Identifying key barriers to effective breast cancer control in rural settings.

Breast cancer is the most common cancer and the second most common cause of cancer mortality among women in the United States. Efforts to promote breast cancer control in rural settings face specific challenges. Access to breast cancer screening, diagnosis, and treatment services is impaired by shortages of primary care and specialist providers, and geographic distance from medical facilities. Women in rural areas have comparable breast cancer mortality rates compared to women in urban settings, but this is due in large part to lower incidence rates and masks a substantial rural/urban disparity in breast cancer survival among women diagnosed with breast cancer. Mammography screening utilization rates are slightly lower among rural women than their urban counterparts, with a corresponding increase in late stage breast cancer. Differences in breast cancer survival persist after controlling for stage at diagnosis, largely due to disparities in access to treatment. Travel distance to treatment centers is the most substantial barrier to improved breast cancer outcomes in rural areas. While numerous interventions have been demonstrated in controlled studies to be effective in promoting treatment access and adherence, widespread dissemination in public health and clinical practice remains lacking. Efforts to improve breast cancer control in rural areas should focus on implementation strategies for improving access to breast cancer treatments.

Risk for breast cancer and management of unaffected individuals with non-BRCA hereditary breast cancer.

About 5%-10% of breast cancer is hereditary with BRCA1 and BRCA2 being the most common genes associated with hereditary breast cancer (HBC). Several additional genes have recently been associated with HBC. These genes can be classified as highly or moderately penetrant genes with lifetime risk >30% or 17%-30%, respectively. Highly penetrant genes associated with HBC include TP53, PTEN, CDH1, STK11, and PALB2. While, moderately penetrant genes include CHEK2, ATM, BARD1, BRIP1, NBN, NF1, RAD51D, and MSH6. Breast cancer risk and recommendations for screening and risk-reduction vary by gene. In general, screening breast MRI is recommended for women at >20% lifetime risk, which includes women with mutations in highly penetrant genes and the majority (but not all) moderately penetrant genes. Consideration of chemoprevention is recommended for women with mutations in high and moderately penetrant genes. Risk-reducing mastectomy does reduce the risk of breast cancer to the greatest extent and can be considered for women with highly penetrant genes. However, this procedure is associated with significant morbidities that should be considered, especially given the benefit of using screening breast MRI for high-risk women. BSO is only recommended for women with mutations in genes associate with increased risk for ovarian cancer and not as a breast cancer risk-reducing strategy. As more women undergo testing, additional genes may be identified and risk estimates for current genes and management recommendations may be modified.

Importance of family history and indications for genetic testing.

Family history is an important cancer risk assessment tool, and it is easy to use. The family history is integral in identifying an individual's risk for primary cancer and assists in the assessment of risk for a second primary cancer. For oncology providers, the critical family history is defined as including first- and second-degree family history, maternal and paternal history, type of primary cancer, and age at diagnosis and ethnicity. Family history should be taken at diagnosis and updated periodically. Despite the importance of family history to patient care, there are significant barriers to taking a family history. We review the impact of collecting complete family history data with respect to calculation of cancer risk, recommendations for screening, and prevention strategies and referral for genetic testing.

Increasing Adherence to Adjuvant Hormone Therapy Among Patients With Breast Cancer: A Smart Phone App-Based Pilot Study.

PURPOSE: This study tested the feasibility and efficacy of using a text-based intervention to increase initiation, decrease discontinuation, and improve adherence as prescribed to adjuvant hormone therapy (AHT) among hyphenate post-menopausal breast cancer survivors. METHODS: The 3-month intervention consisted of daily text message reminders to take medication, coupled with a dynamic (eg, feedback on progress) tailored intervention using weekly interactive surveys delivered by a smartphone app. Five clinic sites within the Alliance for Clinical Trials in Oncology participated. Hormone levels were measured prior to AHT initiation and at study exit. RESULTS: Of the 39 patients recruited to the pilot study, 27 (69.2%) completed all study requirements (completed both the baseline and the exit surveys, both blood draws, and did not miss more than 2 weekly surveys). Significant improvements were observed pre- to postintervention for self-reported medication adherence (P = .015), mental health functioning (P = .007), and perceived stress (P = .04). Significant decreases in estradiol, estrogen, and estrone hormone levels were observed from baseline to study exit (P < .001), indicating the accuracy of self-reported AHT adherence. Participants (91.9%) and physicians (100%) agreed that participant participation in the intervention was beneficial. CONCLUSIONS: The results of this pilot study established the general feasibility and efficacy of an app-based intervention to support patient AHT adherence. Larger controlled, randomized trials are needed to examine the effectiveness of the app-based intervention in improving AHT and quality of life among breast cancer survivors.

Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2 allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11.

For 21 putative BRCA1 and BRCA2 splice site variants, the concordance between mRNA analysis and predictions by in silico programs was evaluated. Aberrant splicing was confirmed for 12 alterations. In silico prediction tools were helpful to determine for which variants cDNA analysis is warranted, however, predictions for variants in the Cartegni consensus region but outside the canonical sites, were less reliable. Learning algorithms like Adaboost and Random Forest outperformed the classical tools. Further validations are warranted prior to implementation of these novel tools in clinical settings. Additionally, we report here for the first time activated cryptic donor sites in the large exon 11 of BRCA2 by evaluating the effect at the cDNA level of a novel tandem duplication (5' breakpoint in intron 4; 3' breakpoint in exon 11) and of a variant disrupting the splice donor site of exon 11 (c.6841+1G > C). Additional sites were predicted, but not activated. These sites warrant further research to increase our knowledge on cis and trans acting factors involved in the conservation of correct transcription of this large exon. This may contribute to adequate design of ASOs (antisense oligonucleotides), an emerging therapy to render cancer cells sensitive to PARP inhibitor and platinum therapies.

Aspirin use is associated with lower mammographic density in a large screening cohort.

BACKGROUND: Observational and biologic studies suggest that aspirin is a promising prevention therapy for breast cancer. However, clinical trials to date have not corroborated this evidence, potentially due to study design. We evaluated the effect of aspirin on mammographic density (MD), an established modifiable risk factor for breast cancer. METHODS: Electronic medical records from the University of Pennsylvania were evaluated for women who underwent screening mammography, saw their primary care provider, and had a confirmed list of medications during 2012-2013. Logistic regression was performed to test for associations between clinically recorded MD and aspirin use, after adjusting for age, body mass index (BMI), and ethnicity. RESULTS: We identified 26,000 eligible women. Mean age was 57.3, mean BMI was 28.9 kg/m2, 41% were African American, and 19.7% reported current aspirin use. Aspirin users were significantly older and had higher BMI. There was an independent, inverse association between aspirin use and MD (P trend < 0.001). Women with extremely dense breasts were less likely to be aspirin users than women with scattered fibroglandular density (OR 0.73; 95% CI 0.57-0.93). This association was stronger for younger women (P = 0.0002) and for African Americans (P = 0.011). The likelihood of having dense breasts decreased with aspirin dose (P trend = 0.007), suggesting a dose response. CONCLUSIONS: We demonstrate an independent association between aspirin use and lower MD in a large, diverse screening cohort. This association was stronger for younger and African American women: two groups at greater risk for ER- breast cancer. These results contribute to the importance of investigating aspirin for breast cancer prevention.

Platelet phenotype changes associated with breast cancer and its treatment.

Platelets and their granular contents influence both angiogenesis and breast cancer progression. This study was performed to assess the effect of breast cancer and its treatment on platelet biology and the response to inhibition of the platelet P2Y12 receptor. Receptor-specific platelet activation and inhibition was studied for three platelet-associated proteins important in cancer angiogenesis and progression, vascular endothelial growth factor (VEGF), thrombospondin1 (TSP1), and transforming growth factor beta 1 (TGF-ß1). Twenty-four women with active breast cancer and 10 healthy controls not receiving antiplatelet therapy participated in the study. Ex vivo activation of platelets in whole blood was accomplished using PAR1AP, PAR4AP, convulxin, and ADP. Platelet inhibition was accomplished using the P2Y12 receptor antagonist cangrelor (the in vitro equivalent of clopidogrel). VEGF, TSP1, and TGF-ß1 were measured using standard ELISA. Platelet activation by ADP, PAR1, PAR4, and collagen receptors increased VEGF, TSP1, and TGF-ß1 secretion in patients with breast cancer. Agonist-induced release of VEGF was greater in cancer patients as compared to healthy controls (p = 0.02 for ADP, p < 0.001 for PAR1AP, PAR4AP, and convulxin) despite a decrease in the efficiency of VEGF secretion in patients with breast cancer. These differences were not observed for TSP1 and TGF-ß1 secretion. P2Y12 receptor inhibition decreased VEGF, TSP1, and TGF-ß1 secretion. In patients with cancer, cangrelor inhibited TSP1 release to a greater extent than VEGF and TGF-ß1 release. In patients with breast cancer, the magnitude of platelet inhibition achieved by cangrelor was greater than that achieved with healthy controls for all agonists and platelet proteins studied. While platelets are known to influence progression of breast cancer, our results show that breast cancer and its treatment influence the platelet phenotype by increasing the secretion of pro-angiogenic proteins following platelet activation, modulating the efficiency of platelet protein release as well as increasing the response to antiplatelet therapy.

