Triple-negative Status Research Articles

RASEF expression correlates with hormone receptor status in breast cancer.

Breast cancer (BC) is the most frequently diagnosed malignant tumor in women worldwide, and the development of new molecules associated with BC is essential for the management of this disease. RAS and EF-hand domain-containing (RASEF) encodes the GTPase enzyme that belongs to the Rab family. Although the effects of this gene have been reported in several malignant tumor types, the role of RASEF in BC has not been completely elucidated. The aim of the present study was to investigate the importance of RASEF expression in BC. RASEF mRNA expression levels were evaluated in BC and non-cancerous mammary cell lines. The association between RASEF mRNA expression levels and clinicopathological factors in 167 patients with BC were then determined. Among the 13 examined BC cell lines, ER-negative/HER2-negative cell lines expressed lower RASEF mRNA levels, when compared with the other examined cell lines (P=0.014). Of the 167 patients examined, patients with negative hormone receptor status exhibited significantly lower RASEF mRNA expression levels (P<0.001). In addition low RASEF expression in BC tissues was associated with negative estrogen receptor status (P<0.001), negative progesterone receptor status (P<0.001), and triple-negative status (P<0.001). Additionally, although the differences were not statistically significant, patients with low RASEF expression levels exhibited poorer disease-free survival (P=0.123) and overall survival (P=0.086) than other patients. The results of the present study indicate that RASEF mRNA expression levels are associated with hormone receptor status in BC.

Prognostic significance of p16 & p53 immunohistochemical expression in triple negative breast cancer

Backgroundp16 and p53 genes are frequently mutated in triple negative breast cancer & prognostic value of these mutations have been shown; however, their role as immunohistochemical overexpression has not been fully validated. Therefore we aimed to evaluate the association of p16 and p53 overexpression in triple negative breast cancer with various prognostic parameters.MethodsTotal 150 cases of triple negative breast cancers were selected from records of pathology department archives that underwent surgeries at Liaquat National hospital, Karachi from January 2008 till December 2013. ER, PR and Her2neu immunohistochemistry were re-performed to confirm triple negative status. p16 & p53 immunohistochemistry was performed on all cases and association with various clinicopathologic parameters was determined.ResultsMean age of the patients involved in the study was 48.9 years. Most of the patients presented at stage T2 with a high mean ki67 index i.e. 46.9%. 42.7% of cases had nodal metastasis. Although 84% cases were of invasive ductal carcinoma; however a significant proportion of cases were of metaplastic histology (9.3%). Fifty-one percent (76 cases) of cases showed positive p53 expression while 49% (74 cases) were negative. Higher percentage of p53 expression was found to correlate with higher T stage, high ki67 index and higher nodal stage. On the other hand, strong intensity of p53 expression was positively correlated with higher tumor grade and ki67 index. Seventy-one percent (98 cases) of cases showed positive p16 expression, whereas 24.8% (34 cases) were negative and 3.6% (5 cases) showed focal positive p16 expression. However, no significant association was found between p16 expression and various clinical and pathologic parameters. Similarly, no significant association of either p16 or p53 over-expression was noted with recurrence status of patients.ConclusionOn the basis of significant association of p53 over-expression with worse prognostic factors in triple negative breast cancer, therefore we suggest that more large scale studies are needed to validate this finding in loco-regional population. Moreover, high expression of p16 in triple negative breast cancer suggests a potential role of this biomarker in triple negative breast cancer pathogenesis which should be investigated with molecular based research in our population.

Impact of breast cancer prognostic factors on the response to controlled ovarian stimulation patients undergoing fertility preservation

The objective is to know if breast cancer (BC) prognostic factors influence ovarian function and response to controlled ovarian stimulation (COS) in patients seeking fertility preservation (FP)? A total of 151 BC patients undergoing COS for FP were prospectively included between November 2013 and December 2016. COS was initiated regardless of the phase of the cycle, with or without letrozole supplementation. Matured oocytes and/or embryos obtained were vitrified. COS characteristics and outcomes were analyzed in all women BC prognostic factors considered in the present study were Scarff-Bloom-Richardson (SBR) SBRIII grade, Ki 67> 20%, HER2 overexpression and "triple negative” tumor. Univariate and multivariate analysis were performed to determine their impact on ovarian reserve markers (serum Anti-Müllerian Hormone (AMH) and antral follicle count (AFC)) as well as on ovarian response to exogenous FSH. Less than 8 mature oocytes vitrified, maturation rate under 70% or Follicle Output RaTe (FORT) under 35% were considered as poor COS outcomes A total of 154 COS cycles were performed and analyzed in BC patients 33.4±4.1 years of age were analyzed. Mean AMH and AFC were 3.2±4.5 ng/mL and 20.2±14.3 follicles, respectively. HER2 overexpression was observed in 18.9% and 34.7% of tumors expressed estrogen or progesterone receptors. Triple negative status characterized 25% of tumors. BRCA1/2 mutation was found in 22.4% of patients. A mean of 9.2 ± 7.4 mature oocytes were cryopreserved per cycle. After multivariate analysis, only serum AMH levels, AFC and smoking status were significantly associated with the number of mature oocytes obtained following COS. BC prognostic factors did not appear to have a significant influence on ovarian reserve markers, number of retrieved oocytes, maturity rate or on ovarian response to exogenous FSH assessed by FORT index, defined as the ratio of the number of pre-ovulatory follicle (16-22 mm) count on the triggering day X100 to the antral follicle (3-8 mm) count at baseline BC prognostic factors probably have no or low impact on ovarian function in terms of ovarian reserve and response to COS. Further analysis, in particular after oocyte thawing will be needed to clarify a possible impact egg quality.

