Longitudinal, Long-Term Comparison of Single- versus Multipoint Upper Limb Circumference Periodical Measurements as a Tool to Predict Persistent Lymphedema in Women Treated Surgically for Breast Cancer: An Optimized Strategy to Early Diagnose Lymphedema and Avoid Permanent Sequelae in Breast Cancer Survivors.

PURPOSE: We aim to evaluate whether upper limb (UL) circumference (ULC) and UL swelling sensation (ULSS) performed shortly after surgery or later on during follow-up can predict long-term/persistent forms of lymphedema in women who underwent surgery for breast cancer. PATIENTS AND METHODS: Eighty-five women completed at least 24 months of follow-up. At each follow-up visit (1, 3, 6, 12, and 24 months after surgery), patients were tested for lymphedema using ULC and ULSS. Two different approaches to ULC were compared: (1) a "positive" lymphedema diagnosis if a difference ≥ 2 cm between the affected and contralateral UL was detected in at least two contiguous measurement points (MPs) and (2) a "positive" result if just one MP ≥ 2 cm. Patients were also questioned about their perception of weight, swelling, and/or tension (ULSS). The gold standard for long-term lymphedema was a water displacement difference between the UL ≥ 200 mL 24 months after surgery (ULWD). RESULTS: Twenty-four months after surgery, 19 (22.4%) women were diagnosed with long-term lymphedema. Using 24-month data, comparison of log-likelihoods denoted a clear superiority of the ULC approach 1 compared with 2 for the diagnosis of long-term lymphedema (p < 0.001). Using approach 1, the best prediction of a woman developing long-term lymphedema if she had a positive ULC in the follow-up was obtained at 6 months after surgery (posterior probability of 60%). CONCLUSIONS: Our study reveals that performing ULC 6 months after surgery, regarding as "positive" only women with a difference ≥ 2 cm at two contiguous MPs, is the best strategy to identify women at increased risk of later developing permanent forms of lymphedema.

Multiplatform Investigation of Plasma and Tissue Lipid Signatures of Breast Cancer Using Mass Spectrometry Tools.

Plasma and tissue from breast cancer patients are valuable for diagnostic/prognostic purposes and are accessible by multiple mass spectrometry (MS) tools. Liquid chromatography-mass spectrometry (LC-MS) and ambient mass spectrometry imaging (MSI) were shown to be robust and reproducible technologies for breast cancer diagnosis. Here, we investigated whether there is a correspondence between lipid cancer features observed by desorption electrospray ionization (DESI)-MSI in tissue and those detected by LC-MS in plasma samples. The study included 28 tissues and 20 plasma samples from 24 women with ductal breast carcinomas of both special and no special type (NST) along with 22 plasma samples from healthy women. The comparison of plasma and tissue lipid signatures revealed that each one of the studied matrices (i.e., blood or tumor) has its own specific molecular signature and the full interposition of their discriminant ions is not possible. This comparison also revealed that the molecular indicators of tissue injury, characteristic of the breast cancer tissue profile obtained by DESI-MSI, do not persist as cancer discriminators in peripheral blood even though some of them could be found in plasma samples.

Plasma Metabolome Signatures to Predict Responsiveness to Neoadjuvant Chemotherapy in Breast Cancer.

BACKGROUND: Neoadjuvant chemotherapy (NACT) has arisen as a treatment option for breast cancer (BC). However, the response to NACT is still unpredictable and dependent on cancer subtype. Metabolomics is a tool for predicting biomarkers and chemotherapy response. We used plasma to verify metabolomic alterations in BC before NACT, relating to clinical data. METHODS: Liquid chromatography coupled to mass spectrometry (LC-MS) was performed on pre-NACT plasma from patients with BC (n = 75). After data filtering, an SVM model for classification was built and validated with 75%/25% of the data, respectively. RESULTS: The model composed of 19 identified metabolites effectively predicted NACT response for training/validation sets with high sensitivity (95.4%/93.3%), specificity (91.6%/100.0%), and accuracy (94.6%/94.7%). In both sets, the panel correctly classified 95% of resistant and 94% of sensitive females. Most compounds identified by the model were lipids and amino acids and revealed pathway alterations related to chemoresistance. CONCLUSION: We developed a model for predicting patient response to NACT. These metabolite panels allow clinical gain by building precision medicine strategies based on tumor stratification.

