BMI, physical activity, and breast cancer subtype in white, black, and Sea Island breast cancer survivors.

Higher BMI, lower rates of physical activity (PA), and hormone receptor-negative breast cancer (BC) subtype are associated with poorer BC treatment outcomes. We evaluated the prevalence of high BMI, low PA level, and BC subtype among survivors with white/European American (EA) and African American (AA) ancestry, as well as a distinct subset of AAs with Sea Island/Gullah ancestry (SI). We used the South Carolina Central Cancer Registry to identify 137 (42 EAs, 66 AAs, and 29 SIs) women diagnosed with BC and who were within 6-21 months of diagnosis. We employed linear and logistic regression to investigate associations between BMI, PA, and age at diagnosis by racial/ethnic group. Most participants (82%) were overweight/obese (P=0.46). BMI was highest in younger AAs (P=0.02). CDC PA guidelines (≥150min/week) were met by only 28% of participants. The frequency of estrogen receptor (ER)-negative BC subtype was lower in EAs and SIs than in AAs (P<0.05). This is the first study to identify differences in obesity and PA rates, and BC subtype in EAs, AAs, and SIs. BMI was higher, PA rates were lower, and frequency of ER-negative BC was higher in AAs as compared to EAs and SIs. This study highlights the need to promote lifestyle interventions among BC survivors, with the goal of reducing the likelihood of a BC recurrence. Integrating dietary and PA interventions into ongoing survivorship care is essential. Future research could evaluate potential differential immune responses linked to the frequency of triple negative BC in AAs.

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

PURPOSE: Lifestyle 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. METHODS: We 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. RESULTS: An 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. CONCLUSIONS: There 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.

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.

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.

Management of the asymptomatic BRCA mutation carrier.

Current management of an asymptomatic BRCA mutation carrier includes early initiation and intensive cancer screening in combination with risk reduction strategies. The primary objectives of these interventions are earlier detection and cancer prevention to increase quality of life and prolonged survival. Existing recommendations are often based on the consensus of experts as there are few, supportive, randomized control trials. Management strategies for unaffected patients with BRCA mutations are continually redefined and customized as more evidence-based knowledge is acquired with regard to current intervention efficacy, mutation-related histology, and new treatment modalities. This review provides an outline of current, supported management principles, and interventions in the care of the asymptomatic BRCA mutation carrier. Topics covered include surveillance modalities and risk reduction achieved through behavioral modification, chemoprevention, and prophylactic surgery.

The efficacy of sertraline for controlling hot flashes in women with or at high risk of developing breast cancer.

The aim of the study is to evaluate the efficacy of sertraline for controlling hot flashes in women with or at high risk of breast cancer. This was a randomized, double-blind, placebo-controlled study. All participants were asked to complete hot flash diaries. Participants reporting weekly hot flash scores >15 during baseline week underwent a 1-week single-blind placebo run-in. Those reporting hot flash score reductions >50% following placebo run-in were excluded. The remaining women received an assigned treatment for 4 weeks. Both groups' demographic and clinical characteristics were similar with a greater decline, but not statistically significant, in hot flash frequencies and scores in the sertraline-treated group compared with the placebo (P = 0.13 and P = 0.15, respectively). Emotional well-being improved significantly in the sertraline group (P = 0.041). The study failed to demonstrate effectiveness of sertraline in attenuating hot flashes in women with or at high risk of developing breast cancer who were not recommended to take hormone replacement therapy.

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 > or =6 months of amenorrhea, many women < or =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 < or =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.

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

BACKGROUND: 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. METHODS: Using a database of 10,782 patients, 2685 patients were identified who experienced recurrence distantly. Clinical and biological features were analyzed in 2 ways: (1) patients who ever had versus those who never had CNS metastases, and (2) CNS metastases as the first site of recurrence versus those who had other sites. Correlations of survival after CNS metastasis with clinical and biologic features were also analyzed. RESULTS: In the ever versus never analysis, CNS metastases were significantly associated with younger age, premenopausal status, infiltrating ductal carcinoma histology (IDC), estrogen receptor (ER) and progesterone receptor (PR) negativity, low Bcl-2, high S-phase, aneuploidy, and altered p53. Tumor size, lymph node status, and use of adjuvant systemic therapy played little role. HER-2 overexpression was not associated with an increased risk in these patients (none of whom were treated with trastuzumab) (P = .91). However, epidermal growth factor receptor (EGFR) overexpression was associated with increased risk (P = .02). A multivariate analysis revealed ER negativity (odds ratio [OR] 2.8, P < .001), IDC histology (OR 2.5, P = .02), and young age (P < .001) as independent factors for CNS metastases. The clinical and biologic profiles of primary tumors with CNS metastases at first recurrence did not differ from those with CNS metastases after recurrence to other sites, except for HER-2 status. HER-2-positive tumors were not more likely to undergo recurrence initially in the CNS (P =.04). The median survival after CNS metastases was 5.5 months and HER-2-positive patients had a shorter survival. CONCLUSIONS: Younger patients with hormone receptor-negative, highly proliferative, genomically unstable, and p53-altered tumors were at increased relative risk for CNS metastases. HER-2 expression and adjuvant systemic therapies did not increase this risk.

