Targetable alterations in invasive pleomorphic lobular carcinoma of the breast.

BACKGROUND: Invasive pleomorphic lobular carcinoma (PLC) of the breast is a subtype of invasive lobular cancer which compromises approximately 1% of all epithelial breast malignancies and is characterized by higher nuclear pleomorphism and poorer prognosis than classic invasive lobular cancer (ILC). Since PLC is more aggressive than classical ILC, we examined the underlying molecular alterations in this subtype of breast cancer to understand the possible benefit from targeted therapies. METHODS: In this study, we investigate the clinical characteristics and molecular alterations in 16 PLC from our institution. Additionally, we examined the clinical and genomic features in 31 PLC from the Cancer Genome Atlas (TCGA). RESULTS: Overall, our analysis of PLC found that 28% had activating ERBB2 mutations, 21% had ERBB2 amplification, and 49% activating PIK3CA mutations. Among cases from our institution, we found 19% with activating ERBB2 mutations, 25% had ERBB2 amplification, and 38% with activating PIK3CA mutations. In data from TCGA, 32% had activating ERBB2 mutations, 19% had ERBB2 amplification, and 55% had activating PIK3CA mutations. While classic ILC in TCGA had similar percentages of PIK3CA alterations compared to PLC, activating ERBB2 alterations were exceedingly rare, with no activating ERBB2 mutations and only one case with ERBB2 amplification. Interestingly, in further examining TCGA data which included FGFR1 and PTEN, 94% of PLC had alterations in ERBB2, FGFR1, or the PI3K pathway. CONCLUSIONS: Our results show a high frequency of ERBB2 and PIK3CA alterations in PLC and suggest all PLC should be tested for potential therapeutic targeting.

Systemic therapy, survival and end-of-life costs for metastatic triple-negative breast cancer: retrospective SEER-Medicare study of women age ≥65 years.

Aim: To analyze therapy for metastatic triple-negative breast cancer (mTNBC), factors contributing to survival and costs. Patients & methods: Using 2010-2016 SEER-Medicare data, we identified women (≥65 years) with mTNBC. Results: Of 302 eligible patients, 152 (50%) received systemic therapy. In multivariable regression analyses, only age <75 years was associated with therapy receipt (odds ratio: 2.91; 95% CI: 1.79-4.74); and only systemic therapy significantly reduced risk of death (hazard ratio: 0.34; 95% CI: 0.26-0.44). Median overall survival was 13.4 (95% CI: 11.3-15.1) vs 3.3 months (95% CI: 2.7-3.9) in therapy vs no-therapy cohorts. Mean per-patient-per-month costs <30 days before end-of-life/follow-up were $14,100 and $15,600 (2019 USD), respectively. Conclusion: Poor outcomes and high costs indicate need for more effective mTNBC therapy.

Early triple-negative breast cancer in women aged ≥65: retrospective study of outcomes, resource use and costs, 2010-2016.

Aim: To examine real-world treatment patterns and outcomes in neoadjuvant and adjuvant settings for early-stage triple-negative breast cancer (TNBC). Patients & methods: Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified patients (≥65 years) with newly diagnosed stage II/III TNBC in 2010-2015 who had surgery plus neoadjuvant and/or adjuvant (systemic and/or radiation) therapy. Treatment, survival, healthcare resource use and costs were assessed through 2016. Results: Of 1569 patients (>99% women), 6%/74%/20% received neoadjuvant-only/adjuvant-only/both (neo + adj) therapies, respectively. Median overall survival was 23 months/not reached (NR)/78 months, with longer survival at stage II (NR/NR/78 months) than stage III (22/43/38 months). Mean per patient per month costs were $10,620 and $17,872 in neoadjuvant and adjuvant periods. Conclusion: These findings provide insights into clinical and economic outcomes for early-stage TNBC in 2010-2016.

DTIE, a novel core promoter element that directs start site selection in TATA-less genes.