Black race and distant recurrence after neoadjuvant or adjuvant chemotherapy in breast cancer.

Black race compared to white race is associated with more advanced stage and biologically aggressive breast cancer. Consequently, black patients are more frequently treated with neoadjuvant chemotherapy (NAC) than white patients. However, it is unclear how distant recurrence-free survival (DRFS) of black patients treated with NAC, compares to DRFS of black patients treated with adjuvant chemotherapy (AC). We evaluated the association between race, distant recurrence, and type of chemotherapy (AC or NAC) in localized or locally advanced breast cancer. We evaluated DRFS in 807 patients, including 473 black, 252 white, 56 Hispanic, and 26 women of other or mixed race. The association between AC or NAC and DRFS was examined using multivariate Cox proportional hazard models that included race, age, stage, estrogen receptor (ER) and triple negative (TN) status. When the black and white subjects were pooled for the analysis the features associated with worse DRFS included stage III disease and age < 50 years, but not ER-negative disease, TN disease, the use of NAC, or black race. However, in the analysis stratified by race NAC was associated with worse DRFS compared to AC in black (HR 2.70; 95% CI 1.73-4.22; p < 0.0001), but not in white women (HR 1.29, 95% CI 0.56-2.95; p = 0.36). Black patients treated with NAC had worse DRFS than black patients treated with AC, or white patients treated with either NAC or AC. These findings need to be validated in a large-scale observational study and the effect of NAC on the breast cancer microenvironment in black women needs to be further evaluated.

Association of Genetic Variants in NF-kB with Susceptibility to Breast Cancer: a Case Control Study.

Insofar as altered NF-κB signaling stemming from the presence of specific genetic variants in NF-κB gene contribute to cancer pathogenesis, this study evaluated the association between NF-κB rs147574894/I552V, rs148626207/M860T rs3774937 and rs1598859 variants and breast cancer and associated features and complications. This was a retrospective case-control study, which involved 207 women with breast cancer, and 214 cancer-free women who served as controls. NF-κB genotyping was done by real-time PCR. Significantly higher rs3774937 minor allele frequencies (MAF), and lower rs147574894 MAF were seen among breast cancer patients, thereby imparting disease susceptibility and protective nature to these variants, respectively. Significant association of rs3774937 and rs147574894 genotypes with breast cancer was seen under the dominant model. Histological type and grade, molecular type, Her2 positivity and ER+/Her2- correlated positively, while distant metastasis negatively correlated with rs3774937. On the other hand, rs147574894 negatively correlated with histological type and grade, tumor size, Her2 positivity, molecular type, and ER+/Her2-, while rs148626207 correlated positively with histological grade, but negatively with distant metastasis and triple-negative status. Breast cancer-susceptible and -protective 4-locus haplotypes were also identified. This is the first report that addresses the contribution of NF-κB variants to the pathogenesis of breast cancer in Middle Eastern-North African population, and the first to document positive association of rs3774937 with breast cancer.

PO-321 Causes and consequences of WDHD1 overexpression in breast cancer

IntroductionWDHD1 (WD repeat and HMG-box DNA binding protein 1) controls DNA replication, sister-chromatid cohesion and centromere integrity. These phenomena are often defective in breast cancer cells. This could lead to mutations, chromosomal aberrations and aneuploidy, which could promote breast cancer development and therapy resistance. This prompted us to investigate WDHD1 misexpression and its consequences in breast cancer.Material and methodsWe performed systematic genomic, transcriptomic and proteomic analyses of WDHD1 expression in breast cancer using publicly available datasets, cell lines, primary cells and immunohistochemistry (IHC) on 547 invasive breast carcinomas with survival data up to 35 years post-diagnosis (Queensland Follow-Up resource). Functional studies included computational approaches, chromatin immunoprecipitations (ChIP), shRNA-mediated knockdown, various in vitro assays and in vivo xenograft modelling.Results and discussionsWe find that WDHD1 mRNA and protein levels are significantly elevated in breast cancer. IHC identified WDHD1 as a novel prognostic marker. WDHD1 protein expression correlates strongly with grade, ER status, HER2 status, triple-negative status, lymphovascular invasion, lymphocytic infiltrate, central scarring or fibrosis, tumour border, Ki-67 expression and prognostic sub-groups. Somatic copy number gains contribute to WDHD1 overexpression, but more importantly, we establish that WDHD1 is an E2F target gene. Hence, defective RB pathway regulation directly promotes WDHD1 overexpression. Knockdown of WDHD1 decreases cell viability and proliferation, but it does not promote apoptosis. It increases genomic instability in vitro and reduces tumour growth in xenograft experiments.ConclusionWe identify WDHD1 mRNA and protein overexpression as novel markers for poor breast cancer prognosis. WDHD1 overexpression is primarily caused by RB pathway defects, which are common in breast tumours. In vitro and in vivo experiments suggest that overexpression of WDHD1 may represent a novel breast cancer therapeutic target.

