Showing papers in "Breast Cancer Research and Treatment in 2020"

Recommendations for prioritization, treatment, and triage of breast cancer patients during the COVID-19 pandemic. the COVID-19 pandemic breast cancer consortium.

Abstract: The COVID-19 pandemic presents clinicians a unique set of challenges in managing breast cancer (BC) patients. As hospital resources and staff become more limited during the COVID-19 pandemic, it becomes critically important to define which BC patients require more urgent care and which patients can wait for treatment until the pandemic is over. In this Special Communication, we use expert opinion of representatives from multiple cancer care organizations to categorize BC patients into priority levels (A, B, C) for urgency of care across all specialties. Additionally, we provide treatment recommendations for each of these patient scenarios. Priority A patients have conditions that are immediately life threatening or symptomatic requiring urgent treatment. Priority B patients have conditions that do not require immediate treatment but should start treatment before the pandemic is over. Priority C patients have conditions that can be safely deferred until the pandemic is over. The implementation of these recommendations for patient triage, which are based on the highest level available evidence, must be adapted to current availability of hospital resources and severity of the COVID-19 pandemic in each region of the country. Additionally, the risk of disease progression and worse outcomes for patients need to be weighed against the risk of patient and staff exposure to SARS CoV-2 (virus associated with the COVID-19 pandemic). Physicians should use these recommendations to prioritize care for their BC patients and adapt treatment recommendations to the local context at their hospital.

Patient-reported treatment delays in breast cancer care during the COVID-19 pandemic.

Abstract: The coronavirus disease (COVID-19) pandemic has had a profound impact on cancer care in the US Guidelines focused on the management of COVID-19, rather than healthcare needs of breast cancer patients requiring access to crucial services. This US survey of breast cancer survivors characterizes treatment delays early period in the pandemic. We developed a survey and administered it to 609 adult breast cancer survivors in the US. We used snowball sampling with invitations distributed via social media. We used logistic regression to select a model of delay from a pool of independent variables including race, cancer stage, site of care, health insurance, and age. We used descriptive statistics to characterize delay types. Forty-four percent of participants reported cancer care treatment delays during the pandemic. Delays in all aspects of cancer care and treatment were reported. The only variable which had a significant effect was age (97 (.95, 99), p < 0.001) with younger respondents (M = 45.94, SD = 10.31) reporting a higher incidence of delays than older respondents (M = 48.98, SD = 11.10). There was no significant effect for race, insurance, site of care, or cancer stage. Our findings reveal a pervasive impact of COVID-19 on breast cancer care and a gap in disaster preparedness that leaves cancer survivors at risk for poor outcomes. Delays are critical to capture and characterize to help cancer providers and healthcare systems develop effective and patient–tailored processes and strategies to manage cases during the current pandemic wave, subsequent waves, and future disasters.

Trends of female and male breast cancer incidence at the global, regional, and national levels, 1990–2017

Abstract: Breast cancer is a major public health concern worldwide and shows significant heterogeneity between male and female. Knowing the global incidence landscape in both sexes is critical for the breast cancer prevention and the reduction in disease burden. We retrieved the incidence data of breast cancer in both sexes from the Global Burden of Disease 2017 database. Average annual percentage change was used to quantify the temporal trends of breast cancer incidence. Between 1990 and 2017, the number of newly diagnosed female breast cancer (FBC) cases increased from 870.2 thousand to 1937.6 thousand, with the age-standardized incidence rate (ASR) significantly increased from 39.2/100,000 to 45.9/100,000. A total of 166 countries experienced a significant increase in FBC-ASR. The most pronounced increase was mainly found in developing countries. The decrease was mostly detected in several developed countries, such as the USA and the UK. Male breast cancer (MBC) is a rare carcinoma and has no evident cluster across the world. Worldwide, the number of newly diagnosed MBC cases increased from 8.5 thousand in 1990 to 23.1 thousand in 2017, with the ASR significantly increased from 0.46/100,000 to 0.61/100,000. A total of 123 countries showed a significant increasing trend in MBC-ASR. Breast cancer incidence rates are increasing in most countries in both sexes, although the epidemiological features were not completely shared between FBC and MBC. More emphases should be placed on breast cancer primary prevention and the prevention strategies might need to be tailored for both FBC and MBC.

Symptom cluster of pain, fatigue, and psychological distress in breast cancer survivors: prevalence and characteristics

Abstract: Breast cancer survivors may experience pain, fatigue, or psychological distress as a result of the treatment. These symptoms may co-occur and form a cluster. However little is known about symptom clusters (SCs) in long-term breast cancer survivors. This study aimed to identify subgroups of breast cancer survivors with the SC of pain, fatigue, and psychological distress, and to examine sociodemographic and clinical characteristics associated with this SC. Data were obtained from a nationwide survey of breast cancer survivors (N = 834). Exhaustive enumeration of possible combination of the three binary variables (pain, fatigue, psychological distress) was conducted. They were identified using the recommended threshold for the Hospital Anxiety and Depression Scale, the Fatigue Questionnaire, and a score of one or more on a numeric rating scale for pain. The SC was defined to include all the three variables, all other combinations were defined as no SC. Logistic regression analyses were conducted to examine the association between sociodemographic and clinical variables and the SC. Of the 834 survivors, 13% had the SC. Younger age (OR 2.3, 95% CI 1.3–4.1, p = 0.003), lymphedema (OR 1.9, 95% CI 1.1–3.2, p = 0.02), working part-time (OR 2.9, 95% CI 1.6–5.3, p < 0.001), or being disabled (OR 4.1, 95% CI 2.2–7.8, p < 0.001) were all associated with the SC. Thirteen percent of the survivors experienced the SC. It appears that premenstrual women are at greater risk, than postmenopausal women. Having this SC might have an impact on the survivors’ ability to work.

Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1, TRIO-18).