The transcription start site (TSS) determines the length and composition of the 5' UTR and therefore can have a profound effect on translation. Yet, little is known about the mechanism underlying start site selection, particularly from promoters lacking conventional core elements such as TATA-box and Initiator. Here we report a novel mechanism of start site selection in the TATA- and Initiator-less promoter of miR-22, through a strictly localized downstream element termed DTIE and an upstream distal element. Changing the distance between them reduced promoter strength, altered TSS selection and diminished Pol II recruitment. Biochemical assays suggest that DTIE does not serve as a docking site for TFIID, the major core promoter-binding factor. TFIID is recruited to the promoter through DTIE but is dispensable for TSS selection. We determined DTIE consensus and found it to be remarkably prevalent, present at the same TSS downstream location in ≈20.8% of human promoters, the vast majority of which are TATA-less. Analysis of DTIE in the tumor suppressor p53 confirmed a similar function. Our findings reveal a novel mechanism of transcription initiation from TATA-less promoters.

Diagnosis and treatment delays among elderly breast cancer patients with pre-existing mental illness.

PURPOSE: This study aimed to compare diagnosis and treatment delays in elderly breast cancer patients with and without pre-existing mental illness. METHODS: A retrospective cohort study was conducted using the Surveillance, Epidemiology and End Results-Medicare data including 16,636 women 68+ years, who were diagnosed with stage I-IIIa breast cancer in the United States from 2005 to 2007. Mental illness was identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes recorded on inpatient and outpatient claims during the 3 years prior to breast cancer diagnosis. Patients were classified as having no mental illness, anxiety, depression, anxiety and depression, or severe mental illness (bipolar disorder, schizophrenia, and other psychotic disorder). Multivariable binomial regression was used to assess the association between mental illness and delays of ≥60 and ≥90 days after adjustment for confounders. RESULTS: Patients with comorbid anxiety and depression had an increased risk for diagnosis delay of ≥90 days from symptom recognition (RR 1.11; 95% CI 1.00, 1.23), and those with severe mental illness had an increased risk for initial treatment delay of ≥60 days from diagnosis (RR 1.36; 95% CI 1.06, 1.74). Patients with any mental illness experienced an increased risk for adjuvant chemotherapy delay of ≥90 days from last operation (RR 1.13; 95% CI 1.01, 1.26) and each category of mental illness, except depression, showed a non-significant trend for this association. CONCLUSION: Breast cancer patients with mental illness should be closely managed by a cross-functional care team, including a psychiatrist, a primary care physician, and an oncologist, to ensure adequate care is received within an appropriate timeframe.

Comprehensive genomic profiling of malignant phyllodes tumors of the breast.

PURPOSE: Malignant phyllodes tumors (MPT) are exceptionally rare, and the genomic drivers of these tumors are still being elucidated. We performed comprehensive genomic profiling (CGP) of MPT to identify genomic alterations that will inform approaches to targeted therapy for patients with MPT, including relapsed, refractory, and metastatic disease. METHODS: DNA was extracted from formalin-fixed, paraffin-embedded samples from 24 consecutive patient cases of MPT. CGP was performed using a hybrid capture, adaptor ligation-based next generation sequencing assay to a high, uniform coverage (mean, 582×). Tumor mutational burden (TMB) was calculated from a minimum of 1.14 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations, including short variants (SV; base substitutions, small insertions, and deletions), rearrangements, and copy number changes, including amplifications and homozygous deletions. RESULTS: The 24 cases of MPT included 15 patients with localized and 9 with metastatic disease. The median TMB was 2.7 mut/Mb, and no cases had a TMB > 10 mut/Mb. 20 out of 24 cases were evaluable for microsatellite status, and all were microsatellite stable. The most commonly mutated genes were TP53 (58.3%), TERT-promoter (57.9%), NF1 (45.8%), MED12 (45.8%), CDKN2A/B (33.3%), and MLL2 (33.3%). Targetable kinase fusions including KIAA1549-BRAF or FGFR3-TACC3 were identified in 2/24 (8.3%) tumors. CONCLUSIONS: This study identifies clinically relevant genomic alterations that suggest novel targeted therapy approaches for patients with MPT.