Abstract A92: Black race is associated with worse distant relapse-free survival in breast cancer patients treated with neoadjuvant compared to adjuvant systemic chemotherapy

Abstract Background: Compared to white women, black women with operable breast cancer treated with primary surgical therapy and adjuvant or neoadjuvant systemic chemotherapy have higher recurrence rates and breast cancer mortality. Large randomized prospective studies did not find significant differences in distant-recurrence-free survival (DRFS) and overall survival (OS) between breast cancer patients treated in the adjuvant and neoadjuvant setting for predominantly white populations. However, data indicating that neoadjuvant treatment is equivalent to adjuvant treatment for black breast cancer patients are missing. Here, we first examined racial differences in DRFS among breast cancer patients treated in the neoadjuvant setting at Einstein-Montefiore Center for Cancer Care (EMCCC) in the Bronx, and then investigated if DRFS in black patients treated in the neoadjuvant setting is comparable to DRFS in the adjuvant setting. Methods: We evaluated DRFS in 241 racially diverse patients with localized or regionally advanced breast cancer treated with neoadjuvant chemotherapy between January 2000 and December 2016. In addition, we evaluated DRFS in 474 white and 701 black patients with localized or regionally advanced breast cancer treated with systemic adjuvant (N=432 [whites], 596 [blacks]) or neoadjuvant (N=42 [whites], 105 [blacks]) chemotherapy. Using multivariate Cox proportional hazard models, we generated hazard ratios (HRs) (95% confidence intervals [CI]) for risk of distant recurrence, with adjustment for age (&amp;lt;50 vs &amp;gt;/50 years), stage (I/II vs III), estrogen receptor (ER) status (+ vs -), HER2/neu overexpression (+ vs -/equivocal/unknown), triple-negative (TN) status (yes vs no), and type of systemic chemotherapy (adjuvant vs neoadjuvant). Results: Black patients treated with neoadjuvant systemic chemotherapy had significantly worse DRFS than white patients (HR=2.29; 95%CI=1.02-5.15, p=0.04). DRFS in non-black Hispanics and patients from racial backgrounds other than Hispanic or black compared to whites was not statistically different. Neoadjuvant chemotherapy was associated with worse DRFS compared to adjuvant chemotherapy in black (HR=3.72; 95%CI=4.03-5.81; p=&amp;lt;0.0001), but not in white women. Conclusion: Black patients with localized breast cancer treated with systemic neoadjuvant chemotherapy not only have inferior DRFS compared to white patients, but also worse DRFS when compared to black patients treated with adjuvant chemotherapy, after adjustment for clinical covariates. This observation needs to be confirmed in further prospective studies, and biologic factors contributing to this finding need to be evaluated. Citation Format: Jessica M. Pastoriza, George S. Karagiannis, Xiaonan Xue, Juan Lin, John S. Condeelis, Joseph A. Sparano, Thomas E. Rohan, Maja H. Oktay. Black race is associated with worse distant relapse-free survival in breast cancer patients treated with neoadjuvant compared to adjuvant systemic chemotherapy [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A92.

PO-192 The EMT factor zeb1 promotes adenoma formation through the inhibition of cell senescence and apoptosis

IntroductionThe major histocompatibility complex (MHC) class II invariant chain (CD74) is a protein which functions as a chaperone for MHC class II in antigen-presenting cells. Furthermore, it acts as a receptor for the cytokine macrophage migration inhibitory factor (MIF), mediating downstream signalling. Many clinical studies have determined that CD74 is overexpressed at the protein level in a subset of human breast tumours. However, there are discrepant findings regarding its correlation to clinical parameters. In some reports, CD74 has been correlated to triple-negative (TN) status and increased presence of metastases, but in separate studies it correlated with better overall survival. In vitro studies of CD74’s molecular functions in cancer cells have generally supported that it has a cancer-promoting effect through stimulating proliferation, survival and invasion.Material and methodsHuman breast cancer cell lines MDA-MB-231 and M4A4 were transfected with siRNA targeting CD74 or a negative control. Cells were then subjected to in vitro analysis of proliferation or invasion through matrigel. Lysates of transfected cells were analysed by immunoblot for protein levels of cell survival and autophagy markers.A tumour microarray (TMA) containing 651 human breast tumour cores was stained by immunohistochemistry (IHC) for CD74 protein expression. Staining intensity was manually scored for each sample in a blinded fashion. Statistical analysis was performed in R.Results and discussionssiRNA knockdown of CD74 in MDA-MB-231 and M4A4 resulted in reduced proliferation and invasion. Furthermore, survival signalling through Akt was decreased. These findings replicate previously published in vitro studies of CD74’s functions in cancer cells. Furthermore, a novel finding was that CD74 knockdown resulted in reduced levels of markers of autophagy.The correlations between CD74 IHC staining of TMA samples and TN status, lymph node status and overall survival were examined. In contrast to previous studies we observed no correlation between expression of CD74 and TN status or cancer spread to the lymph nodes. Instead, survival analysis revealed increased overall survival for cancers with moderate or high CD74 intensity.ConclusionOur results from cell lines support that CD74, when studied in vitro, has functions that stimulate cancer cells to proliferate and invade. However, results from clinical samples show a correlation of CD74 expression with increased survival.