Abstract: Palbociclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, approved in combination with endocrine therapy for the treatment of women and men with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer (HR+/HER2− ABC). In the phase 2, open-label, PALOMA-1 trial, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) versus letrozole alone (hazard ratio, 0.488; 95% CI 0.319‒0.748; P = 0.0004; median PFS, 20.2 vs 10.2 months, respectively) in postmenopausal women with estrogen receptor–positive (ER+)/HER2− ABC. Here, we present the final overall survival (OS) and updated safety results. Postmenopausal women with ER+/HER2− ABC were randomized 1:1 to receive either palbociclib (125 mg/day, 3/1 schedule) plus letrozole (2.5 mg/day, continuous) or letrozole alone (2.5 mg/day, continuous). The primary endpoint was investigator-assessed PFS; secondary endpoints included OS and safety. A total of 165 patients were randomized. At the data cutoff date of December 30, 2016 (median duration of follow-up, 64.7 months), the stratified hazard ratio for OS was 0.897 (95% CI 0.623–1.294; P = 0.281); median OS in the palbociclib plus letrozole and letrozole alone arms was 37.5 and 34.5 months, respectively. The median time from randomization to first subsequent chemotherapy use was longer with palbociclib plus letrozole than letrozole alone (26.7 and 17.7 months, respectively). The most frequently reported adverse event in the palbociclib plus letrozole arm was neutropenia (any grade, 75%; grade 3 or 4, 59%). Palbociclib plus letrozole treatment led to a numerical but not statistically significant improvement in median OS. Pfizer Inc (NCT00721409)

Phase Ib clinical trial of the anti-frizzled antibody vantictumab (OMP-18R5) plus paclitaxel in patients with locally advanced or metastatic HER2-negative breast cancer

Abstract: Vantictumab is a monoclonal antibody that binds to frizzled (FZD) receptors and inhibits canonical WNT signaling. This phase Ib dose escalation study enrolled patients with locally recurrent or metastatic HER2-negative breast cancer who were treated with weekly paclitaxel in combination with escalating doses of vantictumab. Patients were enrolled in dose escalation cohorts treated with weekly paclitaxel 90 mg/m2 on days 1, 8 and 15 in combination with vantictumab 3.5–14 mg/kg days 1 and 15 or 3–8 mg/kg day 1 of every 28-day cycle. Primary endpoints were safety, dose-limiting toxicities (DLTs). Secondary endpoints included pharmacokinetics, efficacy and an exploratory biomarker analysis. Forty-eight female patients with a mean age of 54 were enrolled. The majority (66.6%) received prior chemotherapy for recurrent or metastatic disease; 45.8% were hormone receptor (HR)-positive, HER2-negative and 54.2% triple-negative. The most frequent adverse events related to any study treatment were nausea (54.2%), alopecia (52.1%), fatigue (47.9%), and peripheral neuropathy (43.8%). No DLTs occurred; however, 6 patients experienced fractures outside of the DLT window. The overall response rate was 31.3% and the clinical benefit rate was 68.8%. A 6-gene WNT pathway signature showed significant association with progression-free survival (PFS) and overall survival (OS) for the biomarker high versus biomarker low groups (PFS: p = 0.029 and OS: p = 0.00045, respectively). The combination of vantictumab and weekly paclitaxel was generally well tolerated with promising efficacy; however, the incidence of fractures limits future clinical development of this particular WNT inhibitor in metastatic breast cancer. ClinicalTrials.gov registration: NCT01973309

Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival.

Abstract: MMP9 is a matricellular protein associated with extracellular matrix (ECM) remodelling, that promotes tumour progression, and modulates the activity of cell adhesion molecules and cytokines. This study aims to assess the prognostic value of MMP9 and its association with cytoskeletal modulators in early-stage invasive breast cancer (BC). MMP9 expression was evaluated by immunohistochemistry using a well-characterised series of primary BC patients with long-term clinical follow-up. Association with clinicopathological factors, patient outcome and ECM remodelling BC-biomarkers were investigated. METABRIC dataset, BC-GenExMiner v4.0 and TCGA were used for the external validation of MMP9 expression. GSEA gene enrichment analyses were used to evaluate MMP9 associated pathways. MMP9 immunopositivity was observed in the stroma and cytoplasm of BC cells. Elevated MMP9 protein levels were associated with high tumour grade, high Nottingham Prognostic Index, and hormonal receptor negativity. Elevated MMP9 protein expression correlated significantly with cytokeratin 17 (Ck17), Epidermal Growth Factor Receptor (EGFR), proliferation (Ki67) biomarkers, cell surface adhesion receptor (CD44) and cell division control protein 42 (CDC42). Cytoplasmic MMP9 expression was an independent prognostic factor associated with shorter BC-specific survival. In the external validation cohorts, MMP9 expression was also associated with poor patients’ outcome. Transcriptomic analysis confirmed a positive association between MMP9 and ECM remodelling biomarkers. GSEA analysis supports MMP9 association with ECM and cytoskeletal pathways. This study provides evidence for the prognostic value of MMP9 in BC. Further functional studies to decipher the role of MMP9 and its association with cytoskeletal modulators in BC progression are warranted.

Incidence of pneumonitis/interstitial lung disease induced by HER2-targeting therapy for HER2-positive metastatic breast cancer.

