Coffee and tea consumption, patient-reported, and clinical outcomes in a longitudinal study of patients with breast cancer.

BACKGROUND: Higher consumption of coffee and tea has been associated with improved health outcomes in the general population and improved breast cancer (BC) prognosis. This study investigated patterns of coffee and tea consumption and association with patient-reported outcomes (PROs) and clinical outcomes among survivors of BC. METHODS: The authors included survivors of stage I-III BC enrolled in the CANTO cohort (NCT01993498) that provided post-treatment assessment of coffee and tea consumption from years 1 to 4 after diagnosis. Group-based trajectory modeling clustered patients according to daily consumption of coffee and tea. Multivariable mixed models and Cox models examined associations between consumption, PROs and clinical outcomes. RESULTS: Among 3788 patients, the authors identified four stable patterns of consumption: "Low" (25.8%), "Moderate" (37.6%), "High" (25.3%), and "Very high" (11.3%), corresponding to <1, 2, 3, and ≥ 4 cups of coffee and/or tea per day. Patients in the "Very high" group (vs. "Low"), were more likely to be younger, smokers, with higher monthly income and education. PROs and survival outcomes were similar across the four groups. CONCLUSIONS: Over one in three survivors of BC reported high or very high consumption of coffee and/or tea. The authors found no association between higher consumption of coffee and/or tea, worse PROs and clinical outcomes.

Uptake of Recommendations for Posttreatment Cancer-Related Fatigue Among Breast Cancer Survivors.

BACKGROUND: Physical activity (PA) and psychosocial interventions are recommended management strategies for cancer-related fatigue (CRF). Randomized trials support the use of mind-body techniques, whereas no data show benefit for homeopathy or naturopathy. METHODS: We used data from CANTO (ClinicalTrials.gov identifier: NCT01993498), a multicenter, prospective study of stage I-III breast cancer (BC). CRF, evaluated after primary treatment completion using the EORTC QLQ-C30 (global CRF) and QLQ-FA12 (physical, emotional, and cognitive dimensions), served as the independent variable (severe [score of ≥40/100] vs nonsevere). Outcomes of interest were adherence to PA recommendations (≥10 metabolic equivalent of task [MET] h/week [GPAQ-16]) and participation in consultations with a psychologist, psychiatrist, acupuncturist, or other complementary and alternative medicine (CAM) practitioner (homeopath and/or naturopath) after CRF assessment. Multivariable logistic regression examined associations between CRF and outcomes, adjusting for sociodemographic, psychologic, tumor, and treatment characteristics. RESULTS: Among 7,902 women diagnosed from 2012 through 2017, 36.4% reported severe global CRF, and 35.8%, 22.6%, and 14.1% reported severe physical, emotional, and cognitive CRF, respectively. Patients reporting severe global CRF were less likely to adhere to PA recommendations (60.4% vs 66.7%; adjusted odds ratio [aOR], 0.82; 95% CI, 0.71-0.94; P=.004), and slightly more likely to see a psychologist (13.8% vs 7.5%; aOR, 1.29; 95% CI, 1.05-1.58; P=.014), psychiatrist (10.4% vs 5.0%; aOR, 1.39; 95% CI, 1.10-1.76; P=.0064), acupuncturist (9.8% vs 6.5%; aOR, 1.46; 95% CI, 1.17-1.82; P=.0008), or CAM practitioner (12.5% vs 8.2%; aOR, 1.49; 95% CI, 1.23-1.82; P<.0001). There were differences in recommendation uptake by CRF dimension, including that severe physical CRF was associated with lower adherence to PA (aOR, 0.74; 95% CI, 0.63-0.86; P=.0001) and severe emotional CRF was associated with higher likelihood of psychologic consultations (aOR, 1.37; 95% CI, 1.06-1.79; P=.017). CONCLUSIONS: Uptake of recommendations to improve CRF, including adequate PA and use of psychosocial services, seemed suboptimal among patients with early-stage BC, whereas there was a nonnegligible interest in homeopathy and naturopathy. Findings of this large study indicate the need to implement recommendations for managing CRF in clinical practice.

Identifying the Steps Required to Effectively Implement Next-Generation Sequencing in Oncology at a National Level in Europe.

