Reduce Breast Cancer Recurrence Research Articles

Abstract GS4-02: Regional lymph node irradiation in early stage breast cancer: An EBCTCG meta-analysis of 13,000 women in 14 trials

Abstract Background There is uncertainty as to which lymph node regions should be irradiated following breast cancer surgery. Systematic review of radiation dosimetry indicates that in randomised trials of nodal radiation therapy (RT) versus not, radiation delivery was qualitatively better in modern trials compared to older trials. Methods We undertook an individual patient data meta–analysis of randomised trials assessing the benefits and risks of RT to different lymph node regions including the axilla, supraclavicular fossa (SCF) and internal mammary chain (IMC). Eligible studies started before 2009, and included a randomisation, or pseudo–randomisation (by left–versus–right sided tumours), in which the only difference between treatment groups was the use, or extent, of nodal irradiation. Surgery/RT to the breast was the same in both arms. Analyses used standard log–rank methods, and were stratified by study, age, nodal status and year of follow–up. – Studies were categorised according to estimated mean heart dose in the nodal RT arm and whether regimens were likely to have delivered ≥85% of prescribed dose to target nodal regions. Results Information was available on 13,132 women in 14 comparisons of nodal RT versus not. There were 3260 recurrences, 2545 deaths from breast cancer and 4147 deaths overall. Eight trials starting 1961–1978, with median follow–up 9.2 (interquartile [IQR] range 3.4–17.5) years, had estimated >8 Gy mean heart dose and likely nodal dose <85% in the nodal RT arm. In these older trials, including 2178 women, nodal RT had no effect on breast cancer recurrence [Rate ratio (RR)=0.98, 95% CI 0.85–1.13, p=0.83] or breast cancer mortality (RR=1.05, 0.91–1.21, p=0.54), but increased non–breast cancer mortality (RR=1.44, 1.20–1.73, p<0.0001), leading to a net increase in any death (RR=1.18, 1.06–1.32, p=0.004). Six studies starting 1989–2003, with a mean follow–up 9.1 [IQR 7.0–11.0] years, had likely nodal dose ≥85%, and estimated mean heart dose <8 Gy in the nodal RT arm. In these more recent studies, including 10,954 women, nodal RT reduced breast cancer recurrence (RR=0.86, 95% CI 0.79–0.94, p=0.0006), breast cancer mortality (RR=0.81, 0.74–0.90, p<0.0001) and overall mortality (RR=0.86, 0.80–0.93, p=0.0002). No excess of non–breast cancer mortality was apparent (RR=0.96, 0.79–1.18, p=0.71). Recurrence rate ratios did not vary significantly according to nodal region(s) irradiated (axilla/SCF/IMC), or the use of adjuvant chemotherapy. Conclusions RT to regional lymph nodes in older (1961–78) studies increased the overall risk of death, probably explained by radiation exposure of the lungs and heart. Nodal RT in more recent (1989–2003) studies reduced breast cancer recurrence, breast cancer mortality and overall mortality without increasing non–breast cancer mortality. The proportional benefits from today's RT may be larger. Absolute benefits for individual women will depend on their absolute recurrence and breast cancer mortality risks. Citation Format: Dodwell D, Taylor C, McGale P, Coles C, Duane F, Gray R, Kühn T, Hennequin C, Oliveros S, Wang Y, Overgaard J, Poortmans P, Whelan T. Regional lymph node irradiation in early stage breast cancer: An EBCTCG meta-analysis of 13,000 women in 14 trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS4-02.

Abstract P6-21-05: Concurrent exercise and chemotherapy in preclinical breast cancer models