Abstract: Anti-human epidermal growth factor receptor 2 (HER2) therapies are associated with interstitial lung disease (ILD), also referred to as pneumonitis In this literature review, we describe the incidence of ILD among patients with HER2-positive metastatic breast cancer (MBC) receiving anti-HER2 therapies, and we describe existing recommendations for monitoring and managing drug-induced ILD among these patients We searched PubMed and Embase to identify clinical trials and postmarket observational studies that investigated anti-HER2 therapies for HER2-positive MBC, reported on ILD, and were published during January 1, 2009 to July 15, 2019 Articles were screened by two researchers; data were extracted from the full-text articles The 18 articles selected for this review assessed 9,886 patients who received trastuzumab (8 articles), lapatinib (4 articles), trastuzumab emtansine (3 articles), trastuzumab deruxtecan (2 articles), or trastuzumab duocarmazine (1 article) The overall incidence of all-grade ILD was 24% (n = 234), with 667% (n = 156) occurring as grade 1–2 events, 05% grade 3–4 (n = 54; incidence), and 02% grade 5 (n = 16; incidence) The highest ILD incidence (214%) was among patients receiving trastuzumab combined with everolimus and paclitaxel Ten studies indicated that ILD events were managed via dose interruption, dose reduction, or treatment discontinuation; two studies included detailed guidelines on managing drug-induced ILD ILD is a well-described adverse drug reaction associated with several anti-HER2 drugs Published ILD management guidelines are available for few anti-HER2 treatment regimens; however, guidance for monitoring for anti-HER2 drug-induced ILD is lacking

Tumor-infiltrating lymphocytes (TILs) in ER+/HER2− breast cancer

Abstract: The prognostic role of tumor-infiltrating lymphocytes (TILs) in ER+/HER2− breast cancer (BC) is debated We evaluated the association of TILs and clinico-pathological features with distant disease-free survival (DDFS) in patients with ER+/HER2− BC treated at a single institution A mono-institutional case-cohort series of 987 patients with early ER+/HER2− BC was retrospectively analyzed TILs were considered both as continuous variable, and dichotomized in low (< 5%) vs high (≥ 5%) The main outcome was DDFS Median follow-up was 75 years (01–10) Univariate and multivariable Cox proportional hazards regression with inverse sub-cohort sampling probability weighting were used to evaluate the risk across groups Median TIL count was 2% (Q1–Q3 1–4%) Higher TILs were positively associated with number of lymph nodes involved (p = 0003), tumor grade (p < 00001), peritumoral vascular invasion (p = 0003), higher Ki-67 (p = 00001), luminal B subtype (p < 00001), and chemotherapy use (p < 000019) In multivariable regression analysis, only higher Ki-67 expression retained significant association with TILs At univariate Cox regression analysis, TIL expression (≥ 5% vs < 5%) was not associated with DDFS (HR 108, 95% CI 080–146, p = 062) In patients treated with adjuvant chemotherapy, high TILs were associated with better DDFS (HR 052, 95%CI 033–083, p = 0006), particularly in the group with Ki-67 ≥ 20% (HR 050, 95%CI 029–086, p = 001) High TILs in ER+/HER2− BC are significantly associated with clinico-pathological features of dismal outcome TIL prognostic value seems different in patients treated with or without chemotherapy Our findings suggest that the high-risk subgroup might be more immunogenic, thus deserving the exploration of immunotherapy approaches

Evaluation and management of insomnia in women with breast cancer.

Abstract: Insomnia is a common issue among patients with breast cancer with a potentially devastating impact on quality of life. It can be caused or exacerbated by multiple disease and treatment-related factors. Despite the prevalence and impact of insomnia, it is rarely addressed systematically in the oncology clinic. We conducted a comprehensive review of insomnia to guide clinical care of patient’s with breast cancer and insomnia. This manuscript reviews the prevalence, etiology, emerging science and both non-pharmacologic and pharmacologic options for treatment of insomnia among patients with breast cancer. Multiple factors contribute to insomnia among patients with breast cancer including endocrine therapy and hotflashes, pain and discomfort from local therapy, and fear of recurrence. If we do identify insomnia, there are treatment options and strategies available to help patients. In particular, there is now a considerable body of evidence supporting the use of psychosocial interventions and behavioral treatments, such as cognitive behavioral therapy for insomnia (CBT-I), yoga, and mind-body programs. It is also important for oncology providers to be educated regarding available pharmacologic therapies and emerging data for cannabis-based therapy. This manuscript provides an up-to-date and comprehensive review of the prevalence, etiology, and treatment approaches available for insomnia for clinicians treating patients with breast cancer. We also address strategies and goals for cancer care delivery and future research.

Patient-reported outcome after oncoplastic breast surgery compared with conventional breast-conserving surgery in breast cancer

Abstract: Oncoplastic breast surgery (OBS) has developed as an extension of breast-conserving surgery (BCS) in an effort to improve esthetic and functional outcome following surgery for breast cancer. The aim of the present study was to evaluate the possible benefits of OBS, as compared with BCS, with regard to health-related quality of life (HRQoL), using patient-reported outcome measures (PROMs). Patients treated with OBS (n = 200) and BCS (n = 1304) in the period 1 January 2008 to 31 December 2013 were identified in a research database and in the Danish Breast Cancer Cooperative Group (DBCG) registry. Data on patient, tumor, and treatment characteristics were retrieved from the DBCG registry. Patients were sent a survey including the Breast-Q™ BCT postoperative module and a study-specific questionnaire (SSQ) in 2016. A good outcome in the Breast-Q module was defined as above the median. OBS was compared to BCS using a logistic regression analysis, and then adjusted for potential confounders, yielding odds ratios (OR) with 95% confidence intervals. There was a statistically significant better outcome considering the HRQoL domain “Psychosocial Well-being “ for patients treated with OBS as compared with BCS (OR 2.15: 1.25–3.69). No statistically significant differences were found for the domains “Physical Well-being” (0.83: 0.50–1.39), “Satisfaction with Breast” (0.95: 0.57–1.59), or “Sexual Well-being” (1.42: 0.78–2.58). The present study indicates better outcomes of HRQoL for breast cancer patients treated with OBS as compared to patients treated with BCS. There was no increase in physical discomfort among OBS patients despite more extensive surgery.