Racial differences in the effects of comorbidity on breast cancer-specific survival.

PURPOSE: In an effort to explain racial disparities in breast cancer survival, this study aimed to investigate how comorbidity affects breast cancer-specific mortality by race. METHODS: A retrospective cohort study was conducted using the Surveillance, Epidemiology and End Results-Medicare linked data including 68,090 women 66+ years, who were diagnosed with stage I-III breast cancer in the United States from 1994 to 2004. Hospital and outpatient claims from the year prior to breast cancer diagnosis were used to identify comorbid conditions and patients were followed for survival through 2010. RESULTS: Competing risk survival analysis failed to demonstrate any negative comorbidity effects on breast cancer-specific survival for black women. An increased breast cancer-specific mortality hazard was observed for white women who had diabetes without complication relative to white women without this condition after adjusting for age and year of diagnosis (hazard ratio: 1.22, 95% confidence interval 1.13, 1.30). The Cochran-Armitage Test showed diabetes was associated with a later stage of diagnosis (p < 0.01) and a more aggressive tumor grade (p < 0.01) among white women in the study population. CONCLUSION: Race specific comorbidity effects do not explain breast cancer-specific survival disparities. However, the relationship between diabetes and breast cancer, including the role of aggressive tumor characteristics, warrants special attention.

Clinical Actionability of Comprehensive Genomic Profiling for Management of Rare or Refractory Cancers.

BACKGROUND: The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important. METHODS: A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. RESULTS: Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0-10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol-4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing. CONCLUSION: Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability. IMPLICATIONS FOR PRACTICE: Identification of key factors that facilitate use of genomic tumor testing results and implementation of genomically guided therapy may lead to enhanced benefit for patients with rare or difficult to treat cancers. Clinical use of a targeted next-generation sequencing assay in the setting of an institutional molecular tumor board led to implementable clinical action in over one third of patients with rare and poor prognosis cancers. The major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access both on trial and off label. Approaches to increase actionability include early and serial sequencing in the clinical course and expanded access to genomically guided early phase clinical trials and targeted agents.

Use of comprehensive genomic profiling to direct point-of-care management of patients with gynecologic cancers.

OBJECTIVE: To determine the feasibility and clinical utility of using comprehensive genomic profiling (CGP) in the course of clinical care to identify clinically relevant tumor genomic alterations for patients with either rare or refractory gynecologic cancers to facilitate point-of-care management. Use of an expert, multidisciplinary, institutional molecular tumor board (MTB) assessment is discussed regarding input on putative targeted options for individualized therapy. METHODS: A prospective clinical trial is ongoing. We report on the initial 69 patients with gynecologic cancers that were either rare or refractory to standard therapy. CGP was performed by Foundation Medicine, Inc. Genomic alterations were reviewed by members of an MTB. Consensus recommendations on genomically targeted, FDA-approved, on- and off-label therapies and clinical trials were sent to the treating physician, and decisions and outcomes were assessed. RESULTS: Study outcomes were available for 64 patients. The mean number of genes altered per tumor was 4.97 (median=4; range, 1-26), and the average turnaround time from testing laboratory report to generation of formal recommendations was approximately three weeks. Evaluation of genomic and clinical data by the MTB led to generation of targeted treatment options in all 64 patients, and the percentage of patients for whom one or more of these recommendations were implemented by the treating physician was 39%. Sixty-four percent of the patients receiving targeted therapy based on a CGP result experienced radiologic response or showed evidence of clinical benefit or stable disease. CONCLUSION: These data suggest that an institutional MTB is a feasible venue for reviewing tumor genomic profiling results and generating clinical recommendations. These data also support the need for further studies and guidelines on clinical decision making with greater availability of broad genomically based diagnostics.