Clinicopathological correlation of PD-L1 expression in primary and metastatic breast cancer and infiltrating immune cells

Few studies have evaluated the expression of the programmed cell death-1 and its ligand-1 (PD-L1) in breast cancer. In this study, we correlated differential expression of PD-L1 in breast cancer (BC) and its microenvironment from a cohort of patients with BC, paired locally metastatic disease to regional lymph nodes (LNs) and nonpaired distantly metastatic disease (mets). PD-L1 expression was correlated with several pathologic and clinical parameters in tumor and tumor immune cells (ICs; CD3, CD4, CD8, CD20, and CD68) using the Ventana antibody (SP263) in 41 BCs, 46 paired mets in LNs, and 46 distant mets. There was 100% agreement for PD-L1 expression on tumor and ICs between BC and matched LN. PD-L1 is differentially expressed in primary BC and regional nodal disease. Expression correlated with higher grade, hormone receptor negativity, and highly proliferative tumors (P < .001). In LNs, the high positivity rate was driven by triple-negative status (70% versus 5%; P < .0001). In contrast, there was significantly near-total absence of PD-L1 expression in distant mets compared with BC and LNs (2%-4% in mets versus 17%-20% in BC and LN, P = .009). IC density varied in BC and metastatic tumors with predominance of CD3 and CD68 and near total absence of CD20 cells. PD-L1 expression was mainly associated with CD68 cells. There were consistent higher numbers of CD3 (CD8 > CD4) than CD20 cells in primary and metastatic tumors. Correlation of PD-L1 expression in BC and its microenvironment may be useful for the development of new treatment strategies.

PO-186 In vitro and clinical studies of the role of MHC class II invariant chain (CD74) in breast cancer

Introduction The major histocompatibility complex (MHC) class II invariant chain (CD74) is a protein which functions as a chaperone for MHC class II in antigen-presenting cells. Furthermore, it acts as a receptor for the cytokine macrophage migration inhibitory factor (MIF), mediating downstream signalling. Many clinical studies have determined that CD74 is overexpressed at the protein level in a subset of human breast tumours. However, there are discrepant findings regarding its correlation to clinical parameters. In some reports, CD74 has been correlated to triple-negative (TN) status and increased presence of metastases, but in separate studies it correlated with better overall survival. In vitro studies of CD74’s molecular functions in cancer cells have generally supported that it has a cancer-promoting effect through stimulating proliferation, survival and invasion. Material and methods Human breast cancer cell lines MDA-MB-231 and M4A4 were transfected with siRNA targeting CD74 or a negative control. Cells were then subjected to in vitro analysis of proliferation or invasion through matrigel. Lysates of transfected cells were analysed by immunoblot for protein levels of cell survival and autophagy markers. A tumour microarray (TMA) containing 651 human breast tumour cores was stained by immunohistochemistry (IHC) for CD74 protein expression. Staining intensity was manually scored for each sample in a blinded fashion. Statistical analysis was performed in R. Results and discussions siRNA knockdown of CD74 in MDA-MB-231 and M4A4 resulted in reduced proliferation and invasion. Furthermore, survival signalling through Akt was decreased. These findings replicate previously published in vitro studies of CD74’s functions in cancer cells. Furthermore, a novel finding was that CD74 knockdown resulted in reduced levels of markers of autophagy. The correlations between CD74 IHC staining of TMA samples and TN status, lymph node status and overall survival were examined. In contrast to previous studies we observed no correlation between expression of CD74 and TN status or cancer spread to the lymph nodes. Instead, survival analysis revealed increased overall survival for cancers with moderate or high CD74 intensity. Conclusion Our results from cell lines support that CD74, when studied in vitro, has functions that stimulate cancer cells to proliferate and invade. However, results from clinical samples show a correlation of CD74 expression with increased survival.

Frequency of Rearrangements Versus Small Indels Mutations in BRCA1 and BRCA2 Genes in Turkish Patients with High Risk Breast and Ovarian Cancer.

The current rearrangement ratio of BRCA1 and BRCA2 genes is not known in the Turkish population. Rearrangements are not routinely investigated in many Turkish laboratories. This creates problems and contradictions between clinics. Therefore, the aim of this study was to evaluate the distribution and frequency of rearrangements in BRCA1 and BRCA2 genes in high-risk families and to clarify the limits of BRCA1 and BRCA2 testing in Turkey. The study included 1809 patients at high risk of breast cancer or ovarian cancer. All patients were investigated for both small indels and rearrangements of BRCA genes using DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis. The overall frequency of rearrangements was 2% (25/1262). The frequency of rearrangements was 1.7% (18/1086) and 4% (9/206) in patients with breast cancer and ovarian cancer, respectively. The frequency of rearrangements was 3.7% (8/215) in patients with triple-negative breast cancer. The rearrangement rate was 7.7% (2/26) in patients with both breast and ovarian cancer. Rearrangements were found with high rates and were strongly associated with bilateral and triple-negative status of patients with breast cancer, which are signs of high risk for breast and ovarian cancer. Analysis of rearrangements should definitely be included in routine clinical practice in Turkey for high-risk families and also for improved cancer risk prediction for families.

Outcome of Patients With Breast Cancer Treated in a Private Health Care Institution in Brazil.