COTI-2 reactivates mutant p53 and inhibits growth of triple-negative breast cancer cells

Abstract: Triple-negative breast cancer (TNBC) currently lacks an approved targeted therapy. The tumour suppressor TP53 gene is mutated in approximately 80% of TNBC cases. COTI-2 is a third-generation thiosemicarbazone engineered for high efficacy and low toxicity which acts by reactivating mutant p53 to a WT form. The aim of this study was to investigate COTI-2 as a targeted therapy for TNBC patients. Using a panel of 18 breast cell lines, we carried out MTT assay. p53 protein folding was determined by immunofluorescent staining with the p53 mutant-specific antibody PAb240 and the p53 WT-specific PAb1620. Surface plasmon resonance was used to determine binding affinity of COTI-2 to full length (FL) p53, and the DNA-binding domain (DBD). Flow cytometry was used to measure apoptosis. TNBC cell lines were significantly more responsive to COTI-2 than non-TNBC cell lines (p = 0.04). Furthermore, lower IC50 values were found in p53 mutant compared to p53 WT cells (p = 0.001). COTI-2 was shown to bind to FL and DBD of mutant p53. Treatment resulted in an increase in staining with PAb1620 which coincided with a decrease in staining with PAb240, suggesting refolding of the mutant protein. In addition, COTI-2 was found to induce apoptosis in TNBC cell lines. We conclude that targeting mutant p53 with COTI-2 is a potential approach for treating p53-mutated TNBC.

High-Efficiency Same-Day Approach to Breast Reconstruction During the COVID-19 Crisis.

Abstract: As our hospitals conserve and re-allocate resources during the COVID-19 crisis, there is urgent need to determine how best to continue caring for breast cancer patients During the time window before the COVID-19 critical peak and particularly thereafter, as hospitals are able to resume cancer operations, we anticipate that there will be great need to maximize efficiency to treat breast cancer The goal of this study is to present a same-day protocol that minimizes resource utilization to enable hospitals to increase inpatient capacity, while providing care for breast cancer patients undergoing mastectomy and immediate breast reconstruction during the COVID-19 crisis IRB exempt patient quality improvement initiative was conducted to detail the operationalization of a novel same-day breast reconstruction protocol Consecutive patients having undergone immediate breast reconstruction were prospectively enrolled between February and March of 2020 at Massachusetts General Hospital during the COVID-19 crisis Peri-operative results and postoperative complications were summarized Time interval from surgical closure to patient discharge was 502 ± 129 h All patients were discharged home, with no re-admissions or emergency department visits No postoperative complications were observed This report provides an instruction manual to operationalize a same-day breast reconstruction protocol, to meet demands of providing appropriate cancer treatment during times of unprecedented resource limitations Pre-pectoral implant-based breast reconstruction can be the definitive procedure or be used as a bridge to autologous reconstruction Importantly, we hope this work will be helpful to our patients and community as we emerge from the COVID-19 pandemic

Management of brain metastases in breast cancer: a review of current practices and emerging treatments

Abstract: Breast cancer brain metastases (BCBM) are becoming an increasingly common diagnosis due to improved systemic control and more routine surveillance imaging. Treatment continues to require a multidisciplinary approach managing systemic and intracranial disease burden. Although, improvements have been made in the diagnosis and management of BCBM, brain metastasis patients continue to pose a challenge for practitioners. In this review, a group of medical oncologists, radiation oncologists, radiologists, breast surgeons, and neurosurgeons specializing in the treatment of breast cancer reviewed the available published literature and compiled a comprehensive review on the current state of BCBM. We discuss the pathogenesis, epidemiology, diagnosis, treatment options (including systemic, surgical, and radiotherapy treatment modalities), and treatment response evaluation for BCBM. Furthermore, we discuss the ongoing prospective trials enrolling BCBM patients and their biologic rationale. BCBM management is an increasing clinical concern. Multidisciplinary management combining the strengths of surgical, systemic, and radiation treatment modalities with prospective trials incorporating knowledge from the basic and translational sciences will ultimately lead to improved clinical outcomes for BCBM patients.

Characteristics and outcomes of patients with breast cancer diagnosed with SARS-Cov-2 infection at an academic center in New York City.

Abstract: Previous reports of patients with Coronavirus disease 2019 (COVID-19) showed higher severity of disease in cancer patients, including the intubation rate [1]. These series focused on those with symptoms from COVID-19 requiring hospitalization, with lung cancer being the most frequent malignancy [1, 2]. We report characteristics and outcomes of COVID-19 + patients with breast cancer (BC) at an academic center in New York City.

Research-based PAM50 signature and long-term breast cancer survival

Abstract: Multi-gene signatures provide biological insight and risk stratification in breast cancer. Intrinsic molecular subtypes defined by mRNA expression of 50 genes (PAM50) are prognostic in hormone-receptor positive postmenopausal breast cancer. Yet, for 25–40% in the PAM50 intermediate risk group, long-term risk remains uncertain. Our study aimed to (i) test the long-term prognostic value of the PAM50 signature in pre- and post-menopausal breast cancer; (ii) investigate if the PAM50 model could be improved by addition of other mRNAs implicated in oncogenesis. We used archived FFPE samples from 1723 breast cancer survivors; high quality reads were obtained on 1253 samples. Transcript expression was quantified using a custom codeset with probes for > 100 targets. Cox models assessed gene signatures for breast cancer relapse and survival. Over 15 + years of follow-up, PAM50 subtypes were (P 60% higher hazard. Addition of a 13-gene hypoxia signature improved prognostication with > 40% higher hazard in the highest vs lowest hypoxia tertiles. PAM50 intrinsic subtypes were independently prognostic for long-term breast cancer survival, irrespective of menopausal status. Addition of hypoxia signatures improved risk prediction. If replicated, incorporating the 13-gene hypoxia signature into the existing PAM50 risk assessment tool, may refine risk stratification and further clarify treatment for breast cancer.