Next-generation sequencing (NGS) may enable more focused and highly personalized cancer treatment, with the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines now recommending NGS for daily clinical practice for several tumor types. However, NGS implementation, and therefore patient access, varies across Europe; a multi-stakeholder collaboration is needed to establish the conditions required to improve this discrepancy. In that regard, we set up European Alliance for Personalised Medicine (EAPM)-led expert panels during the first half of 2021, including key stakeholders from across 10 European countries covering medical, economic, patient, industry, and governmental expertise. We describe the outcomes of these panels in order to define and explore the necessary conditions for NGS implementation into routine clinical care to enable patient access, identify specific challenges in achieving them, and make short- and long-term recommendations. The main challenges identified relate to the demand for NGS tests (governance, clinical standardization, and awareness and education) and supply of tests (equitable reimbursement, infrastructure for conducting and validating tests, and testing access driven by evidence generation). Recommendations made to resolve each of these challenges should aid multi-stakeholder collaboration between national and European initiatives, to complement, support, and mutually reinforce efforts to improve patient care.

Determinants of use of oral complementary-alternative medicine among women with early breast cancer: a focus on cancer-related fatigue.

BACKGROUND: Despite the questionable effectiveness of oral complementary and alternative medicine (OCAM) in relieving cancer-related symptoms, including fatigue (CRF), many patients use it aiming to improve their quality of life. We assessed factors associated with OCAM use, focusing on CRF. METHODS: Women with stage I-III breast cancer (BC) were included from CANTO (NCT01993498). OCAM use was defined as taking homeopathy, vitamins/minerals, or herbal/dietary supplements. Multivariable multinomial logistic regressions evaluated associations of CRF (EORTC QLQ-C30), patient, and treatment characteristics with OCAM use. RESULTS: Among 5237 women, 23.0% reported OCAM use overall (49.3% at diagnosis, 50.7% starting post-diagnosis), mostly homeopathy (65.4%). Mean (SD) CRF score was 27.6 (24.0) at diagnosis and 35.1 (25.3) at post-diagnosis. More intense CRF was consistently associated with OCAM use at diagnosis and post-diagnosis [adjusted odds ratio (aOR) for 10-point increase 1.05 (95% Confidence interval 1.01-1.09) and 1.04 (1.01-1.09) vs. never use, respectively]. Odds of using OCAM at diagnosis were higher among older [for 5-year increase, 1.09 (1.04-1.14)] and more educated patients [college vs. primary 1.80 (1.27-2.55)]. Women with income > 3000 [vs. < 1500 euros/month, 1.44 (1.02-2.03)], anxiety [vs. not, 1.25 (1.01-1.54)], and those receiving chemotherapy [vs. not, 1.32 (1.04-1.68)] had higher odds of using OCAM post-diagnosis. CONCLUSION: One-in-four patients reported use of OCAM. More severe CRF was consistently associated with its use. Moreover, older, better educated, wealthier, more anxious women, and those receiving chemotherapy seemed more prone to use OCAM. Characterizing profiles of BC patients more frequently resorting to OCAM may help deliver targeted information about its benefits and potential risks.

Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer.

Hormone receptor (HR)+ breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR+ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR+HER2- BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR+ BC.

Rationale for targeting fibroblast growth factor receptor signaling in breast cancer.

Fibroblast growth factor receptor (FGFR) signaling is involved in multiple biological processes, including cell proliferation, survival, differentiation, migration, and apoptosis during embryonic development and adult tissue homeostasis. Given its role in the activation of critical signaling pathways, aberrant FGFR signaling has been implicated in multiple cancer types. A comprehensive search of PubMed and congress abstracts was conducted to identify reports on FGFR pathway components in breast cancer. In breast cancers, FGFR1 and FGFR4 gene amplification and single nucleotide polymorphisms in FGFR2 and FGFR4 have been detected. Commonly, these FGFR aberrations and gene amplifications lead to increased FGFR signaling and have been linked with poor prognosis and resistance to breast cancer treatments. Here, we review the role of FGFR signaling and the impact of FGFR genetic amplifications/aberrations on breast tumors. In addition, we summarize the most recent preclinical and clinical data on FGFR-targeted therapies in breast cancer. Finally, we highlight the ongoing clinical trials of the FGFR-targeted agents dovitinib, AZD4547, lucitanib, BGJ398, and JNJ-42756493, which are selected for patients with FGFR pathway-amplified breast cancer. Aberrant FGFR pathway amplification may drive some breast cancers. Inhibition of FGFR signaling is being explored in the clinic, and data from these trials may refine our ability to select patients who would best respond to these treatments.