PurposeMiddle-income countries like Brazil often have a dichotomous health care system in which patients may be treated in either public or private institutions that differ substantially in terms of level of access to diagnostic and therapeutic procedures.Patients and MethodsThis was a prospective, observational study to assess real-world data in 1,230 female patients with breast cancer who were treated in a private health care institution between 2012 and 2016 in Brazil.ResultsBreast cancer in these patients mostly was diagnosed at early (79.0% stages I or II) or locally advanced (16.1% stage III) stages. The primary tumor was resected in 89.0% of cases, most often through breast-conserving surgery (55.1%). Patients with locally advanced disease received more aggressive therapy (eg, higher rates of mastectomy, axillary dissection and chemotherapy use) than patients with early-stage disease. The estimated 2-year overall survival (OS) was 95.3%. Survival was significantly longer among patients with stage I or II disease (2-year OS, 97.9% and 97.5%, respectively) than those with stage III or IV disease (89.4% and 69.5%, respectively; P < .01). Tumor grade was also correlated with OS in the overall cohort (P = .05); triple-negative status was only prognostic for patients with stage III disease (P < .01).ConclusionThe data provided aid understanding of the current scenario of breast cancer presentation and treatment in the Brazilian private health care system and may serve as a foundation to guide resource allocation. Our results reinforce the need to pursue adequate access to cancer care in low- and middle-income countries to optimize patient outcome.

Does a Comprehensive Multidisciplinary Care Program Impact Utilization of Genetics in Breast Cancer Management? [11L

INTRODUCTION: To evaluate the utilization of genetic testing after the implementation of a comprehensive multidisciplinary breast cancer care (cMDC) program: ALL breast cancer cases undergo a mandated, standardized/structured review of treatment options and ongoing care (including clinical trial opportunities). METHODS: A retrospective chart review of 542 patients newly diagnosed with invasive breast cancer one year prior to and after the incorporation of a cMDC program was performed for primary outcome: rate of overall appropriate genetic referrals as defined by age, family history, triple negative status, and personal history. Secondary outcomes: compliance and equity in genetic referrals across demographics (race, insurance type and hospital site). SPSS was used for multivariate analysis, (P&lt;.05). RESULTS: There were 123 pre-cMDC and 419 cMDC patients. A positive pathologic genetic mutation was seen in 2.2% of patients. Comparison of pre-cMDC and cMDC patients yielded a significant increase in appropriate genetic referrals (34.1%–41.8%), a decrease in withholding genetic referral when indicated (59.3%–21.7%) and an increase in inappropriate referrals (1.9%–11.7%) respectively (P=.001). Amongst both study arms Caucasians were more compliant genetic appointment compared to their African American counterparts (pre-cMDC P=.011, cMDC P=.016). African Americans in the cMDC group demonstrated an 11% increase in attendance compared to a 1% decrease noted among Caucasians in the cMDC group. Genetic referrals were equally offered appropriately before and after the implementation of the MDC across race, insurance type and location. CONCLUSION: Utilizing a cMDC approach to breast cancer care may help increase appropriate utilization of genetics, reach more African-Americans and identify those with pathologic mutations.

Inducing or Preventing Subsequent Malignancies for Breast Cancer Survivors? Double-edged Sword of Estrogen Receptor and Progesterone Receptor

IntroductionHormone receptor and human epidermal growth factor receptor 2 (HER2) status is important for breast cancer (BC) treatment. Previous studies have shown that the long-term treatment outcomes of BC are significantly impaired by the development of subsequent malignancies. Therefore, in the present study, we evaluated the effect of hormone receptor/HER2 status on subsequent malignancies in breast cancer survivors. Methods and MaterialsThe Surveillance, Epidemiology, and End Results*Stat database (8.3.4) was used as the data source. We identified 535,941 female survivors with first primary BC through the database from 1973 to 2013. Of these patients, 23,964 had developed subsequent contralateral BC, 8398 had developed subsequent uterine or ovarian cancer, and 7435 patients had developed subsequent colorectal cancer. ResultsEstrogen receptor (ER) positivity and progesterone receptor (PR) positivity were significant protective factors against subsequent BC and ovarian cancer. However, ER+ BC and PR+ BC were significant risk factors for subsequent colorectal cancer. In addition, HER2+ status demonstrated a marginally significant risk effect for subsequent thyroid cancer. Triple-negative (ER−/PR−/HER2−) status showed elevated risk of subsequent breast, ovarian, and uterine cancer. ConclusionER+/PR+ patients were less likely develop secondary breast and ovarian malignancies, possibly owing to advancements in anti-ER/PR treatment. However, ER+/PR+ patients were more likely to develop colorectal cancer, suggesting a potential screening necessity for these patients.

Radiogenomics analysis identifies correlations of digital mammography with clinical molecular signatures in breast cancer.

In breast cancer, well-known gene expression subtypes have been related to a specific clinical outcome. However, their impact on the breast tissue phenotype has been poorly studied. Here, we investigate the association of imaging data of tumors to gene expression signatures from 71 patients with breast cancer that underwent pre-treatment digital mammograms and tumor biopsies. From digital mammograms, a semi-automated radiogenomics analysis generated 1,078 features describing the shape, signal distribution, and texture of tumors along their contralateral image used as control. From tumor biopsy, we estimated the OncotypeDX and PAM50 recurrence scores using gene expression microarrays. Then, we used multivariate analysis under stringent cross-validation to train models predicting recurrence scores. Few univariate features reached Spearman correlation coefficients above 0.4. Nevertheless, multivariate analysis yielded significantly correlated models for both signatures (correlation of OncotypeDX = 0.49 ± 0.07 and PAM50 = 0.32 ± 0.10 in stringent cross-validation and OncotypeDX = 0.83 and PAM50 = 0.78 for a unique model). Equivalent models trained from the unaffected contralateral breast were not correlated suggesting that the image signatures were tumor-specific and that overfitting was not a considerable issue. We also noted that models were improved by combining clinical information (triple negative status and progesterone receptor). The models used mostly wavelets and fractal features suggesting their importance to capture tumor information. Our results suggest that molecular-based recurrence risk and breast cancer subtypes have observable radiographic phenotypes. To our knowledge, this is the first study associating mammographic information to gene expression recurrence signatures.