Prospective, randomized, single-blinded, multi-center phase II trial of two HER2 peptide vaccines, GP2 and AE37, in breast cancer patients to prevent recurrence

Abstract: AE37 and GP2 are HER2 derived peptide vaccines. AE37 primarily elicits a CD4+ response while GP2 elicits a CD8+ response against the HER2 antigen. These peptides were tested in a large randomized trial to assess their ability to prevent recurrence in HER2 expressing breast cancer patients. The primary analyses found no difference in 5-year overall disease-free survival (DFS) but possible benefit in subgroups. Here, we present the final landmark analysis. In this 4-arm, prospective, randomized, single-blinded, multi-center phase II trial, disease-free node positive and high-risk node negative breast cancer patients enrolled after standard of care therapy. Six monthly inoculations of vaccine (VG) vs. control (CG) were given as the primary vaccine series with 4 boosters at 6-month intervals. Demographic, safety, immunologic, and DFS data were evaluated. 456 patients were enrolled; 154 patients in the VG and 147 in CG for AE37, 89 patients in the VG and 91 in CG for GP2. The AE37 arm had no difference in DFS as compared to CG, but pre-specified exploratory subgroup analyses showed a trend towards benefit in advanced stage (p = 0.132, HR 0.573 CI 0.275–1.193), HER2 under-expression (p = 0.181, HR 0.756 CI 0.499–1.145), and triple-negative breast cancer (p = 0.266, HR 0.443 CI 0.114–1.717). In patients with both HER2 under-expression and advanced stage, there was significant benefit in the VG (p = 0.039, HR 0.375 CI 0.142–0.988) as compared to CG. The GP2 arm had no significant difference in DFS as compared to CG, but on subgroup analysis, HER2 positive patients had no recurrences with a trend toward improved DFS (p = 0.052) in VG as compared to CG. This phase II trial reveals that AE37 and GP2 are safe and possibly associated with improved clinical outcomes of DFS in certain subgroups of breast cancer patients. With these findings, further evaluations are warranted of AE37 and GP2 vaccines given in combination and/or separately for specific subsets of breast cancer patients based on their disease biology.

A comparison between young and old patients with triple-negative breast cancer: biology, survival and metastatic patterns

Abstract: To determine the biology, recurrence rate, metastatic patterns and survival times in primary triple-negative breast cancer (TNBC) with focus on the comparison between younger and elderly patients. Patients with primary TNBC stage I–IV diagnosed from 2007 to 2015 were identified and information on tumor biology, stage, treatment, recurrences and death recorded. A total of 524 patients, median age 60 years (range 24–94) with a median follow-up of 55 months (range 0–129) were identified. Stage was similar in younger ( 74 years) (n = 96) patients (p = 0.37). A statistically significant difference was found concerning histopathologic grade (p = 0.006) and Ki67 (median 80% versus 70%; p = 0.002) but not for LVI (p = 0.9) with more aggressive tumors among younger patients. Adjuvant/neoadjuvant chemotherapy was more frequently given to younger compared with older patients (96% versus 12%; p = 0.0005). Only brain (p = 0.016) and liver (p = 0.047) metastases were more often registered among younger patients while other locations were similar. Shorter survival times, recurrence-free survival (RFS), distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS) were found in the older group, although not after adjusting for adjuvant/neoadjuvant chemotherapy. Most deaths (68%) in the older group were caused by TNBC. When comparing patients > 75 years (n = 92) with ≤ 75 years (n = 432), a worse outcome among older was also observed: RFS (p = 0.00012), DDFS (p = 0.00041), BCSS (p 60% and outcome is poor. Few older patients in our study were treated with chemotherapy both in adjuvant and palliative setting, underlining the need for more prospective trials and treatment options suitable for this patient population.

Targeted degradation of activating estrogen receptor α ligand-binding domain mutations in human breast cancer.

Abstract: Studies have identified several estrogen receptor α (ERα) ligand-binding domain (LBD) somatic mutations in endocrine therapy resistant, metastatic ER-positive breast cancers. The most common mutations, Tyr537Ser (Y537S) and Asp538Gly (D538G), are detected in ~ 30% of endocrine resistant metastatic breast cancer patients. These ESR1 mutations induce the agonist conformation of ERα, confer an estrogen-independent phenotype, and promote drug resistance to antiestrogens. ER-positive, estrogen-dependent MCF-7 cells were engineered to express either the Y537S or D538G mutants using CRISPR knock-in (cY537S and cD538G). These cells were used to screen several estrogen receptor degrader (ERD) compounds synthesized using the Proteolysis Targeting Chimeras (PROTAC) method to induce degradation of ERα via the ubiquitin–proteasome pathway. Wild-type MCF-7 and ERα LBD mutant cells were treated with ERD-148 (10 pM–1 µM) and assayed for cellular proliferation using the PrestoBlue cell viability assay. ERD-148 attenuated ER-dependent growth with IC50 values of 0.8, 10.5, and 6.1 nM in MCF-7, cY537S, and cD538G cells, respectively. Western blot analysis showed that MCF-7 cells treated with 1 nM ERD-148 for 24 h exhibited reduced ERα protein expression as compared to the mutants. The ER-regulated gene, GREB1, demonstrated significant downregulation in parental and mutant cells after 24 h of ERD-148 treatment at 10 nM. Growth of the ER-negative, estrogen-independent MDA-MB-231 breast cancer cells was not inhibited by ERD-148 at the ~ IC90 observed in the ER-positive cells. ERD-148 inhibits the growth of ER-positive breast cancer cells via downregulating ERα with comparable potency to Fulvestrant with marginal non-specific toxicity.

Associations between breast cancer subtype and neighborhood socioeconomic and racial composition among Black and White women.

