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Triple negative breast cancer (TNBC) subtype is characterized with higher EMT/stemness properties and immune suppressive tumor microenvironment (TME). Women with advanced TNBC exhibit aggressive disease and have limited treatment options. Although immune suppressive TME is implicated in driving aggressive properties of basal/TNBC subtype and therapy resistance, effectively targeting it remains a challenge. Minnelide, a prodrug of triptolide currently being tested in clinical trials, has shown anti-tumorigenic activity in multiple malignancies via targeting super enhancers, Myc and anti-apoptotic pathways such as HSP70. Distinct super-enhancer landscape drives cancer stem cells (CSC) in TNBC subtype while inducing immune suppressive TME. We show that Minnelide selectively targets CSCs in human and murine TNBC cell lines compared to cell lines of luminal subtype by targeting Myc and HSP70. Minnelide in combination with cyclophosphamide significantly reduces the tumor growth and eliminates metastasis by reprogramming the tumor microenvironment and enhancing cytotoxic T cell infiltration in 4T1 tumor-bearing mice. Resection of residual tumors following the combination treatment leads to complete eradication of disseminated tumor cells as all mice are free of local and distant recurrences. All control mice showed recurrences within 3 weeks of post-resection while single Minnelide treatment delayed recurrence and one mouse was free of tumor. We provide evidence that Minnelide targets tumor intrinsic pathways and reprograms the immune suppressive microenvironment. Our studies also suggest that Minnelide in combination with cyclophosphamide may lead to durable responses in patients with basal/TNBC subtype warranting its clinical investigation.

Background There is sparse clinical information on the racial and ethnic distribution of results of multigene panel testing among individuals at high risk for hereditary cancer. Methods We evaluated the results of multigene panel testing across eight clinical sites across the state of Michigan for individuals seen for genetic counseling from May 13, 2013 to October 31, 2019 at the Karmanos Cancer Institute's cancer genetics clinic. We estimated the prevalence of pathogenic variants and variants of uncertain significance (VUS) from genes other than BRCA1/2 among individuals of non‐Hispanic White (NHW), Black or African American (AA), Ashkenazi Jewish (AJ), Arab, Hispanic, and other ancestry. Results The racial and ethnic distribution of 2419 individuals who had panel testing included 68.8% NHW, 22.1% AA, 2.3% Arab, 2.2% AJ, 1.0% Hispanic, and 3.6% other. Of these, 11.2% had pathogenic variants and 17.5% had VUS. After multivariable analyses, compared to NHW, AA were less likely to have pathogenic variants (OR 95% CI, 0.38, 0.24–0.59, p < 0.001). Both AA and Arabs were more likely to have VUS (OR 95% CI, 1.53, 1.18–1.98, p = 0.001 and OR 95% CI, 2.28, 1.17–4.43, p = 0.015, respectively). There were no significant differences for other groups. The most common pathogenic variants were CHEK2 (n = 65), MUTYH (n = 45), ATM (n = 28), and MSH2 (n = 22); the most common pathogenic variants by race and ethnicity were CHEK2 (NHW), MSH2 and MUTYH (AA), MSH2 (Arab), MSH6 and CHEK2 (AJ), and MLH1 (Hispanic); the most common pathogenic variants by primary cancer site were CHEK2 (breast), MSH2 (colon), BRIP1 and MUTYH (ovarian), and MSH2 and MSH6 (endometrial). Conclusions Understanding the racial and ethnic distribution of pathogenic variants in multi‐gene panels has the potential to lead to better identification of individuals at risk for hereditary cancer. Racial and ethnicity variations were described in patients undergoing multi‐gene panel testing. In addition, common pathogenic variants based on race/ethnicity as well as cancer type was described. This descriptive study allows for informed decisions in counseling of patients.

Background The study was conducted to evaluate racial differences in referral and uptake of genetic counseling (GC) in a clinic‐based population of women with breast cancer. Methods Medical records of 150 breast cancer patients at the Karmanos Cancer Institute were reviewed to determine eligibility for GC according to National Comprehensive Cancer Network guidelines, GC referral rates, and appointment completion rates. Logistic regression was used to assess the relationship between demographic and clinical factors and GC eligibility and referral. Results The mean age at diagnosis was 57.1 (SD 12.6) and 66% of the women were Black. There were 91 women (60.7%) eligible for GC and of those, 54 (61.4%) were referred. After multivariable analyses, factors associated with reduced eligibility were older age at diagnosis (OR = 0.91, 95% CI [0.87,0.95]) and Black race (OR = 0.37, 95% CI [0.15, 0.96]). After additional multivariable analysis, eligibility was associated with an increased likelihood of referral (OR = 5.97, 95% CI [2.29, 15.56]), however, Medicare versus private insurance was associated with a lower likelihood for referral (OR = 0.32, 95% CI [0.12–0.80]. Of those referred, 49 (76.6%) completed an appointment, and 47 had genetic testing. Women with Medicare were also less likely to complete an appointment. Race had no impact on referral or appointment completion. Conclusions There were no racial differences in GC referral or appointment completion in a clinic‐based sample of women with breast cancer. Further interventions are needed to promote increased referral and appointment completion for women with breast cancer who are eligible for GC. There were no racial differences in GC referral or appointment completion in a clinic‐based sample of women with breast cancer. Further interventions are needed to promote increased referral and appointment completion for women with breast cancer who are eligible for GC.

