Rita Kramer

Primary breast cancer phenotypes associated with propensity for central nervous system metastases

There is anecdotal evidence that the incidence of central nervous system (CNS) metastases in breast cancer patients is increasing. It is unclear whether specific tumor biological properties or the use of systemic therapies influence this risk.

The rates of chemotherapy-induced amenorrhea in patients treated with adjuvant doxorubicin and cyclophosphamide followed by a taxane

Objective:Adjuvant chemotherapy in premenopausal women with breast cancer may induce amenorrhea, which can affect fertility, choice of hormonal therapy, and increase the risk of late toxicity. The incidence of chemotherapy-induced amenorrhea (CIA) resulting from doxorubicin and cyclophosphamide (AC) followed by a taxane (T) is poorly characterized. Methods:We retrospectively surveyed women who were premenopausal and less than age 50 at initiation of chemotherapy to determine the rates of CIA in women receiving AC followed by T compared with AC alone. Results:One hundred ninety-one eligible women completed the survey. The rate of CIA in women who received AC followed by T was 64% (95% confidence interval [CI] = 55–72%) compared with 55% (95% CI = 43–66%) in AC alone. As expected, CIA rates were higher in older than younger women (82% vs. 55%, P = 0.004). Multivariate logistic regression analysis revealed that age >40 was associated with a 4.6-fold increased risk of CIA (95% CI = 1.7–12.1, P = 0.002). It also revealed that receiving T after AC was associated with an odds ratio of 1.9 for CIA as compared with receiving AC alone (95% CI = 1.0–3.5, P = 0.05). Despite ≥6 months of amenorrhea, many women ≤40 resumed menses (40%). CIA was more likely to be irreversible in those >40. The addition of taxanes did not alter the rate of reversibility for the group as a whole (P = 0.36). Conclusions:Older age and the addition of taxane to AC increased the risk of CIA and the amenorrhea was more likely to be irreversible for women >40. Women ≤40 often resume menstruation even after 6 months of amenorrhea, and the addition of T does not play a role. Subsequent resumption of menstrual function must be considered when initiating appropriate hormonal therapy.

Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy

Peripheral neuropathy is a major dose‐limiting side effect of paclitaxel and cisplatin chemotherapy. In the current study, we tested the involvement of a novel class of neurotoxic sphingolipids, the 1‐deoxysphingolipids. 1‐Deoxysphingolipids are produced when the enzyme serine palmitoyltransferase uses l‐alanine instead of l‐serine as its amino acid substrate. We tested whether treatment of cells with paclitaxel (250 nM, 1 μM) and cisplatin (250 nM, 1 μM) would result in elevated cellular levels of 1‐deoxysphingolipids. Our results revealed that paclitaxel, but not cisplatin treatment, caused a dose‐dependent elevation of 1‐deoxysphingolipids levels and an increase in the message and activity of serine palmitoyltransferase (P < 0.05). We also tested whether there is an association between peripheral neuropathy symptoms [evaluated by the European Organization for Research and Treatment of Cancer (EORTC) QLQ‐chemotherapy‐induced peripheral neuropathy‐20 (CIPN20) instrument] and the 1‐deoxysphingolipid plasma levels (measured by mass spectrometry) in 27 patients with breast cancer who were treated with paclitaxel chemotherapy. Our results showed that there was an association between the incidence and severity of neuropathy and the levels of very‐long‐chain 1‐deoxyceramides such as C24 (P < 0.05), with the strongest association being with motor neuropathy (P < 0.001). Our data from cells and from patients with breast cancer suggest that 1‐deoxysphingolipids, the very‐long‐chain in particular, play a role as molecular intermediates of paclitaxel‐induced peripheral neuropathy.—Kramer, R., Bielawski, J., Kistner‐Griffin, E., Othman, A., Alecu, I., Ernst, D., Kornhauser, D., Hornemann, T., Spassieva, S. Neurotoxic 1‐deoxysphingolipids and paclitaxel‐induced peripheral neuropathy. FASEB J. 29, 4461‐4472 (2015). www.fasebj.org