Abstract The benefits of exercise following a cancer diagnosis is increasingly recognized. Increased physical activity is associated with reduced breast cancer recurrence and breast cancer specific mortality. However, the mechanisms underpinning this effect are still under investigation. The role of exercise as an adjunct to systemic therapy for breast cancer remains unclear. We hypothesize that exercise may exert an anti-tumor effect and a change in tumor immune cell infiltration. Methods We evaluated the effect of exercise alone and in combination with chemotherapy in preclinical patient-derived TNBC xenografts (PDX) established in Nude mice and PyMT mouse tumor models. Mice were individually housed in boxes equipped with running wheels and randomized to 1) clamped wheels (sedentary controls), 2) doxorubicin (Dox, 2mg/kg/week), 3) exercise (Ex) and 4) Ex + Dox. Daily distance run was measured. One week after randomization (acclimatization period), the intervention was commenced. Body composition was measured at randomization and at end point. Tumors were harvested after 5 weeks of intervention or at ethical endpoint. Tumor immune infiltrates were analyzed, and transcriptomic analysis performed. Results In the TNBC PDX model, there was no difference in tumor volume at randomization (p=0.96), or cumulative distance run after 1 week of acclimatization to the running wheel (p=0.47). At 5 weeks, Ex alone significantly reduced tumor growth rate compared with controls (relative reduction 10%, p=0.025). There was no difference between the other interventions. Mice randomized to Ex + Dox ran a shorter cumulative distance over 5 weeks compared with Ex alone (103.6 ± 16.2km vs 168.8 ±23km, p=0.028). There was no correlation between distance run and tumor volume in either of the treatment cohorts involving exercise (p=0.39). PyMT, transcriptomic and immune cell infiltration analysis will be reported. At baseline, there was no significant difference in mean total body mass (TBM), lean mass (LM) or fat mass (FM) between the intervention groups (p>0.05). At 5 weeks, the mean TBM and LM in both groups treated with Dox was significantly lower than Ex only and controls. The Ex and the control mice gained weight (11%), compared with Dox only and Ex + Dox mice which did not gain weight (0% and -6% respectively). Therefore exercise had no significant impact on TBM or LM at 5 weeks, but Dox resulted in loss of TBM and LM compared with mice not treated with Dox. Conclusion Exercise significantly reduced tumor growth compared with sedentary controls in our preclinical TNBC PDX model, however there was not synergistic effect seen with Dox. Cumulative doses of Dox resulted in weight loss and loss of lean mass, and reduced the cumulative running distance, compared with mice not treated with Dox. Citation Format: Wahlroos S, Wilkinson A, Gallego-Ortega D, Febbraio M, Lim E. Concurrent exercise and chemotherapy in preclinical breast cancer models [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-05.

Optimizing HER2-Directed Therapy in Early-Stage Breast Cancer

HER2-positive early breast cancer has been revolutionized by the development of HER2-directed therapy, which has significantly reduced breast cancer recurrence risk and improved overall survival. Here, we review the available treatment options for this patient population and discuss how we might individualize therapy in the future to optimize the balance of efficacy and toxicity. The addition of pertuzumab to a trastuzumab-based adjuvant regimen improves pathologic complete response rates and invasive disease-free survival (DFS). Addition of neratinib for patients with high-risk disease also contributes to improved DFS. Current data supports use of dual HER2-directed therapy in combination with chemotherapy, as well as extended HER2-directed therapy (beyond 1 year), in those with high-risk HER2-positive early breast cancer. Ongoing studies aim to identify biomarkers of response and resistance to standard approaches, as well as identify those who might benefit from a chemotherapy-free treatment paradigm.

Molecular determinants of post-mastectomy breast cancer recurrence

Breast cancer (BC) adjuvant therapy after mastectomy in the setting of 1–3 positive lymph nodes has been controversial. This retrospective Translational Breast Cancer Research Consortium study evaluated molecular aberrations in primary cancers associated with locoregional recurrence (LRR) or distant metastasis (DM) compared to non-recurrent controls. We identified 115 HER2 negative, therapy naïve, T 1–3 and N 0-1 BC patients treated with mastectomy but no post-mastectomy radiotherapy. This included 32 LRR, 34 DM, and 49 controls. RNAseq was performed on primary tumors in 110 patients; with no difference in RNA profiles between patients with LRR, DM, or controls. DNA analysis on 57 primary tumors (17 LRR, 15 DM, and 25 controls) identified significantly more NF1 mutations and mitogen-activated protein kinase (MAPK) pathway gene mutations in patients with LRR (24%, 47%) and DM (27%, 40%) compared to controls (0%, 0%; p < 0.0001 and p = 0.0070, respectively). Three patients had matched primary vs. LRR samples, one patient had a gain of a NF1 mutation in the LRR. There was no significant difference between the groups for PTEN loss or cleaved caspase 3 expression. The mean percentage Ki 67 labeling index was higher in patients with LRR (29.2%) and DM (26%) vs. controls (14%, p = 0.0045). In summary, mutations in the MAPK pathway, specifically NF1, were associated with both LRR and DM, suggesting that alterations in MAPK signaling are associated with a more aggressive tumor phenotype. Validation of these associations in tissues from randomized trials may support targeted therapy to reduce breast cancer recurrence.