The adherence to practice guidelines in the assessment of bone health in women with chemotherapy-induced menopause.

Premenopausal women are diagnosed with 25% of all invasive breast cancers;adjuvant chemotherapy given to many of this population may induce menopause and increase the risk of osteoporosis development. Guidelines issued by the American Society of Clinical Oncology recommend regular assessment of bone health in such women. To assess appropriate attention to bone health, we performed a retrospective, cross-sectional survey of young women at high risk of osteoporosis secondary to chemotherapy-induced premature menopause. In all, 102 women with chemotherapy-induced menopause, 75% of whom were 40 years of age or younger, were asked whether they underwent screening and preventive measures for osteoporosis. Only 56% had discussed bone health with their healthcare providers; age at diagnosis, race, and use of tamoxifen were not linked to the likelihood of such discussions. Regular exercise was recommended to 73% of the women, calcium supplementation to 56%, and bone mineral density (BMD) testing to 40%. Approximately one half of the women regularly exercised and took a calcium supplement; however, over 37% of those using a supplement took less calcium than that recommended to prevent osteoporosis. Further, 32% reported having had BMD testing;women 40 years of age or younger were less likely to have had such tests (27%) than were older women (48%;P = 0.05). More emphasis must be given to educating breast cancer survivors with chemotherapy-induced menopause about bone health and its maintenance. Approved therapies to prevent osteoporosis probably are underused in this population.

Reproductive issues for women with BRCA mutations.

Women carrying BRCA1 and BRCA2 mutations face difficult and confusing reproductive decisions that fall into three categories: issues relating to risk-reducing surgeries, issues relating to use of oral contraceptives/tubal ligation, and issues relating to pregnancy and breastfeeding. Risk-reducing surgeries may confer survival benefits, but they also affect quality of life. Oral contraceptives potentially protect mutation carriers against ovarian cancer but increase the risk of early-onset breast cancer, and evidence for the efficacy of tubal ligation in reducing ovarian cancer risk in BRCA mutation carriers is contradictory. Women with BRCA mutations may increase their risk of breast cancer by becoming pregnant before age 40 years, but breastfeeding may decrease risk of breast cancer in women with BRCA mutations, regardless of age. BRCA mutation carriers desiring to become pregnant must deal with a variety of psychosocial issues, some with significant ethical implications, with minimal guidance from research.

Use of a T cell-specific monoclonal antibody, T10B9, in a novel allogeneic stem cell transplantation protocol for hematologic malignancy high-risk patients.

To reduce the toxicity of traditional conditioning regimens for allogeneic stem cell transplantation (allo-SCT), we used single-agent chemotherapy conditioning with either busulfan (total cumulative dose, 16 mg/kg) or melphalan (200 to 240 mg/m 2 ), followed by the anti-T cell-specific monoclonal antibody T10B9 (MEDI-500) daily for 3 days. T cell-replete SCT was performed from HLA-identical sibling donors. Acute graft-versus-host disease (aGVHD) prophylaxis consisted of 7 additional days of T10B9 and delayed onset of cyclosporine (ie, on day +4 or +5). Twenty-six high-risk hematologic malignancy patients were entered onto this study. All 24 patients who survived longer than 8 days engrafted, although 1 patient experienced late graft failure. Deaths occurred in 21 of 26 patients because of infection (n = 7), progression/recurrence of primary disease (n = 6), aGVHD (n = 4), regimen-related toxicity (n = 1), and other causes (n = 3). Five of these patients are enjoying disease-free survival with a median survival of 1193 days after allo-SCT. The conditioning regimen induced modulation of surface expression of CD3 (but not CD4 or CD8) and was associated with decreasing tumor necrosis factor-alpha (but not interleukin-6) serum levels. In conclusion, single-agent chemotherapy conditioning with T10B9 produced durable engraftment and long-term survival in some patients who would not have qualified for a traditional allo-SCT.

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.

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.