Contribution of extended family history in assessment of risk for breast and colon cancer.

BACKGROUND: Family history is important for identifying candidates for high risk cancer screening and referral for genetic counseling. We sought to determine the percentage of individuals who would be eligible for high risk cancer screening or genetic referral and testing if family history includes an extended (vs limited) family history. METHODS: Family histories were obtained from 626 women at UVMMC associated mammography centers from 2001 to 2002. ACS guidelines were used to determine eligibility for high risk breast or colon cancer screening. Eligibility for referral for genetic counseling for hereditary breast and colon cancer was determined using the Referral Screening Tool and Amsterdam II screening criteria, respectively. All family histories were assessed for eligibility by a limited history (first degree relatives only) and extended history (first and second degree relatives). RESULTS: Four hundred ninety-nine histories were eligible for review. 18/282 (3.6 %) and 62/123 (12 %) individuals met criteria for high risk breast and colon cancer screening, respectively. 13/18 (72 %) in the high risk breast cancer screening group and 12/62 (19 %) in the high risk colon cancer screening group met criteria based upon an extended family history. 9/282 (1.8 %) and 31/123 (6.2 %) individuals met criteria for genetic counseling referral and testing for breast and colon cancer, respectively. 2/9 (22 %) of individuals in the genetic breast cancer screening group and 21/31 (68 %) individuals in the genetic colon cancer screening group met criteria based upon extended family history. CONCLUSIONS: This is one of the first studies to suggest that first degree family history alone is not adequate for identification of candidates for high risk screening and referral for genetic counseling for hereditary breast and colon cancer syndromes. A larger population is needed to further validate this data.

Standardizing analysis of circulating microRNA: clinical and biological relevance.

Circulating microRNAs (c-miRNAs) provide a new dimension as clinical biomarkers for disease diagnosis, progression, and response to treatment. However, the discovery of individual miRNAs from biofluids that reliably reflect disease states is in its infancy. The highly variable nature of published studies exemplifies a need to standardize the analysis of miRNA in circulation. Here, we show that differential sample handling of serum leads to inconsistent and incomparable results. We present a standardized method of RNA isolation from serum that eliminates multiple freeze/thaw cycles, provides at least three normalization mechanisms, and can be utilized in studies that compare both archived and prospectively collected samples. It is anticipated that serum processed as described here can be profiled, either globally or on a gene by gene basis, for c-miRNAs and other non-coding RNA in the circulation to reveal novel, clinically relevant epigenetic signatures for a wide range of diseases.

Weekly vs Every-3-Week Carboplatin with Weekly Paclitaxel in Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer: A Retrospective Analysis.

Background: Adding carboplatin to weekly paclitaxel as part of neoadjuvant chemotherapy (NACT) for stage II-III triple negative breast cancer (TNBC) has been shown to significantly increase the pathologic complete response (pCR) rate. Hematologic toxicities associated with every 3-week dosing of carboplatin have led some oncologists to explore weekly dosing as an alternative, but there are little published data comparing the two dosing schedules. Methods: We performed a retrospective analysis of patients who received paclitaxel and carboplatin, usually followed by AC, as initial NACT for TNBC at two academic cancer centers between 2008 and 2018 for whom pathologic results and post-operative follow-up were available. We recorded pCR, defined as ypT0/isN0, treatment delivery and disease-free survival, censored as of the patient's last follow-up visit. Results: A total of 76 patients were identified (median age 49 years). A total of 47 received weekly carboplatin, of whom 83% received at least 11 of 12 planned doses, and 29 received every 3-week carboplatin, of whom 90% received all 4 planned doses. pCR rates were similar, 53% with weekly and 55% with every 3-week carboplatin dosing. At median follow-up of 18 months (range <1-118), 93% of patients who achieved pCR were alive and free from recurrence, compared to 74% of those who did not. Conclusion: pCR rates were similar between patients receiving weekly or every 3-week carboplatin and were similar to those reported in prior trials with carboplatin. These data suggest that providers can choose either weekly or every 3-week carboplatin dosing without compromising the likelihood of achieving pCR.

