Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer.

BACKGROUND: The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). METHODS: In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10-5. RESULTS: The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10-6 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively. CONCLUSIONS: Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).

A phase Ib study of capecitabine and ziv-aflibercept followed by a phase II single-arm expansion cohort in chemotherapy refractory metastatic colorectal cancer.

BACKGROUND: Patients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options. In this phase Ib/II clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then we evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC. METHODS: All patients were required to have a Karnofsky Performance Status > 70% and adequate organ function. The phase Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies. Using a standard 3 + 3 design, we identified the MTD and RPTD for the combination. Fifty patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase II expansion cohort, and were treated at the RPTD. Prior EGFR antibody therapy was required for subjects with RAS wildtype tumors. The primary endpoint for the expansion cohort was progression-free survival (PFS) at two months. Secondary endpoints included objective response rate (ORR) and overall survival (OS). RESULTS: A total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion). The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1-14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle. In the expansion cohort, 72% of patients were progression-free at two months (95% confidence interval [CI], 60-84%). Median PFS and OS were 3.9 months (95% CI, 2.3-4.5) and 7.1 months (95% CI: 5.8-10.0), respectively. Among all patients evaluable for toxicity, the most common treatment related adverse events (all grade [%]; grade ≥ 3 [%]) included palmar-plantar erythrodysesthesia (41%; 6%), hypertension (33%; 22%), and mucositis (19%; 5%). RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes. CONCLUSION: The combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability. PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study. TRIAL REGISTRATION: This clinical trial was registered in the www.clinicaltrials.gov system as NCT01661972 on July 31, 2012.

Phase 1 study of seviteronel, a selective CYP17 lyase and androgen receptor inhibitor, in women with estrogen receptor-positive or triple-negative breast cancer.

PURPOSE: Seviteronel (INO-464) is an oral, selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) and androgen receptor inhibitor with in vitro and in vivo anti-tumor activity. This open-label phase 1 clinical study evaluated safety, tolerability, pharmacokinetics (PK), and activity of once-daily (QD) seviteronel in women with locally advanced or metastatic TNBC or ER+ breast cancer. METHODS: Seviteronel was administered in de-escalating 750, 600, and 450 mg QD 6-subject cohorts. The 750 mg QD start dose was a phase 2 dose determined for men with castration-resistant prostate cancer in (Shore et al. J Clin Oncol 34, 2016). Enrollment at lower doses was initiated in the presence of dose-limiting toxicities (DLTs). The primary objective of this study was to determine seviteronel safety, tolerability, and MTD. The secondary objectives included description of its PK in women and its initial activity, including clinical benefit rate at 4 (CBR16) and 6 months (CBR24). RESULTS: Nineteen women were enrolled. A majority of adverse events (AEs) were Grade (Gr) 1/2, independent of relationship; the most common were tremor (42%), nausea (42%), vomiting (37%), and fatigue (37%). Four Gr 3/4 AEs (anemia, delirium, mental status change, and confusional state) deemed possibly related to seviteronel occurred in four subjects. DLTs were observed at 750 mg (Gr 3 confusional state with paranoia) and 600 mg (Gr 3 mental status change and Gr 3 delirium) QD, with none at 450 mg QD. The recommended phase 2 dose (RP2D) was 450 mg QD, and at the RP2D, 4 of 7 subjects reached at least CBR16 (2 TNBC subjects and 2 ER+ subjects achieved CBR16 and CBR24, respectively); no objective tumor responses were reported. CONCLUSIONS: Once-daily seviteronel was generally well tolerated in women with and 450 mg QD was chosen as the RP2D.

Ascertainment, classification, and impact of neoplasm detection during prolonged treatment with dual antiplatelet therapy with prasugrel vs. clopidogrel following acute coronary syndrome.