Decision-making from multidisciplinary team meetings to the bedside: factors influencing the recruitment of breast cancer patients into clinical trials.

AIM OF THE STUDY: Our aim was to determine factors influencing physicians and breast cancer patients to respectively propose or accept participation in a clinical trial following proposals made during a multidisciplinary team meeting (MTM) in a Comprehensive Cancer Centre. PATIENTS AND METHODS: Consecutive patients considered eligible for a clinical trial by a breast cancer-specific MTM were included. A detailed analysis of factors predictive of the physician proposing the trial and the patient's acceptance and final inclusion was conducted. RESULTS: MTM proposed 547 inclusions in 25 clinical trials for 397 patients between March and September 2011. The physician proposed the scheduled clinical trial in only 39% of the cases. The patients accepted the proposal in 74% of the cases, and finally 29% were included. The main reason for non-inclusion was the physician's failure to propose the trial in 45-81%, depending on the type of study. The only factor predictive of both the physician proposing the trial and final inclusion was the type of study (both p < 0.001). Diagnostic/prognostic studies were the most frequently proposed trials. The professional status (of the subject) was predictive of acceptance (p = 0.03) with higher rates among retired patients and executives (84 and 76% respectively). CONCLUSION: The major reason for non-inclusion in clinical trials was the physician's failure to propose the trial, while the patient's professional status and the type of study influenced both physicians and patients. Educative measures mostly directed at physicians could be implemented to overcome such poor compliance.

Reproducibility of research and preclinical validation: problems and solutions.

Lack of reproducibility in the scientific and lay literature of many scientific reports is an increasing concern, as are the high rates of failure to validate highly promising preclinical observations in clinical trials. There are many technical reasons why experimental results, particularly in cancer research, cannot be reproduced, including unrecognized variables in the complex experimental model, poor documentation of procedures, selective reporting of the most-positive findings, misinterpretation of technical noise as biological signal and, in the most extreme cases, fabrication of data. We suggest that cognitive biases in research and flaws in the academic incentive system also contribute to the publication of immature results. Recognition of these factors, which are often not discussed, provides additional strategies to improve reproducibility. We suggest that in addition to establishing better standards of data presentation and creating venues for publication of negative results, some changes to the grant submission and funding system could further improve the reproducibility of research findings.

Issues in clinical research for metastatic breast cancer.

PURPOSE OF REVIEW: Technical advances and progresses in tumor biology hold promise for the advent of new anticancer agents. These changes are impacting the conduct and design of clinical trials. This review describes the changing landscape of clinical research in metastatic breast cancer (MBC). RECENT FINDINGS: Clinical trials in breast cancer that started between 2007 and 2011 were analyzed. In the metastatic setting, 72% (n = 479) of these studies evaluated targeted therapies and 21% (n = 139) conventional treatments. During this period, the number of phase II trials decreased over time, whereas biology-driven studies, although small in terms of absolute number, now represent 15% of the total. Nevertheless, genomic segments are too rare to allow conventional drug development and require changes in the way clinical trials are being done. Several options are being explored to address this challenge: develop large consortium, perform molecular screening in larger populations, develop clinical trials testing algorithm for treatment decision, and no longer drugs. SUMMARY: The landscape of clinical research in MBC is changing with the development of molecular medicine. Research institutions and cooperative groups will need to adapt to this changing landscape in clinical research.

Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer.