Abstract B13: Plasma G-CSF levels are predictive of lack of response to zoledronic acid treatment in reducing breast cancer recurrence

Abstract Some breast cancer patients have no evidence of metastatic disease at the time of original diagnosis, yet ~30-40% of patients will experience recurrent breast cancer. Over 90% of breast cancer deaths occur due to distant spread of the disease, and bone is the most common site of breast cancer metastasis. Bisphosphonates, such as zoledronic acid (ZA), are used to treat patients with osteolytic disease, including metastatic breast cancer. ZA has been demonstrated to reduce disseminated tumor cells (DTCs) and breast cancer recurrence, but not all patients see this benefit and it is not yet clear what predicts benefit from adjuvant ZA treatment; the mechanism of action for this effect of ZA in reducing breast cancer remains undetermined. Here, we establish that ZA renders osteoclast progenitor cells (OCPs) tumor suppressive, primarily by directing their lineage potential. In instances where the OCP lineage potential was modulated via systemic or tumor-derived granulocyte-colony stimulating factor (G-CSF), OCPs did not differentiate into tumor-suppressive populations but instead into mature osteoclasts. High G-CSF was sufficient to abrogate the tumor-suppressive effect of ZA. Furthermore, we determined that in a subset of patient plasma samples from the AZURE clinical trial where stage II/III breast cancer patients were randomized to receive standard systemic treatment alone with adjuvant ZA treatment, patients who had baseline plasma G-CSF levels &amp;gt;23 pg/mL had reduced disease-free survival as assessed over a 10-year period post treatment initiation compared to patients with baseline plasma G-CSF levels &amp;lt;23 pg/mL (p=0.02). These findings indicate that patients with higher baseline plasma G-CSF levels will not likely observe reduction in breast cancer recurrence with adjuvant ZA treatment, and in fact may have worse prognosis with adjuvant ZA treatment as compared to control treatment. Our data are the first to demonstrate that ZA mediates its tumor-suppressive function via the OCP population and implicate capitalizing on the differentiation potential of the OCPs to maximize patient response to adjuvant ZA treatment in breast cancer risk of recurrence. Citation Format: Jessalyn M. Ubellacker, Ninib Baryawno, Nicolas Severe, Molly J. DeCristo, Jaclyn Sceneay, Marie-Therese Haider, Catherine S. Rhee, Yuanbo Qin, Ingunn Holen, Walter M. Gregory, Janet E. Brown, Robert E. Coleman, David T. Scadden, Sandra S. McAllister. Plasma G-CSF levels are predictive of lack of response to zoledronic acid treatment in reducing breast cancer recurrence [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B13.

Effect of neuromuscular taping on musculoskeletal disorders secondary to the use of aromatase inhibitors in breast cancer survivors: a pragmatic randomised clinical trial