Lifestyle, Behavioral, and Dietary Risk Factors in Relation to Mammographic Breast Density in Women at High Risk for Breast Cancer.

BACKGROUND: Women at high risk for breast cancer due to genetics or risk factor profiles are counseled to adopt lifestyle, behavioral, and dietary changes to help reduce their risk. These recommendations are based on studies of women at average risk, so their effectiveness in high-risk women is unclear. METHODS: We evaluated the impact of physical activity, smoking, alcohol consumption, and intake of folate and carotenoids on mammographic breast density-a proxy for breast cancer risk-among 387 high-risk women. Exposures were self-reported on questionnaires. Breast dense area, nondense area, and percent dense area were measured from screening mammograms with Library for Breast Radiodensity Assessment software. Cross-sectional associations were estimated with multivariable quantile regression models. RESULTS: After adjusting for age, adiposity, reproductive history, and use of postmenopausal hormones, no breast density measure was associated with physical activity level, smoking status, alcohol consumption, or estimated intake of folate, alpha-carotene, beta-carotene, lutein/zeaxanthin, and beta-cryptoxanthin. Lycopene intake was associated with lower dense area when comparing the highest and lowest intake categories (adjusted difference in median = -14 cm2, 95% confidence interval: -29 to 1.3 cm2). This association may be explained by incomplete adjustment for adiposity. CONCLUSIONS: Recommended lifestyle, behavioral, and dietary changes to mitigate personal risk of breast cancer do not substantially impact mammographic breast density measures. IMPACT: Alternative strategies, such as increased uptake of chemoprevention, may better serve risk reduction efforts in women at high risk for breast cancer.

The Influence of Vitamin D on Mammographic Density: Results from CALGB 70806 (Alliance) a Randomized Clinical Trial.

Current therapies for breast cancer prevention only prevent estrogen receptor positive (ER+) disease and toxicity limits use of these agents. Vitamin D is a potential prevention therapy for both ER+ and ER- disease and is safe with few side effects. This study evaluates the effect of 1-year of vitamin D supplementation on mammographic density (MD), a biomarker of breast cancer risk in a multicenter randomized controlled trial. Premenopausal women with ≥25% MD and no history of cancer were randomly assigned to 2,000 international units (IU) of vitamin D or placebo orally daily for 1 year. Change in percent MD was evaluated using Cumulus software after all participants completed treatment. Three hundred women enrolled between January 2011 and December 2013 with a mean age of 43 and diverse ethnicity [14% Hispanic, 12% African American (AA)]. Supplementation significantly increased vitamin D levels compared with placebo (14.5 ng/mL vs. -1.6 ng/mL; P < 0.0001) with all participants on the vitamin D arm achieving vitamin D sufficiency at 12 months. Vitamin D was safe and well tolerated. After adjustment for baseline MD, the mean between-arm difference (vitamin D vs. placebo) at 1 year was -0.75 (-0.26, 1.76; P = 0.56). A greater effect was seen for women with ≥50% MD and AA women, although neither reached significance. This randomized controlled trial demonstrated significant improvement in vitamin D levels with 2,000 IU for 1 year, with 100% of supplemented women achieving sufficiency. However, a null effect was seen regarding change in MD for premenopausal women (the primary outcome of the study). PREVENTION RELEVANCE: Current therapies for breast cancer prevention only prevent estrogen receptor positive (ER+) disease and are underutilized due to toxicity and side effects. Vitamin D is a potential prevention therapy for both ER+ and ER- disease and is safe with few side effects.

Primary care physicians' use of family history for cancer risk assessment.