PURPOSE: Fibroblast growth factor receptor 1 (FGFR1) and FGFR2 amplifications are observed in approximately 10% of breast cancers and are related to poor outcomes. We evaluated whether dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, presented antitumor activity in FGFR-amplified breast cancers. EXPERIMENTAL DESIGN: Preclinical activity of dovitinib was evaluated in both breast cancer cell lines and an FGFR1-amplified xenograft model (HBCx2). Dovitinib was then evaluated in a phase II trial that included 4 groups of patients with human EGF receptor 2-negative metastatic breast cancer on the basis of FGFR1 amplification and hormone receptor (HR) status. FGFR1 amplification was assessed by silver in situ hybridization. Preplanned retrospective analyses assessed predictive value of FGFR1, FGFR2, and FGF3 amplifications by quantitative PCR (qPCR). RESULTS: Dovitinib monotherapy inhibits proliferation in FGFR1- and FGFR2-amplified, but not FGFR-normal, breast cancer cell lines. Dovitinib also inhibits tumor growth in FGFR1-amplified breast cancer xenografts. Eighty-one patients were enrolled in the trial. Unconfirmed response or stable disease for more than 6 months was observed in 5 (25%) and 1 (3%) patient(s) with FGFR1-amplified/HR-positive and FGFR1-nonamplified/HR-positive breast cancer. When qPCR-identified amplifications in FGFR1, FGFR2, or FGF3 were grouped to define an FGF pathway-amplified breast cancer in HR-positive patients, the mean reduction in target lesions was 21.1% compared with a 12.0% increase in patients who did not present with FGF pathway-amplified breast cancer. CONCLUSION: Dovitinib showed antitumor activity in FGFR-amplified breast cancer cell lines and may have activity in breast cancers with FGF pathway amplification.

mTOR inhibitors in advanced breast cancer: ready for prime time?

Current therapeutic approaches for advanced breast cancer frequently target receptors mediating cell survival and proliferation, such as the estrogen receptor and/or progesterone receptor and human epidermal growth factor receptor-2. Although these approaches are effective for many patients, treatment resistance is common. Therefore, new treatment approaches are needed for patients with advanced breast cancer. Mammalian target of rapamycin is a highly conserved serine-threonine kinase that acts as a major signaling hub that integrates and synergizes with cellular proliferation, survival, and/or motility signals mediated by estrogen receptor, human epidermal growth factor receptor-2, and other receptor tyrosine kinases. Dysregulation of mammalian target of rapamycin signaling occurs in various tumor types, including breast cancer, and has been associated with cancer pathogenesis, disease progression, and treatment resistance. Recent clinical trials show that combined inhibition of mammalian target of rapamycin and estrogen receptor represents an effective strategy for treating hormone receptor-positive advanced breast cancer progressing on nonsteroidal aromatase inhibitor therapy, and data from ongoing trials combining mammalian target of rapamycin inhibition with human epidermal growth factor receptor-2-targeted therapy are awaited. This review focuses on the molecular rationale underlying strategies to enhance sensitivity to treatment in hormone receptor-positive and human epidermal growth factor receptor-2-positive advanced breast cancer, the clinical efficacy of such approaches, and future perspectives.

Implications of personalized medicine--perspective from a cancer center.

Three advances are dramatically changing the landscape of oncology. First, hundreds of drugs are available that inhibit targets involved in oncogenesis. Second, efforts to reclassify malignant diseases are expanding the number of orphan molecular diseases. Third, the implementation of high-throughput technologies will allow risk of relapse prediction and drug sensitivity. Patients predicted to relapse will be referred to comprehensive cancer centers where new drugs will be tested. It is anticipated that a high number of small, biology-driven clinical trials will report high sensitivity to targeted agents in rare biologically defined diseases. Drug registration and biomarker analysis needs to be revisited to avoid large phase III trials with control arms. The use of high-throughput technologies will lead to the development of virtual cells. These considerations highlight the need for developing a consortium of comprehensive cancer centers to run clinical trials in rare, molecularly-defined populations, and implement high-throughput technologies for daily practice.

Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers.