Effects of breast cancer on chronic disease medication adherence among older women.

PURPOSE: The purpose of this study was to determine the effects of breast cancer on chronic disease medication adherence among older women. METHODS: The Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked data and a 5% random sample of Medicare enrollees were used. Stage I-III breast cancer patients diagnosed in 2008 and women without cancer were eligible. Three cohorts of medication users 66+ years were identified using diagnosis codes and prescription fill records: diabetes, hypertension, and lipid disorders. For each cohort, breast cancer patients were frequency matched to comparison women by age and geographic area. Medication adherence was measured by the proportion of days covered and medication persistence. RESULTS: During the post-baseline period, the percentage of breast cancer patients who were non-adherent was 26.2% for diabetes medication, 28.9% for lipid-lowering medication, and 14.2% for hypertension medication. Breast cancer patients experienced an increased odds of diabetes medication non-adherence [odds ratio (OR) = 1.44; 95% confidence interval (CI) = 1.07 to 1.95] and were more likely to be non-persistent with diabetes medication (hazard ratio = 1.31; 95%CI: 1.04 to 1.66) relative to women without cancer. The study failed to show a difference between breast cancer and comparison women in the odds of non-adherence to hypertensive (OR = 0.87; 95%CI: 0.71 to 1.05) or lipid-lowering medication (OR = 0. 91; 95%CI: 0.73 to 1.13) with a proportion of days covered threshold of 80%. CONCLUSION: Special attention should be given to the coordination of primary care for older breast cancer patients with diabetes. Copyright © 2016 John Wiley & Sons, Ltd.

Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment.

Epithelial ovarian cancer is a highly heterogeneous disease characterized by multiple histological subtypes. Molecular diversity has been shown to occur within specific histological subtypes of epithelial ovarian cancer, between different tumors of an individual patient, as well as within individual tumors. Recent advances in the molecular characterization of epithelial ovarian cancer tumors have provided the basis for a simplified classification scheme in which these cancers are classified as either type I or type II tumors, and these two categories have implications regarding disease pathogenesis and prognosis. Molecular analyses, primarily based on next-generation sequencing, otherwise known as high-throughput sequencing, are allowing for further refinement of ovarian cancer classification, facilitating the elucidation of the site(s) of precursor lesions of high-grade serous ovarian cancer, and providing insight into the processes of clonal selection and evolution that may be associated with development of chemoresistance. Potential therapeutic targets have been identified from recent molecular profiling studies of these tumors, and the effectiveness and safety of a number of specific targeted therapies have been evaluated or are currently being studied for the treatment of women with this disease.

Metabotropic glutamate receptor 1 disrupts mammary acinar architecture and initiates malignant transformation of mammary epithelial cells.

Metabotropic glutamate receptor 1 (mGluR1/Grm1) is a member of the G-protein-coupled receptor superfamily, which was once thought to only participate in synaptic transmission and neuronal excitability, but has more recently been implicated in non-neuronal tissue functions. We previously described the oncogenic properties of Grm1 in cultured melanocytes in vitro and in spontaneous melanoma development with 100 % penetrance in vivo. Aberrant mGluR1 expression was detected in 60-80 % of human melanoma cell lines and biopsy samples. As most human cancers are of epithelial origin, we utilized immortalized mouse mammary epithelial cells (iMMECs) as a model system to study the transformative properties of Grm1. We introduced Grm1 into iMMECs and isolated several stable mGluR1-expressing clones. Phenotypic alterations in mammary acinar architecture were assessed using three-dimensional morphogenesis assays. We found that mGluR1-expressing iMMECs exhibited delayed lumen formation in association with decreased central acinar cell death, disrupted cell polarity, and a dramatic increase in the activation of the mitogen-activated protein kinase pathway. Orthotopic implantation of mGluR1-expressing iMMEC clones into mammary fat pads of immunodeficient nude mice resulted in mammary tumor formation in vivo. Persistent mGluR1 expression was required for the maintenance of the tumorigenic phenotypes in vitro and in vivo, as demonstrated by an inducible Grm1-silencing RNA system. Furthermore, mGluR1 was found be expressed in human breast cancer cell lines and breast tumor biopsies. Elevated levels of extracellular glutamate were observed in mGluR1-expressing breast cancer cell lines and concurrent treatment of MCF7 xenografts with glutamate release inhibitor, riluzole, and an AKT inhibitor led to suppression of tumor progression. Our results are likely relevant to human breast cancer, highlighting a putative role of mGluR1 in the pathophysiology of breast cancer and the potential of mGluR1 as a novel therapeutic target.