Should tamoxifen be used in breast cancer prevention

Breast cancer is the most commonly diagnosed cancer in women. The risk of developing breast cancer can be lowered by maintaining a healthy bodyweight and avoiding long-term use of combined estrogen and progestogen replacement after menopause. However, many women are at an increased risk of developing breast cancer secondary to age, early menarche, a family history of breast cancer or a personal history of benign breast disease. These women may now be offered tamoxifen as a chemoprevention therapy. Five years of tamoxifen treatment results in a reduction in the relative risk of developing estrogen receptor-positive breast cancer of 48%. This benefit outweighs the risk of tamoxifen-related adverse events for many healthy women. However, the benefit-risk ratio of tamoxifen chemoprevention varies for individual women. The randomized clinical trials evaluating standard-dose tamoxifen versus placebo as chemoprevention therapy are reviewed and analyzed to determine which particular women are most likely to benefit and least likely to experience a tamoxifen-related adverse event. Tamoxifen decreases the risk of breast cancer associated with aging, having a first-degree relative with disease, and a personal diagnosis of atypical ductal hyperplasia or lobular carcinoma in situ. Women who have had a hysterectomy and are at low risk of a thromboembolic event have a decreased risk of adverse effects associated with tamoxifen therapy. The strengths and weaknesses of the Gail model (frequently used to assess an individual’s risk of developing invasive breast cancer over the next 5 years) are highlighted. A method for assessing the benefit-risk ratio for an individual woman is presented. Alternative breast cancer chemoprevention strategies are considered, including the use of aromatase inhibitors. This article discusses the pros and cons of these various preventive therapies and concludes that at this time, tamoxifen remains the gold standard for breast cancer prevention.

Chapter Two – Disparities in Obesity, Physical Activity Rates, and Breast Cancer Survival

Abstract The significantly higher breast cancer (BCa) mortality rates of African‐American (AA) women compared to non‐Hispanic (NHW) white women constitute a major US health disparity. Investigations have primarily focused on biological differences in tumors to explain more aggressive forms of BCa in AA women. The biology of tumors cannot be modified, yet lifestyle changes can mitigate their progression and recurrence. AA communities have higher percentages of obesity than NHWs and exhibit inefficient access to care, low socioeconomic status, and reduced education levels. Such factors are associated with limited healthy food options and sedentary activity. AA women have the highest prevalence of obesity than any other racial/ethnic/gender group in the United States. The social ecological model (SEM) is a conceptual framework on which interventions could be developed to reduce obesity. The SEM includes intrapersonal factors, interpersonal factors, organizational relationships, and community/institutional policies that are more effective in behavior modification than isolation from the participants’ environmental context. Implementation of SEM‐based interventions in AA communities could positively modify lifestyle behaviors, which could also serve as a powerful tool in reducing risk of BCa, BCa progression, and BCa recurrence in populations of AA women.

Abstract A47: MicroRNA-510 as a predictive marker for response to platinum-based chemotherapy in triple negative breast cancer

Breast cancer is a heterogeneous disease with multiple subtypes, which are clinically classified based on the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Associated with the poorest prognosis of all subtypes, triple negative breast cancer (TNBC) is defined as ER-/PR-/HER2-; without these molecular targets, these cancers are insensitive to highly effective targeted therapies and systemic chemotherapy remains the mainstay of treatment for these women. Resent research has shown that platinum chemotherapy agents are particularly active in TNBC, including a clinical trial that demonstrated single agent cisplatin alone can induce response in a subset of TNBC patients. The identification of biomarkers to predict response is required to distinguish patients most likely to benefit from this agent from resistant ones, whom may respond better from other forms of chemotherapy. We have published studies examining the role of miR-510 in breast cancer and observed that miR-510 expression is elevated in tumors when compared to matched non-tumor samples. Drug cytotoxicity assays indicate miR-510 positively correlates with sensitivity to cisplatin in vitro. Furthermore, inhibition of miR-510 causes sensitive breast cancer cell lines to be more resistant in vitro, while overexpression of miR-510 restores sensitivity to cisplatin in resistant breast cancer cell lines both in vitro and in vivo. Recent mechanistic studies have revealed that cisplatin activates the ΔNp63/TAp73 apoptotic pathway specifically in in TNBC with p53 mutations (∼60% of all TNBCs). We have validated peroxiredoxin 1 (Prdx1) as a direct target of miR-510 and studies have also indicated that Prdx1 is a negative regulator of the ΔNp63/Tap73 pathway, suggesting that miR-510 may mediate sensitivity to cisplatin through the negative regulation of Prdx1. We demonstrate an increase in the activation of this pathway in TNBC cells expressing miR-510 upon cisplatin treatment. Based on these data we propose that elevated levels of miR-510 mediates cisplatin sensitivity and that it may serve as a non-invasive biomarker to predict response to cisplatin in TNBC patients. To this end, we have shown by qPCR that miR-510 levels are detectable in serum samples from a subset of human breast cancer patients, and further studies will assess positive correlations between miR-510 expression and cisplatin sensitivity. Citation Format: Qi Jin Guo, Jamie N. Miils, Natalie Mason, Savannah G. Bandurraga, Lourdes M. Nogueira, Rita Kramer, David P. Turner, Victoria J. Findlay. MicroRNA-510 as a predictive marker for response to platinum-based chemotherapy in triple negative breast cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A47.