Chemotherapy Dose Intensity and Overall Survival Among Patients With Advanced Breast or Ovarian Cancer

BackgroundThe effects of chemotherapy dose intensity on patient outcomes in advanced cancer are not well understood. We studied the association between chemotherapy relative dose intensity (RDI) and overall survival (OS) among patients with advanced breast or ovarian cancer. Patients and MethodsThis retrospective cohort study included adults with advanced breast or ovarian cancer who received first-line myelosuppressive chemotherapy (January 2007 to December 2010) in US Oncology Network community practices. Dose delays ≥ 7 days, dose reductions ≥ 15%, and RDI relative to standard regimens were described. OS was measured by the Kaplan-Meier method and Cox proportional hazards models. ResultsAmong 874 patients with advanced breast cancer, 33.2% experienced dose delays ≥ 7 days, 48.7% experienced dose reductions ≥ 15%, and 38.9% had RDI < 85%. In the multivariable Cox proportional hazards model, Eastern Cooperative Oncology Group performance status 1/2 versus 0 (hazard ratio [HR] = 1.45; 95% confidence interval [CI], 1.15-1.82) and triple-negative status (HR = 3.14; 95% CI, 1.15-8.62) were significantly associated with mortality. Among 170 patients with advanced ovarian cancer, 43.5% experienced dose delays ≥ 7 days, 48.2% experienced dose reductions ≥ 15%, and 46.5% had RDI < 85%. In the multivariable Cox proportional hazards model, dose reductions ≥ 15% (HR = 1.94; 95% CI, 1.09-3.46) and other tumor histology (vs. nonserous adenocarcinoma; HR = 3.55; 95% CI, 1.38-9.09) were significantly associated with mortality. ConclusionDose delays, dose reductions, and reduced RDI were common. In advanced breast cancer, health status and triple-negative disease were significantly associated with mortality. In advanced ovarian cancer, dose reductions and tumor histology were significantly associated with mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality.

Abstract P6-08-05: United States real-world drug utilization patterns and associated overall survival in Medicare patients with newly-diagnosed metastatic triple negative breast cancer using surveillance, epidemiology, and end results-Medicare data

Abstract Background: Limited information is available about treatment patterns for elderly patients (pts) with metastatic triple negative breast cancer (mTNBC). This analysis characterized real-world drug utilization patterns and associated overall survival (OS) for Medicare mTNBC pts. Methods: Pts ≥66 years of age who were newly diagnosed with mTNBC between 2004 and 2011 were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Triple negative status was obtained from the SEER registry, except for HER2 that was unavailable from 2004-2009 during which we assumed that pts who had a claim for a HER2 test followed by absence of hormonal therapy to be presumed HER2 negative. Pts were followed from diagnosis to death, Medicare disenrollment, HMO enrollment, or 12/31/2013 (whichever occurred first) to characterize the sequence of chemotherapy received – first regimen (1R), second regimen (2R), and third regimen (3R) and median (interquartile, IQR) duration of and between regimens. OS estimates were reported using the Kaplan-Meier method. Results: Among 694 mTNBC pts, 69 died within 30 days of diagnosis and were excluded. In the remaining 625 pts observed from 2004 through 2013 (median age: 75 years; Charlson comorbidity index (CCI) ≥2: 21%; and median follow-up: 11.4 months), 317 (51%) received chemotherapy. Of the 317 pts, 161 got only 1R, 88 got only 2R, and 68 got 3R+. Compared to pts on 1R, pts on 2R were significantly younger (median age: 2R, 72; 1R, 75 years), married (2R, 40%; 1R, 30%), had fewer comorbidities (CCI≥2: 2R, 16%; 1R, 23%). The top 2 most commonly prescribed single agents in 1R, 2R, and 3R were: 1R, paclitaxel followed by capecitabine; 2R, capecitabine followed by paclitaxel; 3R, gemcitabine followed by capecitabine. The most common combination regimen given was taxane-based in 1R (57%) and 2R (70%). Drug utilization patterns First Regimen (n=317)Second Regimen (n=156)Third Regimen (n=68)Single Agent205 (65%)74 (47%)40 (59%)Microtubule inhibitors80 (39%)23 (31%)NRPaclitaxel72 (35%)18 (24%)NRAnthracyclines29 (14%)13 (18%)NRDoxorubicin27 (13%)13 (18%)NRAntimetabolites/Others96 (47%)38 (51%)27 (73%)Capecitabine51 (25%)20 (27%)NRGemcitabineNRNR13 (35%)OthersNRNRNRCombination Regimens112 (35%)82 (53%)28 (41%)Taxane-based64 (57%)57 (70%)NRNR, not reported per DUA with NCI. %, col. % relative to single/comb. category Median (IQR) durations of 1R, 2R, and 3R were 2.7 (1.4-4.4), 3.1 (1.6-5.0), and 2.3 (0.9-4.5) months, respectively. Median time from diagnosis to start of 1R was 1.6 (0.9-2.8) months. Median time to start of 2R and 3R after the end of the previous regimen was 4.6 (2.1-8.1), and 6.2 (3.3-11.0) months, respectively. The median (12-month) OS was 7 months (34%) for all pts and ranged from 3.5 (17%) in the untreated to 25.3 (88%) months in 3R+ pts. Conclusions: About half of Medicare mTNBC pts do not receive chemotherapy in the real world. Paclitaxel and capecitabine were the most commonly used single agents and taxane-based combination therapy was the most commonly used combination. Citation Format: Aly A, Shah R, Hill K, Waldeck AR, Botteman M. United States real-world drug utilization patterns and associated overall survival in Medicare patients with newly-diagnosed metastatic triple negative breast cancer using surveillance, epidemiology, and end results-Medicare data [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-08-05.