BackgroundAromatase inhibitors reduce breast cancer recurrence rates in postmenopausal women by about 30% compared with tamoxifen while treatments differ. Unfortunately, nearly half of women taking AIs report AI-associated arthralgia (AIA), leading to therapy abandon in on third of patients, which could lead to cancer recurrence. The purpose of the current study was to evaluate the effectiveness of Neuromuscular Taping (NMT) in the treatment of AIA in women who have been treated of BC.MethodsThis study included 40 BC survivors receiving endocrine therapy (either AIs or TMX) from Hospital Universitario Virgen de la Victoria (Málaga, Spain) suffered from AIA. Patients were randomized to one of the two groups that made this pilot study: A. Placebo intervention B. Real NMT. Clinical data were collected from medical history, grip strength, algometry measured, questionnaires and VAS scale. There have been three interventions prior to the completion of the study, 5 weeks later. The primary objective of this pilot study was to achieve an improvement of pain by 20% decrease of VAS.ResultsSignificant differences in measures of VAS (p = 0.009), global health status/QoL (p = 0.005), fatigue (p = 0.01) and pain (p = 0.04) were observed post intervention with NMT.ConclusionsAn intervention by NMT to MSCM under treatment with AIs improves their subjective sensation of pain. In addition, this taping had an impact on variables related to the quality of life. This pilot study may be the basis for others to support the use of NMT for the treatment of AIAs, thereby improving their well-being and reducing the dropout rate.Trial registrationClinicalTrials.gov Identifier: NCT02406794. Registered on 2 April 2015 Retrospectively registered.

The Effects of Metformin and Weight Loss on Biomarkers Associated With Breast Cancer Outcomes.

This study investigated the effects of metformin and weight loss on biomarkers associated with breast cancer prognosis. Overweight/obese postmenopausal breast cancer survivors (n = 333) were randomly assigned to metformin vs placebo and to a weight loss intervention vs control (ie, usual care). The 2 × 2 factorial design allows a single randomized trial to investigate the effect of two factors and interactions between them. Outcomes were changes in fasting insulin, glucose, C-reactive protein (CRP), estradiol, testosterone, and sex-hormone binding globulin (SHBG). The trial was powered for a main effects analysis of metformin vs placebo and weight loss vs control. All tests of statistical significance were two-sided. A total of 313 women (94.0%) completed the six-month trial. High prescription adherence (ie, ≥80% of pills taken) ranged from 65.9% of participants in the metformin group to 81.3% of those in the placebo group (P < .002). Mean percent weight loss was statistically significantly higher in the weight loss group (-5.5%, 95% confidence interval [CI] = -6.3% to -4.8%) compared with the control group (-2.7%, 95% CI = -3.5% to -1.9%). Statistically significant group differences (ie, percent change in metformin group minus placebo group) were -7.9% (95% CI = -15.0% to -0.8%) for insulin, -10.0% (95% CI = -18.5% to -1.5%) for estradiol, -9.5% (95% CI = -15.2% to -3.8%) for testosterone, and 7.5% (95% CI = 2.4% to 12.6%) for SHBG. Statistically significant group differences (ie, percent change in weight loss group minus placebo group) were -12.5% (95% CI = -19.6% to -5.3%) for insulin and 5.3% (95% CI = 0.2% to 10.4%) for SHBG. As adjuvant therapy, weight loss and metformin were found to be a safe combination strategy that modestly lowered estrogen levels and advantageously affected other biomarkers thought to be on the pathway for reducing breast cancer recurrence and mortality.

Adjuvant endocrine therapy after breast cancer: a qualitative study of factors associated with adherence.

IntroductionDespite evidence of the efficacy of adjuvant endocrine therapy (AET) in reducing the risk of recurrence and mortality after treatment for primary breast cancer, adherence to AET is suboptimal. This study aimed to explore factors that influence adherence and nonadherence to AET following breast cancer to inform the development of supportive interventions.MethodsInterviews were conducted with 32 women who had been prescribed AET, 2–4 years following their diagnosis of breast cancer. Both adherers (n=19) and nonadherers (n=13) were recruited. The analysis was conducted using the Framework approach.ResultsFactors associated with adherence were as follows: managing side effects including information and advice on side effects and taking control of side effects, supportive relationships, and personal influences. Factors associated with nonadherence were as follows: burden of side effects, feeling unsupported, concerns about long-term AET use, regaining normality, including valuing the quality of life over length of life, and risk perception.ConclusionProvision of timely information to prepare women for the potential side effects of AET and education on medication management strategies are needed, including provision of timely and accurate information on the efficacy of AET in reducing breast cancer recurrence and on potential side effects and ways to manage these should they arise. Trust in the doctor–patient relationship and clear patient pathways for bothersome side effects and concerns with AET are important. Training and education on AET for GPs should be considered alongside novel care pathways such as primary care nurse cancer care review and community pharmacist follow-up.