Abstract: Studies of Black–White differences in breast cancer subtype often emphasize potential ancestry-associated genetic or lifestyle risk factors without fully considering how the social or economic implications of race in the U.S. may influence risk. We assess whether neighborhood racial composition and/or socioeconomic status are associated with odds of triple-negative breast cancer (TNBC) diagnosis relative to the less-aggressive hormone receptor-positive/HER2-negative subtype (HR+ /HER−), and whether the observed relationships vary across women’s race and age groups. We use multilevel generalized estimating equation models to evaluate odds of TNBC vs. HR+ /HER2− subtypes in a population-based cohort of 7291 Black and 74,208 White women diagnosed with breast cancer from 2006 to 2014. Final models include both neighborhood-level variables, adjusting for individual demographics and tumor characteristics. Relative to the HR+ /HER− subtype, we found modestly lower odds of TNBC subtype among White women with higher neighborhood median household income (statistically significant within the 45–64 age group, OR = 0.981 per $10,000 increase). Among Black women, both higher neighborhood income and higher percentages of Black neighborhood residents were associated with lower odds of TNBC relative to HR+ /HER2−. The largest reduction was observed among Black women diagnosed at age ≥ 65 (OR = 0.938 per $10,000 increase; OR = 0.942 per 10% increase in Black residents). The relationships between neighborhood composition, neighborhood socioeconomic status, and odds of TNBC differ by race and age. Racially patterned social factors warrant further exploration in breast cancer subtype disparities research.

Mismatch repair protein loss in breast cancer: clinicopathological associations in a large British Columbia cohort

Abstract: Alterations to mismatch repair (MMR) pathways are a known cause of cancer, particularly colorectal and endometrial carcinomas. Recently, checkpoint inhibitors have been approved for use in MMR-deficient cancers of any type (Prasad et al. in JAMA Oncol 4:157–158, 2018). Functional studies in breast cancer have shown associations between MMR loss, resistance to aromatase inhibitors and sensitivity to palbociclib (Haricharan et al. in Cancer Discov 7:1168–1183, 2017). Herein, we investigate the clinical meaning of MMR deficiency in breast cancer by immunohistochemical assessment of MSH2, MSH6, MLH1 and PMS2 on a large series of breast cancers linked to detailed biomarker and long-term outcome data. Cases were classified as MMR intact when all four markers expressed nuclear reactivity, but MMR-deficient when at least one of the four biomarkers displayed loss of nuclear staining in the presence of positive internal stromal controls on the tissue microarray core. Among the 1635 cases with interpretable staining, we identified 31 (1.9%) as MMR-deficient. In our cohort, MMR deficiency was present across all major breast cancer subtypes, and was associated with high-grade, low-progesterone receptor expression and high tumor-infiltrating lymphocyte counts. MMR deficiency is significantly associated with inferior overall (HR 2.29, 95% CI 1.02–5.17, p = 0.040) and disease-specific survival (HR 2.71, 95% CI 1.00–7.35, p = 0.042) in the 431 estrogen receptor-positive patients who were uniformly treated with tamoxifen as their sole adjuvant systemic therapy. Overall, this study supports the concept that breast cancer patients with MMR deficiency as assessed by immunohistochemistry may be good candidates for alternative treatment approaches such as immune checkpoint or CDK4 inhibitors.

Sixty spontaneous vertebral fractures after denosumab discontinuation in 15 women with early-stage breast cancer under aromatase inhibitors.

Abstract: At denosumab discontinuation, bone turnover markers increase and the gained BMD is lost. In postmenopausal osteoporosis, there is an increased risk of spontaneous vertebral fractures (VFs) of about 1 to 10%, rarely described in women under denosumab for aromatase inhibitors (AI)-treated breast cancer. We aim to describe the characteristics of 15 patients under denosumab given for AI-treated early-stage breast cancer that presented VFs at its discontinuation. Single-center retrospective case series of 15 patients. We report clinical data, dual X-ray absorptiometry values at denosumab initiation and discontinuation, and serum B-crosslaps dosage at the time of VF occurrence (before denosumab resumption). Fifteen women (66.4 ± 7.1 years at denosumab discontinuation) that received AI for 5.0 ± 0.6 years, denosumab 60 mg for 8.2 ± 2.0 doses, and developed 60 VFs at denosumab discontinuation, were followed for 24.4 ± 9.5 months. Patients suffered from 1 to 11 (mean 4.0 ± 1.9) clinical VFs within 7 to 16 months after last denosumab injection. VFs developed earlier in patients with longer denosumab treatment (R2 = 0.29, p = 0.04) and in patients without osteoporosis before denosumab (9.4 ± 2.0 vs. 13.0 ± 2.0 months; p = 0.005). Serum B-crosslaps at the time of VFs tended to be higher in patients with earlier VFs (R2 = 0.47; p = 0.06) or with longer denosumab treatment (R2 = 0.48; p = 0.06). Denosumab was resumed in all patients, then switched for a bisphosphonate in eight. No new VFs occurred during follow-up. Despite an apparently low fracture risk, women under denosumab for AI-treated early-stage breast cancer develop spontaneous VFs at denosumab discontinuation. This risk increases with treatment duration and may be prevented by a potent bisphosphonate.

Association of depression and anxiety disorder with the risk of mortality in breast cancer: A National Health Insurance Service study in Korea.

Abstract: To examine whether depression, anxiety disorder, and their co-occurrence would increase the risk of mortality in patients with breast cancer, and whether antidepressant treatment would reduce the same. Data were retrieved from the database of the Korean National Health Insurance Service. Of 145,251 patients diagnosed with breast cancer between 2007 and 2014, 20,870 patients diagnosed with depression or anxiety disorder one year before breast cancer diagnosis were excluded. Thus, data of 124,381 patients were included in this study. Depression and anxiety disorder were associated with an increased risk of mortality [Hazard Ratio (HR) 1.26, 95% CI 1.18–1.36; HR 1.14, 95% CI 1.08–1.22, respectively] and their co-occurrence further increased the risk (HR = 1.38, 95% CI 1.24–1.54). Antidepressant treatment was related to a reduced risk of mortality. Compared to patients without any psychiatric comorbidity with no antidepressant treatment, the mortality risk increased in patients with either psychiatric comorbidity or both, but the risk seemed to attenuate with antidepressant treatments. The current findings suggest that psychiatric comorbidities are markers of increased mortality risk in patients with breast cancer, and antidepressant treatment may attenuate the risk. This underscores the need for screening and treating depression and anxiety disorders to improve survival in patients with breast cancer.