Abstract P2-10-02: Basal biomarkers nestin and INPP4b predict gemcitabine benefit in metastatic breast cancer: Results from the phase III SBG0102 clinical trial

Abstract Background: A growing body of evidence is suggesting that basal-like and triple negative breast cancers may be particularly sensitive to nucleoside analogues (gemcitabine, capecitabine). In a prospective-retrospective analysis of the phase III SBG0102 clinical trial randomizing metastatic breast cancer patients to gemcitabine plus docetaxel (GD) or to higher-dose single agent docetaxel (D), patients with basal-like breast cancer by PAM50 gene expression had significantly better overall survival (OS) in the gemcitabine arm. By immunohistochemistry (IHC), triple negative status was not predictive, but is a poor surrogate for the basal-like intrinsic subtype. More accurate IHC biomarkers have since become available defining basal-like breast cancers by nestin positivity or by loss of inositol polyphosphate-4-phosphate (INPP4b). Methods: Formalin-fixed paraffin embedded blocks of primary tumor tissue corresponding to 270 of the 337 patients participated in the SBG0102 trial were used to build tissue microarrays. IHC staining and interpretation for nestin and INPP4b by pathologists (who had no access to clinical data) followed published methods. A prespecified statistical plan was executed independently by Danish Breast Cancer Group statisticians, testing the primary hypothesis that patients with basal breast cancer – defined as positive for nestin or negative for INPP4b, regardless of ER/PR/HER2 status – would have superior OS on the GD treatment arm when compared to the D treatment arm by interaction test. Secondary outcomes included time to tumor progression (TTP) and response rate. Kaplan-Meier method with log-rank test of nestin and INPP4b status was used to measure OS and TTP. Forest plots were used to visualize predictive capacities relative to IHC markers and treatment effects. Results: Two hundred fifty two cases were evaluable for this study, among which 38 (15%) had been classified as basal-like, 45 (18%) as HER2-Enriched, 74 (29%) as luminal A and 91 (36%) as luminal B by PAM50. Among 241 cases being evaluable for both IHC nestin and INPP4b markers, positive staining of nestin or loss of INPP4b was observed in 43 (17%) of the total cases and was significantly associated with PAM50 basal-like subtype (p&amp;lt;0.0001). Within a median follow up of 13 years, patients assigned as IHC-basal by virtue of being “nestin+ or INPP4b-” demonstrated a significantly lower OS when compared to non-basal cases defined as “nestin- and INPP4b+” (HR=2.45, 95% CI: 1.47-4.07) (p=0.0006). The IHC-basal patients did much better on the GD vs. the D arm (HR=0.36, 95% CI: 0.19-0.68) whereas there was no such difference in outcomes for other patients (HR=0.99). The interaction test was significant (p-interaction&amp;lt;0.005). Conclusions: The nestin/INPP4b IHC panel offers a practical and inexpensive technology to identify basal-like patients. In the metastatic setting, women with IHC-basal breast cancers defined using these markers have superior overall survival when randomized to gemcitabine-containing chemotherapy compared to docetaxel alone. Citation Format: Asleh-Aburaya K, Lyck Carstensen S, Burugu S, Gao D, Tykjær Jørgensen CL, Won JR, Jensen M-B, Balslev E, Lænkholm A-V, Nielsen DL, Ejlertsen B, Nielsen TO. Basal biomarkers nestin and INPP4b predict gemcitabine benefit in metastatic breast cancer: Results from the phase III SBG0102 clinical trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-10-02.

Abstract P6-10-02: Black race is associated with worse distant relapse-free survival in breast cancer patients treated with neoadjuvant compared to adjuvant systemic chemotherapy