Factors Influencing Use of Hormone Therapy for Ductal Carcinoma In Situ: A National Cancer Database Study.

Adjuvant hormonal therapy (HT) reduces breast cancer recurrence risk in estrogen receptor-positive (ER+) ductal carcinoma in situ (DCIS). We assessed national practice patterns and influence of surgery and pathology on HT use in DCIS. Data on DCIS patients diagnosed from 2004 to 2014 were extracted from the National Cancer Database, and patients were classified according to ER status and whether HT was received. Factors associated with HT use were assessed using Chi square tests for univariate analysis and logistic regression for multivariate analysis. Overall, 207,738 patients were evaluable as follows: ER+ (69.3%), ER- (13.7%), and ER unknown (17.0%). Among ER+DCIS patients, 46.5% received HT, and HT use increased over time (42.3% in 2004 to 50.6% in 2014; p<0.001). In contrast, 7.8% of ER- DCIS patients received HT, decreasing from 10.7% in 2004 to 5.9% in 2014 (p<0.001). HT use varied by surgery type (BCS, 53.9%; unilateral mastectomy, 31.5%; and bilateral mastectomy, 8.1%; p<0.001) and use was higher in BCS patients receiving adjuvant radiation than those not receiving radiation (62.7 vs. 29.1%; p<0.001). Males treated with BCS were less likely to receive HT than females (43.2 vs. 54.0%; p<0.001). In the BCS subset, higher use of HT was associated with more recent calendar year, age between 40 and 80years, female sex, positive progesterone receptor status, and radiation use. Adjuvant HT use in ER+ DCIS has increased over time, with the highest rates in patients treated with BCS and radiation. While inappropriate HT use was observed in ER- and bilateral mastectomy patients, the frequency of use in these categories decreased over time.

Lifestyle Interventions to Improve Cardiorespiratory Fitness and Reduce Breast Cancer Recurrence.

As patients are living longer after a cancer diagnosis, survivorship is becoming increasingly important in cancer care. The sequelae of multimodality therapies include weight gain and decreased cardiorespiratory fitness, which increase cardiovascular risk. Evidence suggests that physical activity reduces the risk of breast cancer recurrence and death. Avoidance of weight gain after therapy also improves outcomes after a diagnosis of breast cancer. Prospective randomized trials must be performed to determine the benefits of specific physical activity and dietary habits for survivors of breast cancer. This review outlines the important physiologic changes that occur with antineoplastic therapy and the important role of exercise and diet.

An anti-inflammatory dietary intervention to reduce breast cancer recurrence risk: Study design and baseline data

U.S. breast cancer survivors (BCSs) are expected to increase to 4 million in the next 5–10years. Cancer recurrence risk is highest among obese survivors. Inflammatory (Pro-I) biomarkers including C-reactive protein (CRP), Interleukins -3, -6, and -8 (IL-3, IL-6, IL-8), and Tumor Necrosis Factor (TNF)–α have been associated with cancer recurrence risk. Nutritional interventions aimed at reducing inflammation (INF) may contribute to reduced cancer recurrence risk, but studies have been limited to animal models. The goals of this one-year, culinary-based, pilot intervention were to: 1) decrease Pro-I biomarkers and increase anti-inflammatory (AI) cytokine, IL-10, by promoting AI food incorporation into BCS diets; and 2) examine intervention effects on cancer risk factors including body mass index (BMI) and circulating adipose stromal cells (ASCs). A total of 153 BCSs were recruited. Overweight and obese women aged 18 or older were randomized into Intervention (IG; n=76) and Control (CG; n=77) groups. CG received monthly nutritional brochures from the American Institute for Cancer Research. IG attended 6 monthly workshops (lectures on AI topics and chef-prepared food demonstrations), and received monthly newsletters and telephone calls incorporating Motivational Interviewing. At baseline, 6- and 12-month assessments, fasting serum was assayed for Pro-I/AI marker and ASC levels. Using R and Stata version 14 (Stata Corp, 2015), no significant differences were found between groups on baseline demographic variables. Correlations between serum cytokine levels, BMI, % body fat, ASCs, and self-reported variables are discussed.