Aluminum concentrations in central and peripheral areas of malignant breast lesions do not differ from those in normal breast tissues.

BACKGROUND: Aluminum is used in a wide range of applications and is a potential environmental hazard. The known genotoxic effects of aluminum might play a role in the development of breast cancer. However, the data currently available on the subject are not sufficient to establish a causal relationship between aluminum exposure and the augmented risk of developing breast cancer. To achieve maximum sensitivity and specificity in the determination of aluminum levels, we have developed a detection protocol using graphite furnace atomic absorption spectrometry (GFAAS). The objective of the present study was to compare the aluminum levels in the central and peripheral areas of breast carcinomas with those in the adjacent normal breast tissues, and to identify patient and/or tumor characteristics associated with these aluminum levels. METHODS: A total of 176 patients with breast cancer were included in the study. Samples from the central and peripheral areas of their tumors were obtained, as well as from the surrounding normal breast tissue. Aluminum quantification was performed using GFAAS. RESULTS: The average (mean ± SD) aluminum concentrations were as follows: central area, 1.88 ± 3.60 mg/kg; peripheral area, 2.10 ± 5.67 mg/kg; and normal area, 1.68 ± 11.1 mg/kg. Overall and two-by-two comparisons of the aluminum concentrations in these areas indicated no significant differences. We detected a positive relationship between aluminum levels in the peripheral areas of the tumors, age and menopausal status of the patients (P = .02). CONCLUSIONS: Using a sensitive quantification technique we detected similar aluminum concentrations in the central and peripheral regions of breast tumors, and in normal tissues. In addition, we did not detect significant differences in aluminum concentrations as related to the location of the breast tumor within the breast, or to other relevant tumor features such as stage, size and steroid receptor status. The next logical step is the assessment of whether the aluminum concentration is related to the key genomic abnormalities associated with breast carcinogenesis.

Early Blood Flow Abnormalities in Axillary and Brachial Arteries Precede the Onset of Persistent Lymphedema in Women Treated Surgically for Breast Cancer.

Background: surgery to treat breast cancer (BC) is associated with upper limb (UL) lymphedema, which in some cases may become permanent. It is uncertain whether lymphedema results from injury to either lymphatic or blood vessels, or to both. Methods and Results: a cohort of 200 BC patients was examined 1, 3, 6, 12, and 24 months after surgery. Axillary and brachial blood vessels were evaluated using Doppler Ultrasound, and patients had their UL examined for lymphedema at each visit. Patients who developed lymphedema 24 months after surgery presented with higher mean flow velocity (MFV) and end diastolic velocity (EDV) in both axillary (MFV = 13.57 vs. 10.7 cm/s, p = 0.02; EDV = 5.62 vs. 3.47 cm/s; p = 0.004) and brachial (MFV = 11.44 vs. 8.74 cm/s; p = 0.03; EDV = 5.08 vs. 3.04; p = 0.04) arteries as early as 1 month after surgery. Similar associations were found 3, 6, and 12 months after surgery. Early abnormalities of the resistive and pulsatility indexes were also significantly associated with persistent lymphedema. EDV measured 1 month after surgery had the best performance to detect patients who will later develop long-term lymphedema, (sensitivity = 73.7%; specificity = 71.2%; negative predictive value = 57.6%). Conclusion: vascular abnormalities precede and are possible causal factors for UL lymphedema in BC patients.

Metastatic mucinous carcinomas in the ovary: a practical approach to diagnosis related to gross aspects and to immunohistochemical evaluation.

Ovarian mucinous carcinomas are uncommon, and the differential diagnosis is metastatic carcinoma mainly from the gastrointestinal tract. The aim was to verify the importance of immunohistochemical reactions and the algorithm described in literature on the basis of laterality and tumor size. Twenty-five cases identified as metastatic mucinous adenocarcinomas were reviewed, along with clinical records; a tissue microarray was created, and immunohistochemical reactions for CK7, CK20, Ca125, hormonal receptors, WT1, DPC4, ß-catenin, and Cdx2 were determined. The median age was 51, and only 9 patients had a history of cancer. Sixteen patients (64%) had bilateral tumors, with sizes ranging from 5 to 36 cm (average, 20.5 cm); 9 (36%) had unilateral tumors varying from 5.5 to 38 cm (average, 21.8 cm). Algorithm agreement was 76%; most unilateral tumors were >13 cm. Common positive markers were Dpc4 (88%), Cdx2 (68%), CK20 (60%), and CK7 (44%). The useful markers were CK7, CK20, and Cdx2, although there were cases with overlapping results. The most common primary tumor was of colorectal origin (14 cases). The mean survival age was 32.6 mo. Although the proposed algorithm and immunohistochemical reactions are useful tools for diagnosis, some mucinous tumors cannot be definitively classified as primary or metastatic without further clinical evaluation, emphasizing the limits of this challenging diagnosis.