AIMS: Studies have suggested increased cancer incidence associated with long-term dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). We evaluated cancer incidence and treatment-related differences in an analysis of DAPT for ACS. METHODS AND RESULTS: The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial enrolled 9326 participants with ACS, who received aspirin plus clopidogrel or prasugrel. Median treatment exposure was 15 months. Cancer history and screening procedures were collected. Suspected non-benign neoplasm events were reported and adjudicated. The primary outcome was detection of new, non-benign neoplasm. Factors associated with neoplasm events, the relationship of these events to cardiovascular and bleeding endpoints, and treatment-related differences in neoplasm detection were studied. Among 9240 participants who received ≥1 dose of study drug, 1.8% had a confirmed neoplasm event. The efficacy composite of cardiovascular death, myocardial infarction, or stroke occurred more frequently among those with a neoplasm event vs. those without (18.2 vs. 13.5%) as did Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding (11.2 vs. 1.5%). Screening rates were substantially higher in North America and Western Europe/Scandinavia vs. other regions. Factors most strongly associated with detection of neoplasm events were older age, region, male sex, and current/recent smoking. Among the pre-specified population without a history of neoplasm or previous curative treatment for neoplasm (n = 9105), the incidence of neoplasm events was similar with prasugrel vs. clopidogrel (1.8 vs. 1.7%; HR = 1.04; 95% CI 0.77-1.42; P = 0.79). CONCLUSIONS: Neoplasm events were infrequent during long-term DAPT after ACS, were associated with differential cancer-screening practices across regions, and the frequency of neoplasm detection was similar with prasugrel vs. clopidogrel. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00699998.

Genomic profiling in locally advanced and inflammatory breast cancer and its link to DCE-MRI and overall survival.

PURPOSE: We have previously reported that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion patterns obtained from locally advanced breast cancer (LABC) patients prior to neoadjuvant therapy predicted pathologic clinical response. Genomic analyses were also independently conducted on the same patient population. This retrospective study was performed to test two hypotheses: (1) gene expression profiles are associated with DCE-MRI perfusion patterns, and (2) association between long-term overall survival data and gene expression profiles can lead to the identification of novel predictive biomarkers. METHODS: We utilised RNA microarray and DCE-MRI data from 47 LABC patients, including 13 inflammatory breast cancer (IBC) patients. Association between gene expression profile and DCE-MRI perfusion patterns (centrifugal and centripetal) was determined by Wilcoxon rank sum test. Association between gene expression level and survival was assessed using a Cox rank score test. Additional genomic analysis of the IBC subset was conducted, with a period of follow-up of up to 11 years. Associations between gene expression and overall survival were further assessed in The Cancer Genome Atlas Data Portal. RESULTS: Differences in gene expression profiles were seen between centrifugal and centripetal perfusion patterns in the sulphotransferase family, cytosolic, 1 A, phenol-preferring, members 1 and 2 (SULT1A1, SULT1A2), poly (ADP-ribose) polymerase, member 6 (PARP6), and metastasis tumour antigen1 (MTA1). In the IBC subset our analyses demonstrated that differential expression of 45 genes was associated with long-term survival. CONCLUSIONS: Here we have demonstrated an association between DCE-MRI perfusion patterns and gene expression profiles. In addition we have reported on candidate prognostic biomarkers in IBC patients, with some of the genes being significantly associated with survival in IBC and LABC.

Self-efficacy for coping with symptoms moderates the relationship between physical symptoms and well-being in breast cancer survivors taking adjuvant endocrine therapy.

PURPOSE: This study examined the relationships between physical symptoms, self-efficacy for coping with symptoms, and functional, emotional, and social well-being in women who were taking adjuvant endocrine therapy for breast cancer. METHODS: One hundred and twelve women who were taking adjuvant endocrine therapy (tamoxifen or an aromatase inhibitor) for breast cancer completed measures of physical symptoms, self-efficacy for coping with symptoms, and functional, social, and emotional well-being at the time of routine medical follow-up (women were on average 3.4 years post-surgery; range 3 months to 11 years). RESULTS: Multiple linear regression analyses showed that higher self-efficacy for coping with symptoms was associated with greater functional, emotional, and social well-being after controlling for physical symptoms (p < 0.05). Self-efficacy for coping with symptoms moderated the relationship between physical symptoms and functional (B = 0.05, SE = 0.02, t = 2.67, p = 0.009) and emotional well-being (B = 0.03, SE = 0.01, t = 2.45, p = 0.02). As self-efficacy increased, the relationship between greater physical symptoms and lower well-being became weaker. Among women with high levels of self-efficacy, physical symptoms were not related to functional and emotional well-being. CONCLUSIONS: Self-efficacy for coping with symptoms may reduce the negative impact of physical symptoms and contribute to well-being in breast cancer survivors taking adjuvant endocrine therapy. Future studies could examine whether psychosocial interventions aimed at increasing self-efficacy for managing symptoms help women better cope with treatment side effects and improve quality of life.

Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer.