Extended Endocrine Therapy: Is 5Years Enough?

Women with hormone receptor (HR)-positive breast cancer remain at risk for cancer recurrence for decades. In this review, we address recent data regarding the benefits and risks of extended endocrine therapy. Ten years of treatment with either tamoxifen or an aromatase inhibitor resulted in superior disease-free survival compared to 5years of treatment. However, there are risks associated with extended therapy with either class of medication. Multiparameter genetic tests are in development to individualize the risk of late breast cancer recurrence and predict benefit from extended endocrine treatment. Extended endocrine therapy is a promising strategy to reduce breast cancer recurrence in women with HR-positive breast cancer. This approach should be considered based on individual risk of cancer recurrence compared to potential benefit, comorbidities, and tolerance of therapy.

Abstract P3-07-14: Targeting ERR-α regulated lactate metabolism eliminates drug-resistant breast cancer cells

Abstract Novel therapeutic strategies to eliminate chemo-resistant tumour cells responsible for the development of secondary lesions are essential in order to prevent breast cancer relapse. We have developed an in vitro model system enabling isolation of a putative metastasis-initiating breast cancer cell sub-population with a mitotically quiescent, drug-resistant phenotype. We hypothesise that this population is able to utilise oestrogen-related receptor-alpha (ERR-α)-regulated oxidative lactate metabolism and that inhibition of this critical survival pathway will result in elimination of tumour cells that have survived anti-cancer therapies. Flow cytofluormetric monitoring of Vybrant® DiD retention identified a mitotically quiescent sub-population (~0.05%) in MDA-MB-231 human breast cancer cells grown under high glucose (11mM) conditions. DiD-retaining cells accumulated in the G2/M phase of the cell cycle and were shown to be non-senescent following cytochemical analysis of β-galactosidase activity. Cytotoxicity assays with doxorubicin (0.40μM for 72 hours) demonstrated increased survival in the quiescent fraction (40.76%) compared with the rapidly dividing bulk cell population (1.63%, P ≤ 0.0001). Isolated drug-resistant cells contained a sub-fraction (~1%) that was able to form new clonal populations following cessation of treatment. Mitotically quiescent cells were cultured under high glucose (11mM) or glucose-depleted conditions with high lactate (22mM) in the presence of ERR-α inhibitors Cpd29 (10μM) or XCT790 (10μM). Colony formation was completely eliminated in Cpd29- and XCT790-treated samples compared to untreated controls. Drug-resistant sub-clones were isolated from the quiescent population following 72 hours treatment with doxorubicin (0.40μM) and were cultured under glucose-depleted conditions with high lactate (22mM) in the presence of ERR-α inhibitors Cpd29 (10μM) or XCT790 (10μM). In both instances, colony formation was completely prevented. We provide the first evidence that blocking cellular energy production through inhibition of ERR-α regulated oxidative lactate metabolism can eradicate a chemo-resistant, quiescent breast cancer cell population. Our data suggest that ERR-α inhibitors may be used in combination with chemotherapy to eliminate minimal residual disease and reduce breast cancer recurrence. Citation Format: Quayle L, Park S, McDonnell DP, Ottewell PD, Holen I. Targeting ERR-α regulated lactate metabolism eliminates drug-resistant breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-07-14.

Low glycemic index diet, exercise and vitamin D to reduce breast cancer recurrence (DEDiCa): design of a clinical trial