Metabolomics by NMR Combined with Machine Learning to Predict Neoadjuvant Chemotherapy Response for Breast Cancer.

Neoadjuvant chemotherapy (NACT) is offered to patients with operable or inoperable breast cancer (BC) to downstage the disease. Clinical responses to NACT may vary depending on a few known clinical and biological features, but the diversity of responses to NACT is not fully understood. In this study, 80 women had their metabolite profiles of pre-treatment sera analyzed for potential NACT response biomarker candidates in combination with immunohistochemical parameters using Nuclear Magnetic Resonance (NMR). Sixty-four percent of the patients were resistant to chemotherapy. NMR, hormonal receptors (HR), human epidermal growth factor receptor 2 (HER2), and the nuclear protein Ki67 were combined through machine learning (ML) to predict the response to NACT. Metabolites such as leucine, formate, valine, and proline, along with hormone receptor status, were discriminants of response to NACT. The glyoxylate and dicarboxylate metabolism was found to be involved in the resistance to NACT. We obtained an accuracy in excess of 80% for the prediction of response to NACT combining metabolomic and tumor profile data. Our results suggest that NMR data can substantially enhance the prediction of response to NACT when used in combination with already known response prediction factors.

Hormonal contraceptives and the length of their use are not independent risk factors for high-risk HPV infections or high-grade CIN.

AIMS: To evaluate the role of hormonal contraceptives as a risk factor of high-risk human papillomavirus (HR-HPV), cervical intraepithelial lesions (CIN) and cervical cancer in our multi-center population-based LAMS (Latin American Screening) study. METHODS: A cohort study with >12,000 women from Brazil and Argentina using logistic regression to analyze the covariates of hormonal contraception (HOC - oral, injections, patches, implants, vaginal ring and progesterone intrauterine system) use followed by multivariate modeling for predictors of HR-HPV and CIN2+. RESULTS: HR-HPV infection was a consistent risk factor of high-grade CIN in all three groups of women. The length of HOC use was not significantly related to high-grade squamous intraepithelial lesions (HSIL)+ Pap (p = 0.069), LSIL+ Pap (p = 0.781) or ASCUS+ (p = 0.231). The same was true with the length of HOC use and histology CIN3+ (p = 0.115) and CIN2+ (p = 0.515). Frequently, HOC users have previously shown more HPV-related lesions, as well as lower HPV prevalence if they were current smokers. But HOC use and time of usage were not independent risk factors of either HR-HPV infection or high-grade CIN using multiple logistic regressions. CONCLUSIONS: No evidence was found for an association between the use of HOC with an increased risk for HR-HPV infection or high-grade CIN in this cohort.

Increased risk of oncogenic human papillomavirus infections and incident high-grade cervical intraepithelial neoplasia among smokers: experience from the Latin American screening study.

BACKGROUND: The purpose of this study was to assess the effect of smoking on the prevalence and incidence of high-risk human papillomavirus (hr-HPV) infection and cervical intraepithelial neoplasia (CIN) in a large sample of Latin American women. METHODS: The study examines baseline data on over 12,000 women included in the Latin American Screening Study (Brazil and Argentina), and over 1000 women followed-up for a period of 36 months. Three groups were formed: never smokers, current, and past smokers. The prevalence of hr-HPV infection and CIN were compared between the study groups. In the prospective analysis, women were controlled at 6-month intervals to assess the cumulative risk of incident hr-HPV infection, smear abnormalities, and CIN. RESULTS: A higher prevalence (21.7%) of hr-HPV infection was found among current smokers as compared to never smokers (16.5%) or past smokers (13.5%). Being current smoker was significantly (P <0.01) associated with hr-HPV detection (OR = 1.6; 95% CI = 1.2-2.1). Being a current smoker was a significant predictor of incident hr-HPV during the follow-up [Hazards ratio (HR) = 1.4; 95% CI 1.0-1.9]. For incident CIN2+, being a past smoker (HR = 3.6; 95% CI 1.6-9.8) or current smoker (HR = 3.6; 95% CI 1.5-8.6) were the significant independent predictors. Current and past smokers had a significantly increased risk of incident CIN2+ (P <0.01). CONCLUSIONS: Smoking increases the risk of contracting hr-HPV infection and modifies the effect of a persistent hr-HPV infection by further increasing the risk of developing CIN2+. It seems that this effect modification persists over several years after smoking cessation.