PURPOSE: The purpose of this study was to identify genes enriched in breast cancer stroma, assess the stromal gene expression differences between estrogen receptor (ER) -positive and -negative cancers, and separately determine their prognostic value in these two subtypes of breast cancers. METHODS: We compared gene expression profiles of pairs of fine-needle (stroma-poor) and core-needle (stroma-rich) biopsies from 37 cancers to identify stroma-associated genes. We defined stromal metagenes and tested their prognostic values in 684 node-negative patients who received no systemic adjuvant therapy and 259 tamoxifen-treated patients. RESULTS: We identified 293 probe sets overexpressed in core biopsies; these included five highly coexpressed gene clusters (metagenes) corresponding to immune functions and extracellular matrix components. These genes showed quantitative and qualitative differences between ER-positive and ER-negative cancers. A B-cell/plasma cell metagene showed strong prognostic value in ER-positive highly proliferative cancers, a lesser prognostic value in ER-negative cancers, and no prognostic value in ER-positive cancers with low proliferation. The hazard ratio for distant relapse in the lowest compared with the highest tertile of the pooled prognostic data set was 4.29 (95% CI, 2.04 to 9.01; P = .001) in ER-positive cancers and 3.34 (95% CI, 1.60 to 6.97; P = .001) in ER-negative cancers. This remained significant in multivariate analysis including routine variables and other genomic prognostic scores. As a result of quantitative differences in this metagene between ER-positive and ER-negative cancers, different thresholds apply in the two subgroups. Other stromal metagenes had inconsistent prognostic value. CONCLUSION: Among ER-negative and ER-positive highly proliferative cancers, a subset of tumors with high expression of a B-cell/plasma cell metagene carries a favorable prognosis.

Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers.

The predictive value of p53 for the efficacy of front-line anthracycline-based chemotherapy regimens has been a matter of significant controversy. Anthracyclines are usually combined with widely different doses of alkylating agents, which may significantly modulate tumor response to these combinations. We analyzed three series of de novo stage II-III breast cancer patients treated front line with anthracycline-based regimens of various cyclophosphamide dose intensities: 65 patients with estrogen receptor (ER)(-) tumors treated with anthracyclines alone (Institut Jules Bordet, Brussels), 51 unselected breast cancer patients treated with intermediate doses of cyclophosphamide (MD Anderson Cancer Center, Houston, TX), and 128 others treated with a dose-dense anthracycline-cyclophosphamide combination (St. Louis, Paris). After chemotherapy and surgery, pathologic complete response (pCR) was evaluated. p53 status was determined by a yeast functional assay on the pretreatment tumor sample. In a multivariate analysis of the pooled results, a lack of ER expression and high-dose cyclophosphamide administration were associated with a higher likelihood of pCR. A sharp statistical interaction was detected between p53 status and cyclophosphamide dose intensity. Indeed, when restricting our analysis to patients with ER(-) tumors, we confirmed that a mutant p53 status was associated with anthracycline resistance, but found that p53 inactivation was required for response to the dose-intense alkylating regimen. The latter allowed very high levels of pCR in triple-negative tumors. Thus, our data strongly suggest that cyclophosphamide dose intensification in ER(-) p53-mutated breast cancer patients could significantly improve their response.

Evaluation of biological pathways involved in chemotherapy response in breast cancer.

INTRODUCTION: Our goal was to examine the association between biological pathways and response to chemotherapy in estrogen receptor-positive (ER+) and ER-negative (ER-) breast tumors separately. METHODS: Gene set enrichment analysis including 852 predefined gene sets was applied to gene expression data from 51 ER- and 82 ER+ breast tumors that were all treated with a preoperative paclitaxel, 5-fluoruracil, doxorubicin, and cyclophosphamide chemotherapy. RESULTS: Twenty-seven (53%) ER- and 7 (9%) ER+ patients had pathologic complete response (pCR) to therapy. Among the ER- tumors, a proliferation gene signature (false discovery rate [FDR] q = 0.1), the genomic grade index (FDR q = 0.044), and the E2F3 pathway signature (FDR q = 0.22, P = 0.07) were enriched in the pCR group. Among the ER+ tumors, the proliferation signature (FDR q = 0.001) and the genomic grade index (FDR q = 0.015) were also significantly enriched in cases with pCR. Ki67 expression, as single gene marker of proliferation, did not provide the same information as the entire proliferation signature. An ER-associated gene set (FDR q = 0.03) and a mutant p53 gene signature (FDR q = 0.0019) were enriched in ER+ tumors with residual cancer. CONCLUSION: Proliferation- and genomic grade-related gene signatures are associated with chemotherapy sensitivity in both ER- and ER+ breast tumors. Genes involved in the E2F3 pathway are associated with chemotherapy sensitivity among ER- tumors. The mutant p53 signature and expression of ER-related genes were associated with lower sensitivity to chemotherapy in ER+ breast tumors only.