Background Many of the 3.8 million breast cancer survivors in the United States experience long‐term side effects of cancer therapy including peripheral neuropathy (PN). We assessed the prevalence and predictors of PN among women with breast cancer followed in the Women's Health Initiative's Life and Longevity After Cancer survivorship cohort. Methods The study population included 2420 women with local (79%) or regional (21%) stage disease. Presence of PN was based on the reports of “nerve problems and/or tingling sensations” after treatment and PN severity was assessed using the Functional Assessment of Cancer Therapy‐Gynecologic Oncology Group/Neurotoxicity instrument. Logistic regression analysis was used to evaluate the socio‐demographic and clinical factors associated with PN prevalence and severity. Results Initial breast cancer treatment included surgery‐only (21%), surgery and radiation (53%), or surgery and chemotherapy (±radiation) (26%). Overall, 17% of women reported PN occurring within days (30%), months (46%), or years (24%) after treatment and 74% reported ongoing symptoms at a median of 6.5 years since diagnosis. PN was reported by a larger proportion of chemotherapy recipients (33%) compared to those who had surgery alone (12%) or surgery+radiation (11%) (p < 0.0001). PN was reported more commonly by women treated with paclitaxel (52%) and docetaxel (39%), versus other chemotherapy (17%) (p < 0.0001). In multivariable analyses, treatment type (chemotherapy vs. none; OR, 95% CI: 3.31, 2.4–4.6), chemotherapy type (taxane vs. no‐taxane; 4.74, 3.1–7.3), and taxane type (paclitaxel vs. docetaxel; 1.59, 1.0–2.5) were associated with higher odds of PN. Conclusion PN is an important long‐term consequence of taxane‐based chemotherapy in breast cancer survivors.

Statins, inhibitors of HMG-CoA reductase, have been shown to have potential anti-carcinogenic effects through the inhibition of the mevalonate pathway and their impact on Ras and RhoGTAases. Prior studies have demonstrated a reduction in breast tumor proliferation, as well as increased apoptosis, among women with early-stage breast cancer who received statins between the time of diagnosis and the time of surgery. The aim of this study was to evaluate the impact of short-term oral high-potency statin therapy on the expression of markers of breast tumor proliferation, apoptosis, and cell cycle arrest in a window-of-opportunity trial. This single-arm study enrolled 24 women with stage 0-II invasive breast cancer who were administered daily simvastatin (20 mg) for 2–4 weeks between diagnosis and surgical resection. Pre- and post-treatment tumor samples were analyzed for fold changes in Ki-67, cyclin D1, p27, and cleaved caspase-3 (CC3) expression. Out of 24 enrolled participants, 18 received statin treatment and 17 were evaluable for changes in marker expression. There was no significant change in Ki-67 expression (fold change = 1.4, p = 0.597). There were, however, significant increases in the expression of cyclin D1 (fold change = 2.8, p = 0.0003), p27 cytoplasmic (fold change = 3.2, p = 0.025), and CC3 (fold change = 2.1, p = 0.016). Statin treatment was well tolerated, with two reported grade-1 adverse events. These results align with previous window-of-opportunity studies suggesting a pro-apoptotic role of statins in breast cancer. The increased expression of markers of cell cycle arrest and apoptosis seen in this window-of-opportunity study supports further investigation into the anti-cancer properties of statins in larger-scale clinical trials.