PURPOSE: Unresectable chest wall recurrences of breast cancer (CWR) in heavily pretreated patients are especially difficult to treat. We hypothesised that thermally enhanced drug delivery using low temperature liposomal doxorubicin (LTLD), given with mild local hyperthermia (MLHT), will be safe and effective in this population. PATIENTS AND METHODS: This paper combines the results of two similarly designed phase I trials. Eligible CWR patients had progressed on the chest wall after prior hormone therapy, chemotherapy, and radiotherapy. Patients were to get six cycles of LTLD every 21-35 days, followed immediately by chest wall MLHT for 1 hour at 40-42 °C. In the first trial 18 subjects received LTLD at 20, 30, or 40 mg/m2; in the second trial, 11 subjects received LTLD at 40 or 50 mg/m2. RESULTS: The median age of all 29 patients enrolled was 57 years. Thirteen patients (45%) had distant metastases on enrolment. Patients had received a median dose of 256 mg/m2 of prior anthracyclines and a median dose of 61 Gy of prior radiation. The median number of study treatments that subjects completed was four. The maximum tolerated dose was 50 mg/m2, with seven subjects (24%) developing reversible grade 3-4 neutropenia and four (14%) reversible grade 3-4 leucopenia. The rate of overall local response was 48% (14/29, 95% CI: 30-66%), with. five patients (17%) achieving complete local responses and nine patients (31%) having partial local responses. CONCLUSION: LTLD at 50 mg/m2 and MLHT is safe. This combined therapy produces objective responses in heavily pretreated CWR patients. Future work should test thermally enhanced LTLD delivery in a less advanced patient population.

A randomized phase II study of lapatinib + pazopanib versus lapatinib in patients with HER2+ inflammatory breast cancer.

This multi-center Phase II study evaluated lapatinib, pazopanib, and the combination in patients with relapsed HER2+ inflammatory breast cancer. In Cohort 1, 76 patients were randomized 1:1 to receive lapatinib 1,500 mg + placebo or lapatinib 1,500 mg + pazopanib 800 mg (double-blind) once daily until disease progression, unacceptable toxicity, or death. Due to high-grade diarrhea observed with this dose combination in another study (VEG20007), Cohort 1 was closed. The protocol was amended such that an additional 88 patients (Cohort 2) were randomized in a 5:5:2 ratio to receive daily monotherapy lapatinib 1,500 mg, lapatinib 1,000 mg + pazopanib 400 mg, or monotherapy pazopanib 800 mg, respectively. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival, and safety. In Cohort 1, ORR for the lapatinib (n = 38) and combination (n = 38) arms was 29 and 45 %, respectively; median PFS was 16.1 and 14.3 weeks, respectively. Grade ≥3 adverse events (AEs) were more frequent in the combination arm (71 %) than in the lapatinib arm (24 %). Dose reductions and interruptions due to AEs were also more frequent in the combination arm (45 and 53 %, respectively) than in the lapatinib monotherapy arm (0 and 11 %, respectively). In Cohort 2, ORR for patients treated with lapatinib (n = 36), lapatinib + pazopanib (n = 38), and pazopanib (n = 13) was 47, 58, and 31 %, respectively; median PFS was 16.0, 16.0, and 11.4 weeks, respectively. In the lapatinib, combination, and pazopanib therapy arms, grade ≥3 AEs were reported for 17, 50, and 46 % of patients, respectively, and the incidence of discontinuations due to AEs was 0, 24, and 23 %, respectively. The lapatinib-pazopanib combination was associated with a numerically higher ORR but no increase in PFS compared to lapatinib alone. The combination also had increased toxicity resulting in more dose reductions, modifications, and treatment delays. Activity with single-agent lapatinib was confirmed in this population.

Prevalence of Germline Findings Among Tumors From Cancer Types Lacking Hereditary Testing Guidelines.