Double reading of diffusion-weighted magnetic resonance imaging for breast cancer detection.

Abstract: To estimate the performance of diffusion-weighted imaging (DWI) for breast cancer detection. Consecutive breast magnetic resonance imaging examinations performed from January to September 2016 were retrospectively evaluated. Examinations performed before/after neoadjuvant therapy, lacking DWI sequences or reference standard were excluded; breasts after mastectomy were also excluded. Two experienced breast radiologists (R1, R2) independently evaluated only DWI. Final pathology or > 1-year follow-up served as reference standard. Mc Nemar, χ2, and κ statistics were applied. Of 1,131 examinations, 672 (59.4%) lacked DWI sequence, 41 (3.6%) had no reference standard, 30 (2.7%) were performed before/after neoadjuvant therapy, and 10 (0.9%) had undergone bilateral mastectomy. Thus, 378 women aged 49 ± 11 years (mean ± standard deviation) were included, 51 (13%) with unilateral mastectomy, totaling 705 breasts. Per-breast cancer prevalence was 96/705 (13.6%). Per-breast sensitivity was 83/96 (87%, 95% confidence interval 78–93%) for both R1 and R2, 89/96 (93%, 86–97%) for double reading (DR) (p = 0.031); per-lesion DR sensitivity for cancers ≤ 10 mm was 22/31 (71%, 52–86%). Per-breast specificity was 562/609 (93%, 90–94%) for R1, 538/609 (88%, 86–91%) for R2, and 526/609 (86%¸ 83–89%) for DR (p < 0.001). Inter-observer agreement was substantial (κ = 0.736). Acquisition time varied from 3:00 to 6:22 min:s. Per-patient median interpretation time was 46 s (R1) and 51 s (R2). DR DWI showed a 93% sensitivity and 88% specificity, with 71% sensitivity for cancers ≤ 10 mm, pointing out a potential for DWI as stand-alone screening method.

Gut microbiome associations with breast cancer risk factors and tumor characteristics: a pilot study.

Abstract: To investigate the association between gut microbiome with breast tumor characteristics (receptor status, stage and grade) and known breast cancer risk factors. In a pilot cross-sectional study of 37 incident breast cancer patients, fecal samples collected prior to chemotherapy were analyzed by 16S ribosomal RNA (rRNA) gene-based sequencing protocol. Alpha diversity and specific taxa by tumor characteristics and breast cancer risk factors were tested by Wilcoxon rank sum test, and by differential abundance analysis, using a zero-inflated negative binomial regression model with adjustment for total counts, age and race/ethnicity. There were no significant alpha diversity or phyla differences by estrogen/progesterone receptor status, tumor grade, stage, parity and body mass index. However, women with human epidermal growth factor receptor 2 positive (HER2+) (n = 12) compared to HER2− (n = 25) breast cancer showed 12–23% lower alpha diversity [number of species (OTU) p = 0.033, Shannon index p = 0.034], lower abundance of Firmicutes (p = 0.005) and higher abundance of Bacteroidetes (p = 0.089). Early menarche (ages ≤ 11) (n = 11) compared with later menarche (ages ≥ 12) (n = 26) was associated with lower OTU (p = 0.036), Chao1 index (p = 0.020) and lower abundance of Firmicutes (p = 0.048). High total body fat (TBF) (> 46%) (n = 12) compared to lower (≤ 46%) TBF was also associated with lower Chao 1 index (p = 0.011). There were other significant taxa abundance differences by HER2 status, menarche age, as well as other tumor and breast cancer risk factors. Further studies are needed to identify characteristics of the human microbiome and the interrelationships between breast cancer hormone receptor status and established breast cancer risk factors.

Multiparametric radiomics methods for breast cancer tissue characterization using radiological imaging

Abstract: Multiparametric radiological imaging is vital for detection, characterization, and diagnosis of many different diseases. Radiomics provide quantitative metrics from radiological imaging that may infer potential biological meaning of the underlying tissue. However, current methods are limited to regions of interest extracted from a single imaging parameter or modality, which limits the amount of information available within the data. This limitation can directly affect the integration and applicable scope of radiomics into different clinical settings, since single image radiomics are not capable of capturing the true underlying tissue characteristics in the multiparametric radiological imaging space. To that end, we developed a multiparametric imaging radiomic (mpRad) framework for extraction of first and second order radiomic features from multiparametric radiological datasets. We developed five different radiomic techniques that extract different aspects of the inter-voxel and inter-parametric relationships within the high-dimensional multiparametric magnetic resonance imaging breast datasets. Our patient cohort consisted of 138 breast patients, where, 97 patients had malignant lesions and 41 patients had benign lesions. Sensitivity, specificity, receiver operating characteristic (ROC) and areas under the curve (AUC) analysis were performed to assess diagnostic performance of the mpRad parameters. Statistical significance was set at p < 0.05. The mpRad features successfully classified malignant from benign breast lesions with excellent sensitivity and specificity of 82.5% and 80.5%, respectively, with Area Under the receiver operating characteristic Curve (AUC) of 0.87 (0.81–0.93). mpRad provided a 9–28% increase in AUC metrics over single radiomic parameters. We have introduced the mpRad framework that extends radiomic analysis from single images to multiparametric datasets for better characterization of the underlying tissue biology.

G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer.