BackgroundMechanisms influencing breast cancer (BC) development and recurrence include hyperglycemia, hyperinsulinemia, high insulin-like growth factor-1, high circulating estrogen, inflammation and impaired cellular differentiation/apoptosis. A lifestyle program that targets all the above mechanisms may be warranted. Low glycemic index (GI) foods produce lower post-prandial glucose and insulin responses and have been associated with lower BC risk. Moderate physical activity post-diagnosis reduces BC recurrence and mortality, partly explained by reduced insulin and estrogen levels. Vitamin D increases cell differentiation/apoptosis and high serum vitamin D levels improve BC survival. Yet no trial has evaluated the combined effect of a low GI diet, moderate physical activity and vitamin D supplementation on BC recurrence in the context of a Mediterranean lifestyle setting.MethodsWomen (30-74 yr) who had undergone surgery for primary histologically confirmed BC (stages I-III) within the previous 12 months, in cancer centres in Italy, will be randomized to follow, for a maximum of 33 months, either a high intensity treatment (HIT) composed of low GI diet + exercise + vitamin D (60 ng/mL serum concentration) or a lower intensity treatment (LITE) with general advice to follow a healthy diet and exercise pattern + vitamin D to avoid insufficiency. Both interventions are on a background of a Mediterranean diet. Considering a 20% recurrence rate within 3 years for BC cases and a predicted rate of 10% in the HIT group, with power of 80% and two-sided alpha of 0.05, the subject number required will be 506 (n = 253 in each arm). Clinic visits will be scheduled every 3 months. Dietary and exercise counselling and vitamin D supplements will be given at each clinic visit when blood samples, anthropometric measures and 7-day food records will be collected.DiscussionDEDiCa study aims to reduce BC recurrence in women with BC using a lifestyle approach with additional vitamin D and to investigate possible cardio-metabolic benefits as well as epigenetic modifications according to lifestyle changes. Given the supporting evidence and safety of the components of our intervention we believe it is feasible and urgent to test it in cancer patients.Trial registrationMay 11, 2016; NCT02786875. EudraCT Number2015-005147-14

Lifestyle Interventions to Improve Cardiorespiratory Fitness and Reduce Breast Cancer Recurrence

Lifestyle Interventions to Improve Cardiorespiratory Fitness and Reduce Breast Cancer Recurrence

Suppression of the metastatic spread of breast cancer by DN10764 (AZD7762)-mediated inhibition of AXL signaling.

Breast cancer is the most common malignant disease occurring in women and represents a substantial proportion of the global cancer burden. In these patients, metastasis but not the primary tumor is the main cause of breast cancer-related deaths. Here, we report the novel finding that DN10764 (AZD7762, a selective inhibitor of checkpoint kinases 1 and 2) can suppress breast cancer metastasis. In breast cancer cells, DN10764 inhibited cell proliferation and GAS6-mediated AXL signaling, consequently resulting in suppressed migration and invasion. In addition, DN10764 induced caspase 3/7-mediated apoptosis in breast cancer cells and inhibited tube formation of human umbilical vein endothelial cells. Finally, DN10764 significantly suppressed the tumor growth and metastasis of breast cancer cells in in vivo metastasis models. Taken together, these data suggest that therapeutic strategies targeting AXL in combination with systemic therapies could improve responses to anti-cancer therapies and reduce breast cancer recurrence and metastases.

RANK Signaling Blockade Reduces Breast Cancer Recurrence by Inducing Tumor Cell Differentiation.

RANK expression is associated with poor prognosis in breast cancer even though its therapeutic potential remains unknown. RANKL and its receptor RANK are downstream effectors of the progesterone signaling pathway. However, RANK expression is enriched in hormone receptor negative adenocarcinomas, suggesting additional roles for RANK signaling beyond its hormone-dependent function. Here, to explore the role of RANK signaling once tumors have developed, we use the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT), which mimics RANK and RANKL expression patterns seen in human breast adenocarcinomas. Complementary genetic and pharmacologic approaches demonstrate that therapeutic inhibition of RANK signaling drastically reduces the cancer stem cell pool, decreases tumor and metastasis initiation, and enhances sensitivity to chemotherapy. Mechanistically, genome-wide expression analyses show that anti-RANKL therapy promotes lactogenic differentiation of tumor cells. Moreover, RANK signaling in tumor cells negatively regulates the expression of Ap2 transcription factors, and enhances the Wnt agonist Rspo1 and the Sca1-population, enriched in tumor-initiating cells. In addition, we found that expression of TFAP2B and the RANK inhibitor, OPG, in human breast cancer correlate and are associated with relapse-free tumors. These results support the use of RANKL inhibitors to reduce recurrence and metastasis in breast cancer patients based on its ability to induce tumor cell differentiation. Cancer Res; 76(19); 5857-69. ©2016 AACR.

Reducing Breast Cancer Recurrence: The Role of Dietary Polyphenolics.