Importance: Germline testing guidelines are suggested for specific disease types or a family history of cancer, yet alterations are found in cancer types in which germline testing is not routinely indicated. The clinical role of identifying germline variants in these populations is valuable to patients and their at-risk relatives. Objective: To evaluate the prevalence of germline findings in patients undergoing tumor/normal matched sequencing among cancer types lacking guidelines. Design, Setting, and Participants: This retrospective cross-sectional study took place on August 18, 2021, and included data from deidentified records of patients tested, using the Tempus xT tumor/normal matched approach from November 2017 to August 2021. Records included in this study were from 34 642 patients treated in geographically diverse oncology practices in the US with a diagnosis of any of the following cancers: bladder, brain, lung, esophagus, cholangiocarcinoma, head and neck, breast, ovarian, pancreatic, prostate, endometrial, and colorectal. Main Outcomes and Measures: The rate of germline findings (ie, single-nucleotide variants and small insertions or deletions) detected in 50 reportable hereditary cancer genes was calculated for cancer types lacking guidelines for germline testing (bladder, brain, lung, esophagus, cholangiocarcinoma, and head and neck) and cancer types for which germline testing is frequently performed (breast, ovarian, pancreatic, prostate, endometrial, and colorectal). Same-gene second somatic hits were assessed to provide a comprehensive assessment on genomic drivers. Results: Of 34 642 patients, 18 888 were female (54.5%); of 27 498 patients whose age at diagnosis was known, mean (SD) age was 62.23 (3.36) years. A total of 2534 of 34 642 patients (7.3%) harbored pathogenic or likely pathogenic germline variants. Within the tumor types lacking testing guidelines, germline mutations were at 6.6% (79/1188) in bladder cancer and 5.8% (448/7668) in lung cancer. Conclusions and Relevance: This study may present the largest retrospective analysis to date of deidentified real-world data from patients diagnosed with advanced cancer with tumor/normal matched sequencing data and the prevalence of pathogenic or likely pathogenic germline variants in cancer types lacking hereditary cancer testing guidelines. The findings suggest there may be clinical implications for patients and their at-risk family members in cancers for which germline assessment primarily based on the cancer diagnosis is rarely obtained.

Longitudinal Shifts of Solid Tumor and Liquid Biopsy Sequencing Concordance in Metastatic Breast Cancer.

Tissue-based next-generation sequencing (NGS) in metastatic breast cancer (mBC) is limited by the inability to noninvasively track tumor evolution. Cell-free DNA (cfDNA) NGS has made sequential testing feasible; however, the relationship between cfDNA and tissue-based testing in mBC is not well understood. Here, we evaluate concordance between tissue and cfDNA NGS relative to cfDNA sampling frequency in a large, clinically annotated mBC data set. METHODS: Tempus LENS was used to analyze deidentified records of mBC cases with Tempus xT (tissue) and xF (cfDNA) sequencing results. Then, various metrics of concordance were assessed within overlapping probe regions of the tissue and cfDNA assays (104 genes), focusing on pathogenic variants. Variant allele frequencies of discordant and concordant pathogenic variants were also compared. Analyses were stratified by mBC subtype and time between tests. RESULTS: Records from 300 paired tissue and liquid biopsies were analyzed. Median time between tissue and blood collection was 78.5 days (standard deviation = 642.99). The median number of pathogenic variants/patient was one for cfDNA and two for tissue. Across the cohort, 77.8% of pathogenic tissue variants were found in cfDNA and 75.7% of pathogenic cfDNA variants were found in tissue when tests were ≤ 7 days apart, which decreased to 50.3% and 51.8%, respectively, for > 365 days. Furthermore, the median patient-level variant concordance was 67% when tests were ≤7 days apart and 30%-37% when > 30 days. The median variant allele frequencies of discordant variants were generally lower than those of concordant variants within the same time frame. CONCLUSION: We observed high concordances between tissue and cfDNA results that generally decreased with longer durations between tests. Thus, cfDNA NGS reliably measures tissue genomics and is likely beneficial for longitudinal monitoring of molecular changes in mBC.

Analysis of tumor environmental response and oncogenic pathway activation identifies distinct basal and luminal features in HER2-related breast tumor subtypes.