Abstract: The combination of targeting the CDK4/6 and estrogen receptor (ER) signaling pathways with palbociclib and fulvestrant is a proven therapeutic strategy for the treatment of ER-positive breast cancer. However, the poor physicochemical properties of fulvestrant require monthly intramuscular injections to patients, which limit the pharmacokinetic and pharmacodynamic activity of the compound. Therefore, an orally available compound that more rapidly reaches steady state may lead to a better clinical response in patients. Here, we report the identification of G1T48, a novel orally bioavailable, non-steroidal small molecule antagonist of ER. The pharmacological effects and the antineoplastic mechanism of action of G1T48 on tumors was evaluated using human breast cancer cells (in vitro) and xenograft efficacy models (in vivo). G1T48 is a potent and efficacious inhibitor of estrogen-mediated transcription and proliferation in ER-positive breast cancer cells, similar to the pure antiestrogen fulvestrant. In addition, G1T48 can effectively suppress ER activity in multiple models of endocrine therapy resistance including those harboring ER mutations and growth factor activation. In vivo, G1T48 has robust antitumor activity in a model of estrogen-dependent breast cancer (MCF7) and significantly inhibited the growth of tamoxifen-resistant (TamR), long-term estrogen-deprived (LTED) and patient-derived xenograft tumors with an increased response being observed with the combination of G1T48 and the CDK4/6 inhibitor lerociclib. These data show that G1T48 has the potential to be an efficacious oral antineoplastic agent in ER-positive breast cancer.

Lymphovascular invasion in breast cancer is associated with gene expression signatures of cell proliferation but not lymphangiogenesis or immune response.

Abstract: While the prognostic relevance of lymphovascular invasion (LVI) in breast cancer is well known, its molecular biology is poorly understood. We hypothesized that pathologically determined LVI reflects molecular features of tumors and can be discerned from their genomic and transcriptomic profiles. LVI status and Nottingham histological scores of primary breast tumors of The Cancer Genome Atlas (TCGA) project were assessed from pathology reports; other clinical and molecular data were obtained from TCGA data portals and publications. Two independent datasets (GSE5460 and GSE7849) were combined and used for validation. LVI status was determinable for 639 and 196 cases of the TCGA and validation cohorts, among whom LVI incidence was 37.8% and 37.2%, respectively. LVI was associated with high tumor Ki67 expression, advanced pathologic stage, and high Nottingham scores. LVI-positive cases had worse overall and progression-free survival regardless of cancer subtype. Surprisingly, in both cohorts, LVI was not associated with lymphangiogenesis or lymphatic vessel density as estimated from tumor expression of lymphatic endothelium-associated genes. LVI-positive tumors had higher genome copy number aberrations, aneuploidy, and homologous recombination defects, but not single-nucleotide variations or intra-tumor genome heterogeneity. Tumor immune cell composition and cytolytic activity was not associated with LVI status. On the other hand, expression of cell proliferation-related genes was significantly increased in LVI-positive tumors. Our study suggests that breast cancer with LVI is a highly proliferative cancer, and it does not correlate with gene expression markers for lymphangiogenesis or immune response.

Optimism and coping: do they influence health outcomes in women with breast cancer? A systemic review and meta-analysis.

Abstract: Optimism, coping, and resilience may be independent predictors of anxiety, distress, depression, or health-related quality of life (HRQOL) in women with breast cancer. Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) searches of PubMed, PsycINFO, and Google Scholar databases from January 1, 1990, to April 30, 2018, for articles (i.e., studies) determining the impact of optimism, coping, or resilience on anxiety, distress, depression, or HRQOL in women with breast cancer. Articles included only those that measured optimism by the life orientation test (LOT) or LOT-revised (R), coping by the COPE, brief (B)-COPE, or religious (R)-COPE, and resilience by the CD-Resilience Scale (CD-RIS). Forty-one out of 52 (79%) studies showed that optimism is a statistically significant predictor of study-specific aspects of anxiety, distress, depression, or HRQOL. In a meta-analysis focused on depression, optimism was a statistically significant predictor of depression. Coping style is a statistically significant predictor for study-specific aspects of anxiety, distress, depression, or HRQOL in 41/43 (95%) studies. The coping studies were too heterogeneous in their outcome variables to perform meta-analyses. There were too few studies (n = 6) on resilience to draw any conclusions. Despite many limitations of this literature, including the heterogeneity of study designs, differing sample sizes, across different countries, cultures, ethnicities, and races, most studies support that optimism and coping are predictors of anxiety, distress, depression, or HRQOL. Awareness of these psychological constructs and their potential impact on anxiety, depression, and HRQOL are a high priority.

Prediction of pathologic complete response using image-guided biopsy after neoadjuvant chemotherapy in breast cancer patients selected based on MRI findings: a prospective feasibility trial

Abstract: Accurate prediction of pathologic complete response (pCR) in breast cancer using magnetic resonance imaging (MRI) and ultrasound (US)-guided biopsy may aid in selecting patients who forego surgery for breast cancer. We evaluated the accuracy of US-guided biopsy aided by MRI in predicting pCR in the breast after neoadjuvant chemotherapy (NAC). After completion of NAC, 40 patients with near pCR (either tumor size ≤ 0.5 cm or lesion-to-background signal enhancement ratio (L-to-B SER) ≤ 1.6 on MRI) and no diffused residual microcalcifications were prospectively enrolled at a single institution. US-guided multiple core needle biopsy (CNB) or vacuum-assisted biopsy (VAB) of the tumor bed, followed by standard surgical excision, was performed. Matched biopsy and surgical specimens were compared to assess pCR. The negative predictive value (NPV), accuracy, and false-negative rate (FNR) were analyzed. pCR was confirmed in 27 (67.5%) surgical specimens. Preoperative biopsy had an NPV, accuracy, and FNR of 87.1%, 90.0%, and 30.8%, respectively. NPV for hormone receptor-negative and hormone receptor-positive tumors were 83.3% and 100%, respectively. Obtaining at least 5 biopsy cores based on tumor size ≤ 0.5 cm and an L-to-B SER of ≤ 1.6 on MRI (27 patients) resulted in 100% NPV and accuracy. No differences in accuracy were noted between CNB and VAB (90% vs. 90%). Investigation using stringent MRI criteria and ultrasound-guided biopsy could accurately predict patients with pCR after NAC. A larger prospective clinical trial evaluating the clinical safety of breast surgery omission after NAC in selected patients will be conducted based on these findings.