Comparative evaluation of the erbB2 and hormone receptor status of neighboring invasive and in situ components of ductal carcinomas of the breast.

BACKGROUND: It remains unknown whether erbB2 expression and hormone receptor status predict the invasive potential of ductal carcinoma in situ (DCIS) of the breast. OBJECTIVES: To examine erbB2 and estrogen/progesterone receptor (ER/PR) status in the precise areas where DCIS turns into invasive ductal carcinoma (IDC). SUBJECTS AND METHODS: Eighty-seven cases of breast malignancies harboring contiguous regions of DCIS and IDC were selected. Separate histological samples from the DCIS and the neighboring IDC were obtained using tissue microarrays. The erbB2 and ER/PR statuses were assessed using immunohistochemistry (erbB2 and ER/PR) and fluorescence in situ hybridization (FISH - only erbB2). RESULTS: The expression of erbB2 did not differ in the DCIS and IDC components of the breast tumors (p=0.35). There was good agreement in sample-by-sample comparisons of erbB2 (intraclass correlation coefficient [ICC]=0.78), PR (ICC=0.61) and ER (ICC=0.70) expression in the DCIS and IDC components. CONCLUSION: Our findings suggest that the expressions of erbB2 and ER/PR do not differ in the contiguous regions from DCIS to IDC.

Smoking worsens the prognosis of mild abnormalities in cervical cytology.

OBJECTIVE: To examine the effect of smoking on the incidence of low- and high-grade cervical intraepithelial neoplasia (CIN) in women with a baseline Pap smear of atypical squamous cells (ASC) or a low-grade squamous intraepithelial lesion (LSIL). DESIGN: Prospective study in which a cohort of women with normal colposcopy and ASC/LSIL at baseline were followed at 6-month intervals of up to 36 months. Women were grouped in post-hoc analysis according to their smoking behavior: never (or past) smokers and current smokers. SETTING: This report was based on data from the Latin American Screening Study, conducted in Sao Paulo, Campinas, Porto Alegre (Brazil) and Buenos Aires (Argentina). POPULATION: A subset of 150 women derived from a cohort of 1,011 women. METHODS: Multivariate Cox analysis and Kaplan-Meier curves were used. MAIN OUTCOME MEASURES: Low- and high-grade CIN during follow-up. RESULTS: The only factor related to an increased risk of developing CIN was the positive high-risk (hr) HPV status (hazard ratio (HR) = 3.42; 95% CI: 1.11-9.43). A total of 21 cases of incident CIN were detected during follow-up. Of these, 11 appeared in the group of 67 smokers and 10 among the 83 non-smoker women (log-rank, p=0.33). Smoking status was not associated with the risk of developing CIN (HR = 0.73; 95% CI: 0.40-1.33). However, when restricting the analysis to high-grade CIN only (11 cases), the probability of developing the disease was significantly higher among smokers (p=0.04). CONCLUSIONS: Smoking contributes additional risk for developing high-grade CIN in women with ASC or LSIL cytology but normal colposcopy.

Copy number alterations associated with clinical features in an underrepresented population with breast cancer.

BACKGROUND: As the most incident tumor among women worldwide, breast cancer is a heterogeneous disease. Tremendous efforts have been made to understand how tumor characteristics as histological type, molecular subtype, and tumor microenvironment collectively influence disease diagnosis to treatment, which impact outcomes. Differences between populations and environmental and cultural factors have impacts on the origin and evolution of the disease, as well as the therapeutic challenges that arise due to these factors. We, then, compared copy number variations (CNVs) in mucinous and nonmucinous luminal breast tumors from a Brazilian cohort to investigate major CNV imbalances in mucinous tumors versus non-mucinous luminal tumors, taking into account their clinical and pathological features. METHODS: 48 breast tumor samples and 48 matched control blood samples from Brazilian women were assessed for CNVs by chromosome microarray. Logistic regression and random forest models were used in order to assess CNVs in chromosomal regions from tumors. RESULTS: CNVs that were identified in chromosomes 1, 5, 8, 17, 19, and 21 classify tumors according to their histological type, ethnicity, disease stage, and familial history. CONCLUSION: Copy number alterations described in this study provide a better understanding of the landscape of genomic aberrations in mucinous breast cancers that are associated with clinical features.