Associations between sociodemographic and clinicopathological factors and breast cancer subtypes in a population-based study.

PURPOSE: This study examines the factors distinguishing breast cancer (BC) subtypes. METHODS: We examined subtypes in 629 women with invasive BC, diagnosed from 2006 to 2012, and enrolled in an epidemiological study in New Jersey. Using molecular characteristics from pathology reports, BCs were categorized as luminal A, luminal B, non-luminal HER2-expressing, or triple-negative breast cancer (TNBC) subtypes. Multinomial logistic models (luminal A as referent) were used to describe BC subtype associations. RESULTS: Women with luminal B tumors were more likely to be younger at diagnosis [odds ratio (OR) 1.8, 95% confidence interval (CI) 1.0-3.4] and to have higher-grade (OR 2.6, 95% CI 1.5-4.7), larger (OR 1.9, 95% CI 1.0-3.6), and Ki67-positive tumors (OR 2.1, 95% CI 1.1-4.0). Women with non-luminal HER2-expressing BCs were more likely to have higher-grade tumors (OR 14.5, 95% CI 5.3-39.7). Women with TNBCs were more likely to be African-American (OR 1.9, 95% CI 1.0-3.4) and to have higher-grade (OR 9.7, 95% CI 5.1-18.4), larger (OR 2.2, 95% CI 1.0-4.8), and Ki67-positive (OR 2.9, 95% CI 1.6-5.2) tumors. Notably, compared to the luminal A subtype, luminal B, non-luminal HER2-expressing, and triple-negative subtypes were more frequently self-detected; however, these associations were attenuated in multivariable models. CONCLUSIONS: These findings suggest that some BC subtypes were associated with features denoting more aggressive phenotypes, namely higher grade, larger size, and Ki67 positivity, and possibly patient self-detection among some women. These findings highlight a need for enhanced screening, particularly among younger women, racial/ethnic minorities, and lower socioeconomic subgroups.

Triple-negative breast cancer: molecular subtypes and targeted therapy.

PURPOSE OF REVIEW: Triple-negative breast cancers (TNBCs), lacking estrogen receptor expression and human epidermal growth factor receptor 2 amplification, have no effective targeted therapy. Large-scale comprehensive genomic analyses have allowed stratification of TNBCs by molecular features. We will review the recent data regarding the classification of these poor prognosis cancers and the associated potential targeted treatment approaches. RECENT FINDINGS: TNBCs are a heterogeneous set of cancers characterized by a diverse set of gene-expression patterns and underlying genomic changes. Mutations in p53 are the only genomic alteration present in the majority of TNBCs. Other potential targetable alterations are only present in small subsets of TNBCs, and include defects in DNA repair present in BRCA1-mutant TNBCs and some sporadic TNBCs. Antiandrogens may be effective for TNBCs that express the androgen receptor and have luminal-like gene-expression features. PI3KCA pathway inhibitors and HSP90 inhibitors may also be effective in a small fraction of TNBCs. SUMMARY: Robust methods to functionally classify TNBCs to determine vulnerable pathways are urgently needed to guide the development of clinical trials. It is quite possible that TNBCs, like non-small cell lung cancer, will be stratified into many individually rare cancer classes, each requiring a distinct treatment approach.