PurposeThe prevalence of pathogenic variants in BRCA1 and BRCA2 in populations other than Ashkenazi Jewish (AJ) is not well defined. We describe the racial and ethnic-specific prevalence of BRCA1/2 pathogenic variants and variants of uncertain significance (VUS) among individuals referred for genetic testing in a large urban comprehensive cancer center over a 20-year period.MethodsThe population included 3,537 unrelated individuals who underwent genetic testing from January 1999 to October 2019 at the Karmanos Cancer Institute. We estimated the prevalence of pathogenic variants and VUS and evaluated associations with race and ethnicity for African American (AA), Arab, AJ and Hispanic individuals compared to Non-Hispanic Whites (NHW). We used multivariable models to adjust for other predictors of pathogenic variants. We also reported the most common pathogenic variants by racial and ethnic group.ResultsThe racial and ethnic breakdown of our population was: NHW (68.9%), AA (20.3%), AJ (2.5%), Arab (2.2%), Hispanic (1.0%), Asian Pacific Islander, Native American/Alaskan Native (4.7%), and < 1% unknown. The overall prevalence of pathogenic variants in BRCA1/2 was 8.9% and the prevalence of VUS was 5.6%. Compared to NHW, there were no racial or ethnic differences in the rate of pathogenic variants. However, AA individuals were more likely to have VUS in BRCA1 (adjusted OR 2.43, 95% CI 1.38–4.28) and AJ were more likely to have VUS in BRCA2 (adjusted OR 3.50, 95% CI 1.61–6.58). ConclusionThese results suggest the continued need for genetic testing and variant reclassification for individuals of all racial and ethnic groups.

Purpose Carriers of pathogenic variants in BRCA1 /2 have an elevated lifetime cancer risk warranting high-risk screening and risk-reducing procedures for early detection and prevention. We report on prevention practices among women with pathogenic BRCA variants in order to document follow through with NCCN recommendations and to identify barriers to guideline-recommended care. Methods Our cohort included women who had genetic testing through a cancer genetic clinic and completed a 54-item questionnaire to measure socio-demographics, medical history, rates of cancer screening and risk-reducing surgery, disclosure of test results, and cancer worry. Outcomes included rates of completion of risk-reducing salpingo-oophorectomy (RRSO), risk-reducing mastectomy (RRM), and NCCN risk-reducing and age-dependent screening guidelines (version 3.2019). Multivariable logistic regression analyses were used to evaluate potential predictors of these outcomes. Results Of 129 evaluable women with pathogenic BRCA1 /2 variants, 95 (74%) underwent RRSO and 77 (60%) had RRM, respectively, and 107 (83%) were considered adherent to NCCN guidelines. Women with a history of breast or ovarian cancer were more likely to have RRM (OR = 4.38; 95% CI 1.80–11.51; p  = 0.002). Increasing age was associated with an increased likelihood of RRSO (OR = 1.05; 95% CI 1.01–1.09; p  = 0.019) and decreased likelihood for RRM (OR = 0.95; 95% CI 0.92–0.99; p  = 0.013). Women who had RRM were 3 times more likely to undergo RRSO (OR = 2.81; 95% CI 1.10–7.44; p  = 0.025). Women who had genetic testing after June 2013 were less likely to have RRM than those tested before June 2013 (OR = 0.42; 95% CI 0.18–0.95; p  = 0.040. None of the other measured factors were associated with rates of RRSO, RRM or follow through with NCCN recommendations. There was near universal (127/129) reported disclosure of genetic test results to family members, resulting in the discovery of a median of 1 relative with a pathogenic variant (range = 0–8). Conclusion An evaluation of follow up practice in a cohort of women with pathogenic variants in BRCA1 /2 revealed high rates of reported completion of screening and surgical risk-reducing recommendations. Educational efforts should continue to reinforce the importance of follow-through with guideline recommended care among this high-risk group.

PurposeImproved life expectancy has increased the likelihood for long-term complications from chemotherapy among cancer survivors. One burdensome complication is chemotherapy-induced peripheral neuropathy (CIPN). We evaluated rates of CIPN outcomes in the Detroit Research on Cancer Survivorship (ROCS) cohort.MethodsThe population included 1,034 African American (AA) survivors who received chemotherapy for breast, colorectal, lung or prostate cancer. CIPN prevalence was based on initial occurrence of worsening of self-reported pain, numbness or tingling after chemotherapy. Current CIPN included symptoms still present at the time of the survey, and persistent CIPN symptoms were present 12 or more months post-chemotherapy. CIPN severity was ranked as mild, moderate or severe. Logistic regression was utilized to evaluate sociodemographic and clinical factors associated with the various categories of CIPN.ResultsCIPN prevalence was 68%, with 53% current and 52% persistent. The symptom severity distribution based on prevalent CIPN included 32.2% mild, 30.8% moderate, and 36.9% severe. Factors associated with prevalent CIPN (odds ratio, 95% confidence interval) included primary cancer site (breast: 3.88, 2.02–7.46); and (colorectal: 5.37, 2.69–10.73), lower risk for older age at diagnosis (0.66, 0.53–0.83) and divorced/separated marital status (2.13, 1.42–3.21). Current CIPN was in addition, associated with more advanced stage disease trend (1.34, 1.08–1.66) and greater number of co-morbid medical conditions trend (1.23, 1.09–1.40), as was persistent CIPN. Severity of prevalent CIPN was associated with history of arthritis (1.55, 1.06–2.26) and severity of persistent CIPN with higher BMI (1.58, 1.07–2.35).ConclusionsCIPN is a common and persistent complication in AA cancer survivors. Further research is needed to improve our understanding of CIPN predictors in all groups of cancer survivors.