Molecular Signatures of High-Grade Cervical Lesions.

Cervical cancer is the fourth most common neoplasia in women and the infection with human papilloma virus (HPV) is its necessary cause. Screening methods, currently based on cytology and HPV DNA tests, display low specificity/sensitivity, reducing the efficacy of cervical cancer screening programs. Herein, molecular signatures of cervical cytologic specimens revealed by liquid chromatography-mass spectrometry (LC-MS), were tested in their ability to provide a metabolomic screening for cervical cancer. These molecules were tested whether they could clinically differentiate insignificant HPV infections from precancerous lesions. For that, high-grade squamous intraepithelial lesions (HSIL)-related metabolites were compared to those of no cervical lesions in women with and without HPV infection. Samples were collected from women diagnosed with normal cervix (N = 40) and from those detected with HSIL from cytology and colposcopy (N = 40). Liquid-based cytology diagnosis, DNA HPV-detection test, and LC-MS analysis were carried out for all the samples. The same sample, in a customized collection medium, could be used for all the diagnostic techniques employed here. The metabolomic profile of cervical cancer provided by LC-MS was found to indicate unique molecular signatures for HSIL, being two ceramides and a sphingosine metabolite. These molecules occurred independently of women's HPV status and could be related to the pre-neoplastic phenotype. Statistical models based on such findings could correctly discriminate and classify HSIL and no cervical lesion women. The results showcase the potential of LC-MS as an emerging technology for clinical use in cervical cancer screening, although further validation with a larger sample set is still necessary.

Human papillomavirus (HPV) infections as risk factors for cytological and histological abnormalities in baseline PAP smear-negative women followed-up for 2 years in the LAMS study.

OBJECTIVE: To assess the role of HPV as determinant of the incident cytological abnormalities (SIL) and cervical lesions (CIN) during a 24-month follow-up of baseline PAP smear-negative subgroup of women included in the Latin American Screening study (LAMS). STUDY DESIGN: A group of 365 women with normal Pap smear and negative or positive high-risk Hybrid Capture II test were prospectively followed-up for 24 months at Campinas and São Paulo (Brazil). The incidence rate (IR) and risk ratio (RR and 95% CI) of developing cytological or histological abnormality during the follow-up was calculated for HPV-negative and HPV-positive women. RESULTS: During the 12-month follow-up, women HPV-positive at baseline had developed a significantly higher rate of incident LSIL (IR=3.5%, RR=1.4; 95% CI 1.1-1.7) and HSIL (IR=0.7%, RR=1.5; 95% CI 1.4-1.7) abnormality. For HSIL, the IR increased to 2.1% and the RR increased to 1.7 (95% CI 1.5-1.9) among those followed for 24 months. Similarly, women with positive HPV tests were at a higher risk of developing CIN 2-3 (IR=2.6%, RR=1.5; 95% CI 1.4-1.6) during the first 12 months of follow-up, and for those followed for 24 months, this RR increased further to 1.7 (95% CI 1.5-1.9) although the IR was 0.7%. CONCLUSIONS: Oncogenic HPV infections comprise a significant risk factor for incident cervical abnormalities, and HPV test is a useful adjunct to cytology in detecting the high-risk patients among baseline PAP smear-negative women.

Prognostic significance of PD-L1 and PD-L2 in breast cancer.

PD-L1 and PD-L2 constitute an important antitumor immune response. In breast cancer, their prognostic value is still to be defined. In this study, we investigate the correlation between PD-L1 and PD-L2 protein expressions with clinical and pathologic features and disease-free survival and overall survival. To assess PD-L1 and PD-L2 expressions, we conducted immunohistochemistry studies using a breast cancer tissue microarray encompassing a total of 192 breast cancer cases, stages I, II, and III, with detailed clinical and outcome data. PD-L1 expression was present in 56.6% (107/189), and PD-L2 expression was identified in 50.8% (97/191) of breast cancer cases. Younger age at diagnosis, lymph node positivity, negative estrogen receptor, and recurrence at distant sites were all associated with both PD-L1 and PD-L2 expressions. The presence of larger tumors was associated only with PD-L1 expression. In our study, PD-L1 expression was significantly associated with better overall survival (P = .04) in breast cancer patients. Despite its association with poor clinical and pathologic features, PD-L1 expression emerges as a positive prognostic biomarker in breast cancer. This survival result might be due to the presence of a strong antitumor immune response leading to PD-L1 expression.