26th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 3–6 December 2003: update on clinical research

The San Antonio Breast Cancer Symposium is an international meeting dedicated to the translation of advances in cellular and molecular biology of breast disease into clinical improvements in prevention, diagnosis and treatment. This report summarizes the clinical highlights of the 26th annual meeting held in San Antonio, Texas on 3–6 December 2003. Breast care for women will be improved by reports concerning optimal adjuvant hormonal therapy, advances in chemotherapy and a shift in the clinical philosophy of breast cancer care from maximum tolerable treatment to minimum effective therapy.

Alcohol and Tobacco Use in an Ethnically Diverse Sample of Breast Cancer Patients, Including Sea Island African Americans: Implications for Survivorship

Background/Objective: Data suggest that modifiable risk factors such as alcohol and tobacco use may increase the risk of breast cancer (BC) recurrence and reduce survival. Female BC mortality in South Carolina is 40% higher among African Americans (AAs) than European Americans (EAs). Given this substantial racial disparity, using a cross-sectional survey design we examined alcohol and tobacco use in an ethnically diverse statewide study of women with recently diagnosed invasive breast cancer. This included a unique South Carolina AA subpopulation, the Sea Islanders (SI), culturally isolated and with the lowest European American genetic admixture of any AA group. Methods: Participants (42 EAs, 66 non-SI AAs, 29 SIs), diagnosed between August 2011 and December 2012, were identified through the South Carolina Central Cancer Registry and interviewed by telephone within 21 months of diagnosis. Self-reported educational status, alcohol consumption and tobacco use were obtained using elements of the Behavior and Risk Factor Surveillance System questionnaire. Results: Alcohol: EAs were approximately twice as likely to consume alcohol (40%) and to be moderate drinkers (29%) than either AA group (consumers: 24% of non-SI AAs, 21% of SIs; moderate drinkers 15 and 10% respectively). Users tended to be younger, significantly among EAs and non-SI AAs, but not SIs, and to have attained more education. Heavy drinking was rare (≤1%) and binge drinking uncommon (≤10%) with no differences by race/ethnicity. Among both AA subgroups but not EAs, alcohol users were six to nine times more likely to have late stage disease (Regional or Distant), statistically significant but with wide confidence intervals. Tobacco: Current cigarette smoking (daily or occasional) was reported by 14% of EAs, 14% of non-SI AAs and 7% of SIs. Smoking was inversely associated with educational attainment. Use of both alcohol and cigarettes was reported by 3–6% of cases. Conclusions: Prevalences of alcohol and cigarette use were similar to those in the general population, with alcohol consumption more common among EAs. Up to half of cases used alcohol and/or tobacco. Given the risks from alcohol for disease recurrence, and implications of smoking for various health outcomes, these utilization rates are of concern.