BACKGROUND: Family history (FH) assessment is useful in identifying and managing patients at increased risk for cancer. This study assessed reported FH quality and associations with physician perceptions. METHODS: Primary care physicians practicing in two northeastern U.S. states were surveyed (n = 880; 70% response rate). Outcome measures of FH quality were extent of FH taken and ascertaining age at cancer diagnosis for affected family members. Predictors of quality measured in this survey included: perceived advantages and disadvantages of collecting FH information, knowledge of management options, access to supportive resources, and confidence in ability to interpret FH. RESULTS: Reported collection of information regarding second degree blood relatives and age of diagnosis among affected relatives was low. All hypothesized predictors were associated with measures of FH quality, but not all were consistent independent predictors. Perceived advantages of taking a family history, access to supportive resources, and confidence in ability to identify and manage higher risk patients were independent predictors of both FH quality measures. Perceived disadvantages of taking a family history was independently associated one measure of FH quality. Knowledge of management options was not independently associated with either quality measure. CONCLUSIONS: Modifiable perception and resource factors were independently associated with quality of FH taking in a large and diverse sample of primary care physicians. Improving FH quality for identification of high risk individuals will require multi-faceted interventions.

Effect of neuromuscular electrical stimulation on skeletal muscle size and function in patients with breast cancer receiving chemotherapy.

Exercise has numerous benefits for patients with cancer, but implementation is challenging because of practical and logistical hurdles. This study examined whether neuromuscular electrical stimulation (NMES) can serve as a surrogate for classic exercise by eliciting an exercise training response in skeletal muscle of women diagnosed with breast cancer undergoing chemotherapy. Patients (n = 22) with histologically confirmed stage I, II, or III breast cancer scheduled to receive neoadjuvant or adjuvant chemotherapy were randomized to 8 wk of bilateral neuromuscular electrical stimulation (NMES; 5 days/wk) to their quadriceps muscles or control. Biopsy of the vastus lateralis was performed at baseline and after 8 wk of intervention to assess muscle fiber size, contractility, and mitochondrial content. Seventeen patients (8 control/9 NMES) completed the trial and were included in analyses. NMES promoted muscle fiber hypertrophy (P < 0.001), particularly in fast-twitch, myosin heavy chain (MHC) IIA fibers (P < 0.05) and tended to induce fiber type shifts in MHC II fibers. The effects of NMES on single-muscle fiber contractility were modest, and it was unable to prevent declines in the function in MHC IIA fibers. NMES did not alter intermyofibrillar mitochondrial content/structure but was associated with reductions in subsarcolemmal mitochondria. Our results demonstrate that NMES induces muscle fiber hypertrophy and fiber type shifts in MHC II fibers but had minimal effects on fiber contractility and promoted reductions in subsarcolemmal mitochondria. Further studies are warranted to evaluate the utility of NMES as an exercise surrogate in cancer patients and other conditions.NEW & NOTEWORTHY This is the first study to evaluate whether neuromuscular electrical stimulation (NMES) can be used as an exercise surrogate to improve skeletal muscle fiber size or function in cancer patients receiving treatment. We show that NMES promoted muscle fiber hypertrophy and fiber type shifts but had minimal effects on single-fiber contractility and reduced subsarcolemmal mitochondria.

Ductal lavage of cancerous and unaffected breasts: procedure success rate and cancer detection.

OBJECTIVE: To evaluate ductal lavage (DL) performance in women with known breast cancer and to assess cell yield from contralateral high-risk breasts. STUDY DESIGN: Women with newly diagnosed breast cancer were offered study participation. They underwent bilateral nipple aspiration, followed by DL of those ducts demonstrating nipple aspiration fluid (NAF) production. The procedures were conducted in the operating room prior to definitive surgery. Samples were interpreted masked as to which breast was malignant, and the interpretation used a 5-category scheme: insufficient, benign, mildly atypical, markedly atypical or malignant. RESULTS: A total of 23 women with 24 cancers were enrolled, ranging in age from 32 to 76. One had ductal carcinoma in situ; there were 13 T1, 6 T2 and 4 T3 lesions. NAF was identified in 72% of breasts, more commonly in cancerous than unaffected breasts. DL was performed on 33 breasts; of these, 55% were adequate. Only 16.6% of samples from malignant breasts contained abnormality, marked atypia in 1 and malignancy in 3. No samples from unaffected breasts demonstrated cellular abnormalities. CONCLUSION: The low sensitivity of DL performed on malignant breasts to identify abnormal cells adds to the growing body of evidence that this is not an effective tool in identifying existing breast cancer. Numbers are small, but the ability of DL to identify atypia in unaffected high-risk breasts may also be suboptimal. Future efforts should focus on molecular markers of risk and on alternate means of cell or tissue retrieval.