DNA recovery from Hybrid Capture II samples stored in specimen transport medium with denaturing reagent, for the detection of human papillomavirus by PCR.

The purpose of this study was to examine the quality of DNA recovered for human papillomavirus (HPV) detection using polymerase chain reaction (PCR) in samples that had been collected for Hybrid Capture II (HCII), testing and stored in specimen transport medium (STM) with denaturing reagent at -20 degrees C for 18 months. Endocervical tissue was collected from 92 women for HCII assay using the Digene STM, and a Papanicolaou smear was carried out in all cases. Seven women had normal colposcopy results. The remaining 85 patients underwent colposcopy-directed biopsy or cervical conization for histological investigation. Of the 92 samples tested, 84 were HCII-positive and 8 were negative. Quality control for amplification was carried out with beta-globin primers G73 and G74, and HPV was tested using PGMY09 and PGMY11. DNA was recovered from 83 of the 92 samples (90%). Among the 84 samples HCII-positive initially, HPV was detected by PCR in 56 (67%). PCR did not detect HPV DNA in the eight samples that were HCII-negative, although five of them were positive for beta-globin. This paper describes a novel DNA extraction technique that may permit exact HPV typing in stored samples collected originally for HCII testing, making it possible to carry out retrospective investigations to retrieve information on specific HPV types in large HCII series.

Detection of high-risk human papillomavirus (HPV) DNA by Hybrid Capture II in women referred due to atypical glandular cells in the primary screening.

We assessed the detection of high-risk human papillomavirus DNA (HPV-DNA) in women examined by a second Pap smear due to atypical glandular cells (AGC) detected in their screening Pap smear. In 91 women included in the study, a second Pap smear was taken and HPV-DNA test was performed using Hybrid Capture II (HC II). The second Pap smear showed no abnormalities in 28 (31%) cases, ACG in 17 (19%) cases, and high-grade squamous intraepithelial lesions (HSIL) or worse in 24 (26%). HC II test was positive in 36% of the cases. Considering the second Pap smear diagnosis, HPV-DNA was detected in 87% of the women with HSIL, 100% of women with in situ adenocarcinoma, and only in 11% of the women with no abnormalities. The use of the second Pap smear combined with HPV-DNA may improve the management of women with AGC in the primary screening.

Analysis of the contribution of immunologically-detectable HER2, steroid receptors and of the "triple-negative" tumor status to disease-free and overall survival of women with epithelial ovarian cancer.

We assessed associations between steroid receptors including: estrogen-alpha, estrogen-beta, androgen receptor, progesterone receptor, the HER2 status and triple-negative epithelial ovarian cancer (ERα-/PR-/HER2-; TNEOC) status and survival in women with epithelial ovarian cancer. The study included 152 women with primary epithelial ovarian cancer. The status of steroid receptor and HER2 was determined by immunohistochemistry. Disease-free and overall survival were calculated and compared with steroid receptor and HER2 status as well as clinicopathological features using the Cox Proportional Hazards model. A mean follow-up period of 43.6 months (interquartile range=41.4 months) was achieved where 44% of patients had serous tumor, followed by mucinous (23%), endometrioid (9%), mixed (9%), undifferentiated (8.5%) and clear cell tumors (5.3%). ER-alpha staining was associated with grade II-III tumors. Progesterone receptor staining was positively associated with a Body Mass Index≥25. Androgen receptor positivity was higher in serous tumors. In stand-alone analysis of receptor contribution to survival, estrogen-alpha positivity was associated with greater disease-free survival. However, there was no significant association between steroid receptor expression, HER2 status, or TNEOC status, and overall survival. Although estrogen-alpha, androgen receptor, progesterone receptor and the HER2 status were associated with key clinical features of the women and pathological characteristics of the tumors, these associations were not implicated in survival. Interestingly, women with TNEOC seem to fare the same way as their counterparts with non-TNEOC.