Abstract A24: Triple-negative breast Cancer risk: Ancestry and immune response

Background: Blacks in the U.S. have the worst breast cancer survival outcomes of any racial/ethnic group in the nation. However, blacks are not a monolithic group but are comprised of several ethnic groups. One such group in particular is the Sea Island or Gullah population of coastal South Carolina, North Carolina, Georgia, and Florida, whose ancestors came from coastal rice-growing areas of Africa. Sea Islanders (SI) have the lowest rates of European (non-Hispanic white) genetic admixture of any U.S. blacks, and are thus a special population who provide a rare opportunity to investigate genetic contributions to the profound ancestrally linked disparities in BC. Purpose: The purpose of this study was to identify, for the first time, frequencies of selected single nucleotide polymorphisms (SNPs) associated with triple-negative breast cancer (TNBC) in these three non-Hispanic population groups: whites, African Americans without Sea Island ancestry (AA), and African Americans with Sea Island ancestry (SI). Methods: Saliva samples were obtained using a mailed kit from a sample of 90 women in SC who had been diagnosed with TNBC in the past 1.5 years, recruited from the three population groups (30 women per group). Four SNPs on the 19p13 locus of BRCA 1 (rs8170, rs4808611, rs2363956, and rs3745185) were evaluated. Results: The percentage of TNBC cases was 6.7% among whites, 4.2% among SI blacks, and 22% among non-SI blacks. After controlling for TNBC status, similar allele frequencies for each SNP were seen in whites and SI blacks, compared to non-SI blacks (p Discussion: The prevalence of triple-negative breast cancer is significantly higher in African American women, and at younger ages, than in white women. Findings by Mukhtar et al. (2011) implicate immune function in the development of this aggressive breast cancer, as higher proliferating cellular nuclear antigen counts and tumor-associated macrophages were associated with hormone receptor-negative tumors and non-white ethnicity. Human populations differ in their transcriptional responses to immune challenges, and immune-responsive regulatory variants have participated in human adaptation by positive selection. Regulatory variants affecting steady-state gene expression and transcriptional responsiveness to immune challenges, particularly those that were viral related, may have been preferentially introduced into African genomes through admixture with Europeans, which may have conferred a natural selection disadvantage to modern blacks without SI ancestry. Such a natural selection disadvantage may mean that different immunologic therapeutic approaches are required for blacks with cancer than for whites with cancer, particularly for more aggressive disease. Citation Format: Marvella E. Ford, Erika T. Brown, David P. Turner, Victoria J. Findlay, Nestor F. Esnaola, Anthony J. Alberg, Susan Bolick, Deborah Hurley, Rita Kramer, Judith D. Salley, Joan E. Cunningham. Triple-negative breast Cancer risk: Ancestry and immune response [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 A24.

Advanced glycation end products are elevated in estrogen receptor-positive breast cancer patients, alter response to therapy, and can be targeted by lifestyle intervention

PurposeLifestyle factors associated with personal behavior can alter tumor-associated biological pathways and thereby increase cancer risk, growth, and disease recurrence. Advanced glycation end products (AGEs) are reactive metabolites produced endogenously as a by-product of normal metabolism. A Western lifestyle also promotes AGE accumulation in the body which is associated with disease phenotypes through modification of the genome, protein crosslinking/dysfunction, and aberrant cell signaling. Given the links between lifestyle, AGEs, and disease, we examined the association between dietary-AGEs and breast cancer.MethodsWe evaluated AGE levels in bio-specimens from estrogen receptor-positive (ER+) and estrogen receptor-negative (ER−) breast cancer patients, examined their role in therapy resistance, and assessed the ability of lifestyle intervention to reduce circulating AGE levels in ER+ breast cancer survivors.ResultsAn association between ER status and AGE levels was observed in tumor and serum samples. AGE treatment of ER+ breast cancer cells altered ERα phosphorylation and promoted resistance to tamoxifen therapy. In a proof of concept study, physical activity and dietary intervention was shown to be viable options for reducing circulating AGE levels in breast cancer survivors.ConclusionsThere is a potential prognostic and therapeutic role for lifestyle derived AGEs in breast cancer. Given the potential benefits of lifestyle intervention on incidence and mortality, opportunities exist for the development of community health and nutritional programs aimed at reducing AGE exposure in order to improve breast cancer prevention and treatment outcomes.