620; 95% confidence interval [CI], 0.590, 0.652; P < .001; BCSS: hazard ratio = 0.493; 95% CI, 0.462, 0.526; P < .001). Meanwhile, ER⁻/PgR⁺ patients had younger age, larger tumor size, and higher disease grade than dHR⁺ and ER⁺/PgR⁻ patients. In patients who received HT, dHR⁺ patients had a more favorable OS than ER⁺/PgR⁻ patients (hazard ratio = 0.789; 95% CI, 0.635, 0.982; P = .034), and ER⁻/PgR⁺ patients had a worse OS than ER⁺/PgR⁻ patients at 10 years’ follow-up (hazard ratio = 7.991; 95% CI, 1.053, 60.644; P = .044). However, these groups had similar outcomes over longer periods.ConclusionIn HER2-negative breast cancer, sHR⁺ patients are associated with relatively worse characteristics and worse short-term outcomes than dHR⁺ patients. Additionally, the outcome of patients receiving HT may differ according to the HR status. However, further studies are needed to confirm these conclusions.