Abstract Background: Compared to white women, black women with operable breast cancer treated with primary surgical therapy and adjuvant or neoadjuvant systemic chemotherapy have higher recurrence rates and breast cancer mortality. Large randomized prospective studies did not find significant differences in distant-recurrence free survival (DRFS) and overall survival (OS) between breast cancer patients treated in the adjuvant and neoadjuvant setting for predominantly white populations. However, data indicating that neoadjuvant treatment is equivalent to adjuvant treatment for black breast cancer patients are missing. Here, we first examined racial differences in DRFS among breast cancer patients treated in the neoadjuvant setting at Einstein-Montefiore Center for Cancer Care (EMCCC) in the Bronx, and then investigated if DRFS in black patients treated in the neoadjuvant setting is comparable to DRFS in the adjuvant setting. Methods: We evaluated DRFS in 241 racially diverse patients with localized or regionally advanced breast cancer treated with neoadjuvant chemotherapy between January 2000 and December 2016. In addition, we evaluated DRFS in 474 white and 701 black patients with localized or regionally advanced breast cancer treated with systemic adjuvant (432 whites, 596 blacks) or neoadjuvant (42 whites, 105 blacks) chemotherapy. Using multivariate Cox proportional hazard models, we generated hazard ratios (HR) and 95% confidence intervals (95%CI) for risk of distant recurrence, with adjustment for age (&amp;lt;50 vs &amp;gt;/50 years), stage (I/II vs III), estrogen receptor (ER) status (+ vs -), HER2/neu overexpression (+ vs. -/equivocal/unknown), triple negative (TN) status (yes vs no), and type of systemic chemotherapy (adjuvant vs. neoadjuvant). Results: Black patients treated with neoadjuvant systemic chemotherapy had significantly worse DRFS than white patients (HR=2.29; 95%CI=1.02-5.15, p=0.04). DRFS in non-black Hispanics and patients from racial backgrounds other than Hispanic or black compared to whites was not statistically different. Neoadjuvant chemotherapy was associated with worse DRFS compared to adjuvant chemotherapy in black (HR=3.72; 95%CI=4.03-5.81; p=&amp;lt;0.0001), but not in white women. Conclusion: Black patients with localized breast cancer treated with systemic neoadjuvant chemotherapy not only have inferior DRFS compared to white patients, but also worse DRFS when compared to black patients treated with adjuvant chemotherapy, after adjustment for clinical and pathological covariates. This observation needs to be confirmed in further prospective studies and biologic factors contributing to this finding need to be evaluated. Citation Format: Pastoriza JM, Karagiannis GS, Xue X, Lin J, Condeelis JS, Sparanno JA, Rohan TE, Oktay MH. Black race is associated with worse distant relapse-free survival in breast cancer patients treated with neoadjuvant compared to adjuvant systemic chemotherapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-10-02.

Abstract P1-15-03: Management and outcomes of metaplastic breast cancer

Abstract Purpose/Objectives: Metaplastic breast cancer (MBC) is a rare malignancy composed of both epithelial and mesenchymal components that accounts for less than 1% of primary breast carcinomas. Knowledge of effective management of the disease remains limited. We retrospectively evaluated the treatment and outcomes of patients with MBC from three academic hospitals. Materials/Methods: Patients diagnosed with MBC between June 2, 1993 and May 6, 2016 were identified. Demographic and clinical variables were extracted via primary chart review. Descriptive statistics were utilized to summarize the patient cohort's clinical course. The Kaplan-Meier method was used to obtain estimates of local control (LC) and survival. Results: Seventy-six patients were identified with a median follow-up of 7.6 years (range: 0.18-19.9 years). The median age at diagnosis was 54 (range 28-81). About two-thirds of patients (67%, n=51) presented with a palpable mass while the remaining patients were screen-detected via mammogram (32%, n=24). The majority of patients were AJCC-7 stage I (38%, n=29) or stage II (49%, n=37), while 10% (n=8) were stage III and 3% (n= 2) stage IV. About half of tumors (46%, n=35) were subtyped using WHO histologic classification of MBC. Over half of subtyped cases were spindle cell carcinoma (51%, n=18), 17% were matrix-producing carcinoma (n=6), 23% were adenocarcinoma with squamous differentiation (n=8), 6% were carcinosarcoma (n=2), and 3% were mixed (n=1).The majority of patients had triple negative disease (82%, n=62), while 13% (n=10) had HR+/HER2- disease, and 5% (n=4) had HER2+ disease. Most patients had high grade tumors (84%, n=64) and received breast conserving surgery (61%, n=46) while 39% (n=29) had mastectomies. Seventy-six percent (n=58) of patients received chemotherapy and 61% (n=46) received radiation therapy. All HR+ patients received adjuvant endocrine therapy, and 1 patient received immunotherapy. Of patients who received chemotherapy, 78% (n=45) received adjuvant therapy alone, 17% (n=10) neoadjuvant therapy alone, and 5% (n=3) both. Seventy percent (n=41) of chemotherapy regimens included a taxane. Among 74 patients without metastatic disease at presentation, recurrences were observed in 18% (n=13). Most patients recurred distantly (69%, n=9), while the remainder had isolated local recurrences (n=4). Of 9 distant failures, 3 had MBC subtype information and all 3 were spindle cell carcinoma. Of 4 local recurrences, 3 of 4 were adenocarcinoma with squamous cell differentiation and 1 was spindle cell carcinoma. At a median follow-up of 7.6 years, the local recurrence-free survival was 88%, disease-free survival was 80%, and overall survival was 80%. Kaplan-Meier point estimates for remaining free of local recurrence versus distant recurrence were 99% (95% C.I., 90- 100) versus 96% (95% C.I., 87- 99) at 2 years and 88% (95% C.I., 76-94) versus 87% (95% C.I., 75- 93) at 5 years. Conclusions: MBC is a rare histologic subtype that commonly presents with high-grade disease and triple-negative receptor status. In contrast to other smaller series, local and distant failure rates in this cohort were consistent with non-MBC triple negative cohorts. Additional molecular based research is warranted to further characterize features associated with local and distant failure. Citation Format: Thomas H, Horick N, Spring LM, Brachtel EF, Jimenez RB. Management and outcomes of metaplastic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-15-03.