Purpose. Women with locally advanced/high-risk triple-negative breast cancer treated with the current standard chemotherapy continue to have a poor prognosis. High-dose chemotherapy with autologous stem cell transplant as treatment for locally advanced/high-risk breast cancer remains controversial due to a lack of survival benefit seen in previous phase III trials. However, these trials evaluated a heterogeneous group of patients with different receptor subtypes. A marginal benefit was observed in certain subgroups. We report long-term outcomes of women with stage IIB or III triple-negative breast cancer treated with high-dose chemotherapy followed by autologous stem cell transplant at our institution between 1995 and 2001. Methods. This is a retrospective analysis of stage IIB or stage III triple-negative breast cancer treated with high-dose chemotherapy followed by autologous stem cell transplant. We excluded women with hormone-positive, HER2/neu-positive/unknown, and/or metastatic disease prior to transplant as per updated AJCC 7th edition guidelines. Patients underwent surgery and either neoadjuvant or adjuvant anthracycline and taxane-based chemotherapy and then proceeded to high-dose chemotherapy and autologous stem cell transplant using carmustine 600 mg/sqm, cyclophosphamide 5.6gm/sqm, and cisplatin 165 mg/sqm (STAMP 1 regimen) for consolidation. This was followed by locoregional breast and lymph node radiation per standard of care. Results. Twenty-nine women (2 stage IIB and 27 stage III) were evaluated. The median age at diagnosis was 43 years (IQR: 40, 51). Eleven patients had 4–9 regional lymph nodes (LN) involved and 16 had 10+ involved LNs. Four patients had T4 or inflammatory breast cancer and two had ipsilateral supraclavicular LNs involved. The median follow-up time is 16 years (95% CI: 12, 19, range <1–19 y) posttransplant. The median overall survival was 15 years (95% CI: 3, 19); the median DFS was 14 years (95% CI: 1, 19). Conclusions. This study of locally advanced/high-risk triple-negative breast cancer treated with adjuvant high-dose chemotherapy and autologous stem cell transplant reveals high overall survival rate. With the current improvement in treatment-related mortality, re-evaluating this approach in this subset of high-risk breast cancer in prospective randomized studies may be worthwhile.

Cell Cycle and Apoptosis Regulatory Protein (CARP-1/CCAR1) is a peri-nuclear phosphoprotein that regulates apoptosis via chemotherapeutic Adriamycin (doxorubicin) and a novel class of CARP-1 functional mimetic (CFM) compounds. Although Adriamycin causes DNA damage, data from Comet assays revealed that CFM-4.16 also induced DNA damage. Phosphorylation of histone 2AX (γH2AX) protein is involved in regulating DNA damage repair and apoptosis signaling. Adriamycin or CFM-4.16 treatments inhibited cell growth and caused elevated CARP-1 and γH2AX in human breast (HBC) and cervical cancer (HeLa) cells. In fact, a robust nuclear or peri-nuclear co-localization of CARP-1 and γH2AX occurred in cells undergoing apoptosis. Knock-down of CARP-1 diminished γH2AX, their co-localization, and apoptosis in CFM-4.16- or Adriamycin-treated cells. We found that CARP-1 directly binds with H2AX, and H2AX interacted with CARP-1, but not CARP-1 (Δ600–652) mutant. Moreover, cells expressing CARP-1 (Δ600–652) mutant were resistant to apoptosis, and had diminished levels of γH2AX, when compared with cells expressing wild-type CARP-1. Mutagenesis studies revealed that H2AX residues 1–35 harbored a CARP-1-binding epitope, while CARP-1 amino acids 636–650 contained an H2AX-interacting epitope. Surface plasmon resonance studies revealed that CARP-1 (636–650) peptide bound with H2AX (1–35) peptide with a dissociation constant (Kd) of 127 nM. Cells expressing enhanced GFP (EGFP)-tagged H2AX (1–35) peptide or EGFP-tagged CARP-1 (636–650) peptide were resistant to inhibition by Adriamycin or CFM-4.16. Treatment of cells with transactivator of transcription (TAT)-tagged CARP-1 (636–650) peptide resulted in a moderate, statistically significant abrogation of Adriamycin-induced growth inhibition of cancer cells. Our studies provide evidence for requirement of CARP-1 interaction with H2AX in apoptosis signaling by Adriamycin and CFM compounds.