Evidence from numerous observational and clinical studies suggest that polyphenolic phytochemicals such as phenolic acids in olive oil, flavonols in tea, chocolate and grapes, and isoflavones in soy products reduce the risk of breast cancer. A dietary food pattern naturally rich in polyphenols is the Mediterranean diet and evidence suggests those of Mediterranean descent have a lower breast cancer incidence. Whilst dietary polyphenols have been the subject of breast cancer risk-reduction, this review will focus on the clinical effects of polyphenols on reducing recurrence. Overall, we recommend breast cancer patients consume a diet naturally high in flavonol polyphenols including tea, vegetables (onion, broccoli), and fruit (apples, citrus). At least five servings of vegetables and fruit daily appear protective. Moderate soy protein consumption (5–10 g daily) and the Mediterranean dietary pattern show the most promise for breast cancer patients. In this review, we present an overview of clinical trials on supplementary polyphenols of dietary patterns rich in polyphenols on breast cancer recurrence, mechanistic data, and novel delivery systems currently being researched.

Factors Associated with Adherence to Adjuvant Endocrine Therapy Among Privately Insured and Newly Diagnosed Breast Cancer Patients: A Quantile Regression Analysis.

Adherence to adjuvant endocrine therapy (AET) for estrogen receptor-positive breast cancer remains suboptimal, which suggests that women are not getting the full benefit of the treatment to reduce breast cancer recurrence and mortality. The majority of studies on adherence to AET focus on identifying factors among those women at the highest levels of adherence and provide little insight on factors that influence medication use across the distribution of adherence. To understand how factors influence adherence among women across low and high levels of adherence. A retrospective evaluation was conducted using the Truven Health MarketScan Commercial Claims and Encounters Database from 2007-2011. Privately insured women aged 18-64 years who were recently diagnosed and treated for breast cancer and who initiated AET within 12 months of primary treatment were assessed. Adherence was measured as the proportion of days covered (PDC) over a 12-month period. Simultaneous multivariable quantile regression was used to assess the association between treatment and demographic factors, use of mail order pharmacies, medication switching, and out-of-pocket costs and adherence. The effect of each variable was examined at the 40th, 60th, 80th, and 95th quantiles. Among the 6,863 women in the cohort, mail order pharmacies had the greatest influence on adherence at the 40th quantile, associated with a 29.6% (95% CI = 22.2-37.0) higher PDC compared with retail pharmacies. Out-of-pocket cost for a 30-day supply of AET greater than $20 was associated with an 8.6% (95% CI = 2.8-14.4) lower PDC versus $0-$9.99. The main factors that influenced adherence at the 95th quantile were mail order pharmacies, associated with a 4.4% higher PDC (95% CI = 3.8-5.0) versus retail pharmacies, and switching AET medication 2 or more times, associated with a 5.6% lower PDC versus not switching (95% CI = 2.3-9.0). Factors associated with adherence differed across quantiles. Addressing the use of mail order pharmacies and out-of-pocket costs for AET may have the greatest influence on improving adherence among those women with low adherence. This research was supported by a Ruth L. Kirschstein National Research Service Award for Individual Predoctoral Fellowship grant from the National Cancer Institute (grant number F31 CA174338), which was awarded to Farias. Additionally, Farias was funded by a Postdoctoral Fellowship at the University of Texas School of Public Health Cancer Education and Career Development Program through the National Cancer Institute (NIH Grant R25 CA57712). The other authors declare no conflicts of interest. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. Farias was primarily responsible for the study concept and design, along with Hansen and Zeliadt and with assistance from the other authors. Farias, Hansen, and Zeliadt took the lead in data interpretation, assisted by the other authors. The manuscript was written by Farias, along with Thompson and assisted by the other authors, and was revised by Ornelas, Li, and Farias, with assistance from the other authors.

Racial/ethnic difference in initiation and timing of adjuvant endocrine therapy among older women with hormone receptor-positive breast cancer.

e18076Background: Adjuvant endocrine therapy (AET) effectively reduces breast cancer recurrence and mortality, however, a substantial proportion of breast cancer patients indicated for AET treatmen...