The role of anthropometric and nutritional factors on breast cancer risk in African-American women.

OBJECTIVE: While the role of nutrition, physical activity and body size on breast cancer risk has been extensively investigated, most of these studies were conducted in Caucasian populations. However, there are well-known differences in tumour biology and the prevalence of these factors between African-American and Caucasian women. The objective of the present paper was to conduct a review of the role of dietary factors, anthropometry and physical activity on breast cancer risk in African-American women. DESIGN: Twenty-six research articles that presented risk estimates on these factors in African-American women and five articles involving non-US black women were included in the current review. SETTING: Racial disparities in the impact of anthropometric and nutritional factors on breast cancer risk. SUBJECTS: African-American and non-US black women. RESULTS: Based on the few studies that presented findings in African-American women, an inverse association with physical activity was found for pre- and postmenopausal African-American women, while the association for anthropometric and other dietary factors, such as alcohol, was unclear. Studies assessing the effect by molecular subtypes in African-American women were too few and based on sample sizes too small to provide definitive conclusions. CONCLUSIONS: The effect of certain nutrition and lifestyle factors on breast cancer in African-American women is not starkly distinct from those observed in white women. However, there is an enormous need for further research on this minority group to obtain more confirmatory findings.

A genetic variant in a PP2A regulatory subunit encoded by the PPP2R2B gene associates with altered breast cancer risk and recurrence.

A recent candidate gene association study identified a single nucleotide polymorphism (SNP) in the PPP2R2B gene (rs319217, A/G) that manifests allelic differences in the cellular responses to treatment with chemotherapeutic agents (Vazquez et al., Nat Rev Drug Discov 2008;7:979-87). This gene encodes a regulatory subunit of protein phosphatase 2A (PP2A), one of the major Ser/Thr phosphatases implicated in the negative control of cell growth and division. Given the tumor suppressor activities of PP2A, here we evaluate whether this genetic variant associates with the age of diagnosis and recurrence of breast cancer in women. To investigate the linkage disequilibrium in the vicinity of this SNP, PPP2R2B haplotypes were analyzed using HapMap data for 90 Caucasians. It is found that the A variant of rs319217 tags a haplotype that appears tobe under positive selection in the Caucasian population, implying that this SNP is functional. Subsequently, associations with cellular responses were investigated using data reported by the NCI anticancer drug screen and associations with breast cancer clinical variables were analyzed in a cohort of 819 Caucasian women. The A allele associates with a better response of tumor derived cell lines, lower risk of breast cancer recurrence, later time to recurrence, and later age of diagnosis of breast cancer in Caucasian women. Taken together these results indicate that the A variant of the rs319217 SNP is a marker of better prognosis in breast cancer.

Polymorphic variants in TSC1 and TSC2 and their association with breast cancer phenotypes.

TSC1 acts coordinately with TSC2 in a complex to inhibit mTOR, an emerging therapeutic target and known promoter of cell growth and cell cycle progression. Perturbation of the mTOR pathway, through abnormal expression or function of pathway genes, could lead to tumorigenesis. TSC1 and TSC2 expression is reduced in invasive breast cancer as compared with normal mammary epithelium. Because single nucleotide polymorphisms (SNPs) in regulatory genes have been implicated in risk and age at diagnosis of breast cancers, systematic SNP association studies were performed on TSC1 and TSC2 SNPs for their associations with clinical features of breast cancer. TSC1 and TSC2 haplotypes were constructed from genotyping of multiple loci in both genes in healthy volunteers. SNPs were selected for further study using a bioinformatics approach based on SNP associations with drug response in NCI-60 cell lines and evidence of selection bias based on haplotype frequencies. Genotyping for five TSC1 and one TSC2 loci were performed on genomic DNA from 1,137 women with breast cancer. This study found that for TSC1 rs7874234, TT variant carriers had a 9-year later age at diagnosis of estrogen receptor positive (ER+), but not ER-, ductal carcinomas (P = 0.0049). No other SNP locus showed an association with age at diagnosis, nor any other breast cancer phenotype. TSC1 rs7874234 is hypothesized to be functional in ER+ breast cancer because the T allele, but not the C allele, may create an estrogen receptor element (ERE) site, resulting in increased TSC1 transcription and subsequent inhibition of mTOR.