INTRODUCTION: Breast cancer heterogeneity occurs as a consequence of the dysregulation of numerous oncogenic pathways as well as many non-genetic factors, including tumor microenvironmental stresses such as hypoxia, lactic acidosis, and glucose deprivation. Although the importance of these non-genetic factors is well recognized, it is not clear how to integrate these factors within the genetic framework of cancer as the next logical step in understanding tumor heterogeneity. METHODS: We report here the development of a series of gene expression signatures to measure the influences of microenvironmental stresses. The pathway activities of hypoxia, lactic acidosis, acidosis and glucose deprivation were investigated in a collection of 1,143 breast tumors, which have been separated into 17 breast tumor subgroups defined by their distinct patterns of oncogenic pathways. A validation dataset comprised of 547 breast tumors was also used to confirm the major findings, and representative breast cancer cell lines were utilized to validate in silico results and mechanistic studies. RESULTS: Through the integrative pathway analysis of microenvironmental stresses and oncogenic events in breast tumors, we identified many known and novel correlations between these two sources of tumor heterogeneity. Focusing on differences between two human epidermal growth factor receptor 2 (HER2)-related subgroups, previously identified based on patterns of oncogenic pathway activity, we determined that these subgroups differ with regards to tumor microenvironmental signatures, including hypoxia. We further demonstrate that each of these subgroups have features consistent with basal and luminal breast tumors including patterns of oncogenic signaling pathways, expression of subtype specific genes, and cellular mechanisms that regulate the hypoxia response. Importantly, we also demonstrate that the correlated pattern of hypoxia-related gene expression and basal-associated gene expression are consistent across HER2-related tumors whether we analyze the tumors as a function of our pathway-based classification scheme, using the intrinsic gene list (ERBB2+), or based on HER2 IHC status. Our results demonstrate a cell lineage-specific phenomenon in which basal-like tumors, HER2-related tumors with high hypoxia, as well as normal basal epithelial cells express increased mRNA levels of HIF-1α compared to luminal types and silencing of HIF-1α results in decreased expression of hypoxia-induced genes. CONCLUSIONS: This study demonstrates differences in microenvironmental conditions in HER2-related subgroups defined by distinct oncogenic pathway activities, and provides a mechanistic explanation for differences in the observed hypoxia response between these subgroups. Collectively, these data demonstrate the potential of a pathway-based classification strategy as a framework to integrate genetic and non-genetic factors to investigate the basis of tumor heterogeneity.

Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases.

INTRODUCTION: Activation status of the phosphatidylinositol 3-kinase (PI3K) pathway in breast cancer brain metastases (BCBMs) is largely unknown. We examined expression of phospho(p)-AKT, p-S6, and phosphatase and tensin homologue (PTEN) in BCBMs and their implications for overall survival (OS) and survival after BCBMs. Secondary analyses included PI3K pathway activation status and associations with time to distant recurrence (TTDR) and time to BCBMs. Similar analyses were also conducted among the subset of patients with triple-negative BCBMs. METHODS: p-AKT, p-S6, and PTEN expression was assessed with immunohistochemistry in 52 BCBMs and 12 matched primary BCs. Subtypes were defined as hormone receptor (HR)+/HER2-, HER2+, and triple-negative (TNBC). Survival analyses were performed by using a Cox model, and survival curves were estimated with the Kaplan-Meier method. RESULTS: Expression of p-AKT and p-S6 and lack of PTEN (PTEN-) was observed in 75%, 69%, and 25% of BCBMs. Concordance between primary BCs and matched BCBMs was 67% for p-AKT, 58% for p-S6, and 83% for PTEN. PTEN- was more common in TNBC compared with HR+/HER2- and HER2+. Expression of p-AKT, p-S6, and PTEN- was not associated with OS or survival after BCBMs (all, P > 0.06). Interestingly, among all patients, PTEN- correlated with shorter time to distant and brain recurrence. Among patients with TNBC, PTEN- in BCBMs was associated with poorer overall survival. CONCLUSIONS: The PI3K pathway is active in most BCBMs regardless of subtype. Inhibition of this pathway represents a promising therapeutic strategy for patients with BCBMs, a group of patients with poor prognosis and limited systemic therapeutic options. Although expression of the PI3K pathway did not correlate with OS and survival after BCBM, PTEN- association with time to recurrence and OS (among patients with TNBC) is worthy of further study.

New perspectives on zoledronic acid in breast cancer: potential augmentation of anticancer immune response.

A small subset of T cells (gamma-delta T cells) is able to recognize phosphoantigens that are overexpressed in some cancer cells and may selectively target and kill cancer cells with high levels of phosphoantigen. Moreover, nitrogen-containing bisphosphonates, such as zoledronic acid, are able to induce accumulation of specific phosphoantigens in some cancer cells. A recent preclinical study showed that gamma-delta T cells effectively targeted and killed zoledronic acid-treated estrogen-receptor-positive breast cancer cells. These new data provide growing insight into a potential mechanism of action for some of the anticancer activity demonstrated by zoledronic acid in breast cancer clinical trials.

Safety of bevacizumab in patients with metastatic breast cancer.