Durable Response to PD1 Inhibitor Pembrolizumab in a Metastatic, Metaplastic Breast Cancer.

Metaplastic breast cancer (MBC) is a rare and aggressive subtype of breast cancer. Tumor characteristics typically feature estrogen receptor, progesterone receptor, and HER2-negative, triple-negative breast cancer (TNBC), with a poorer prognosis relative to pure invasive ductal or lobular disease. Resistance to chemotherapy often leads to local recurrence and distant metastasis. Genomic profiling has identified multiple molecular abnormalities that may translate to targetable therapies in MBC. These tumors are known to display higher PD-L1 expressivity than other subtypes of breast cancer, and disease control with pembrolizumab and chemotherapy has been documented. We identify a patient with metastatic, metaplastic TNBC, with mesenchymal components and osseous differentiation, who completed 2 years of pembrolizumab treatment and has remained without evidence of disease after 32 months of observation, while maintaining good quality of life. Future efforts should focus on immunotherapy response with respect to the various subtypes of MBC, and treatment should continue to be incorporated in clinical trials to maximize disease response.

The role of chromodomain helicase DNA binding protein 1 (CHD1) in promoting an invasive prostate cancer phenotype.

BACKGROUND: Prostate cancer (PCa) phenotypes vary from indolent to aggressive. Molecular subtyping may be useful in predicting aggressive cancers and directing therapy. One such subtype involving deletions of chromodomain helicase DNA binding protein 1 (CHD1), a tumor suppressor gene, are found in 10-26% of PCa tumors. In this study, we evaluate the functional cellular effects that follow CHD1 deletion. METHODS: CHD1 was knocked out (KO) in the non-tumorigenic, human papillomavirus 16 (HPV16)-immortalized prostate epithelial cell line, RWPE-1, using CRISPR/Cas9. In vitro assays such as T7 endonuclease assay, western blot, and sequencing were undertaken to characterize the CHD1 KO clones. Morphologic and functional assays for cell adhesion and viability were performed. To study expression of extracellular matrix (ECM) and adhesion molecules, a real-time (RT) profiler assay was performed using RWPE-1 parental, non-target cells (NT2) and CHD1 KO cells. RESULT: Compared to parental RWPE-1 and non-target cells (NT2), the CHD1 KO cells had a smaller, rounder morphology and were less adherent under routine culture conditions. Compared to parental cells, CHD1 KO cells showed a reduction in ECM and adhesion molecules as well as a greater proportion of viable suspension cells when cultured on standard tissue culture plates and on plates coated with laminin, fibronectin or collagen I. CHD1 KO cells showed a decrease in the expression of secreted protein acidic and rich in cysteine (SPARC), matrix metalloproteinase 2 (MMP2), integrin subunit alpha 2 (ITGA2), integrin subunit alpha 5 (ITGA5), integrin subunit alpha 6 (ITGA6), fibronectin (FN1), laminin subunit beta-3 precursor (LAMB3), collagen, tenascin and vitronectin as compared to parental and NT2 cells. CONCLUSION: These data suggest that in erythroblast transformation specific (ETS) fusion-negative, phosphatase and tensin homolog (PTEN) wildtype PCa, deletion of CHD1 alters cell-cell and cell-matrix adhesion dynamics, suggesting an important role for CHD1 in the development and progression of PCa.