Five randomized phase III trials - AVF2119g, E2100, AVADO, RIBBON-1, and RIBBON-2 - have reported data on the efficacy and safety of bevacizumab, combined with a variety of chemotherapy agents and in various settings, in patients with metastatic breast cancer (MBC). The E2100 trial demonstrated a significant improvement in progression-free survival according to the independent review facility, from 5.8 to 11.3 months when bevacizumab was combined with paclitaxel (p < 0.0001) as first-line therapy in patients with HER2-nonamplified MBC; subsequent trials of bevacizumab as first-line (AVADO, RIBBON-1) and second-line (RIBBON-2) therapy for patients with HER2-nonamplified MBC have also met their primary end point of prolonging progression-free survival (PFS). Accumulating safety data for bevacizumab in MBC show that it is generally well tolerated and associated with predictable adverse events, including hypertension and proteinuria. The majority of adverse events are mild and manageable, but bevacizumab is also associated with some severe toxicities. The management of bevacizumab-related adverse events in MBC has improved with increased experience. This review summarizes bevacizumab efficacy in MBC and focuses on bevacizumab-related toxicities as reported in 5 phase III clinical trials. Current adverse event management strategies, based on guidelines and experience from these trials, are outlined.

Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: a review of the randomised data.

Hyperthermia has long been used in combination with radiation for the treatment of superficial malignancies, in part due to its radiosensitising capabilities. Patients who suffer superficial recurrences of breast cancer, be it in their chest wall following mastectomy, or in their breast after breast conservation, typically have poor clinical outcomes. They often develop distant metastatic disease, but one must not overlook the problems associated with an uncontrolled local failure. Morbidity is enormous, and can significantly impair quality of life. There is no accepted standard of care in treating superficial recurrences of breast cancer, particularly in patients that have previously been irradiated. There is a substantial literature regarding the combined use of hyperthermia and radiotherapy for these superficial recurrences. Most of it is retrospective in nature, but there are several larger phase III randomised trials that show an improved rate of clinical complete response in patients treated with both modalities. In this review article, we will highlight the important prospective data that has been published regarding the combined use of hyperthermia and radiation.

Hyperthermia for locally advanced breast cancer.

Hyperthermia (HT) has a proven benefit for treating superficial malignancies, particularly chest wall recurrences of breast cancer. There has been less research utilising HT in patients with locally advanced breast cancer (LABC), but available data are promising. HT has been combined with chemotherapy and/or radiotherapy in the neoadjuvant, definitive and adjuvant setting, albeit in series with small numbers of patients. There is only one phase III trial that examines hyperthermia in LABC, also with relatively small numbers of patients. The goal of this review is to highlight important research utilising HT in patients with LABC as well as to suggest future directions for its use.

Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022.

PURPOSE: This pilot study was performed to test our ability to administer neratinib monotherapy before clinically recommended craniotomy in patients with HER2-positive metastatic breast cancer to the central nervous system, to examine neratinib's central nervous system penetration at craniotomy, and to examine postoperative neratinib maintenance. PATIENTS AND METHODS: Patients with HER2-positive brain metastases undergoing clinically indicated cranial resection of a parenchymal tumor received neratinib 240 mg orally once a day for 7 to 21 days preoperatively, and resumed therapy postoperatively in 28-day cycles. Exploratory evaluations of time to disease progression, survival, and correlative tissue, cerebrospinal fluid (CSF), and blood-based analyses examining neratinib concentrations were planned. The study was registered at ClinicalTrials.gov under number NCT01494662. RESULTS: We enrolled 5 patients between May 22, 2013, and October 18, 2016. As of March 1, 2019, patients had remained on the study protocol for 1 to 75+ postoperative cycles pf therapy. Two patients had grade 3 diarrhea. Evaluation of the CSF showed low concentrations of neratinib; nonetheless, 2 patients continued to receive therapy without disease progression for at least 13 cycles, with one on-study treatment lasting for nearly 6 years. Neratinib distribution in surgical tissue was variable for 1 patient, while specimens from 2 others did not produce conclusive results as a result of limited available samples. CONCLUSION: Neratinib resulted in expected rates of diarrhea in this small cohort, with 2 of 5 patients receiving the study treatment for durable periods. Although logistically challenging, we were able to test a limited number of CSF- and parenchymal-based neratinib concentrations. Our findings from resected tumor tissue in one patient revealed heterogeneity in drug distribution and tumor histopathology.

DCE-MRI parameters have potential to predict response of locally advanced breast cancer patients to neoadjuvant chemotherapy and hyperthermia: a pilot study.

UNLABELLED: Combined therapies represent a staple of modern medicine. For women treated with neoadjuvant chemotherapy (NA ChT) for locally advanced breast cancer (LABC), early determination of whether the patient will fail to respond can enable the use of alternative, more beneficial therapies. This is even more desirable when the combined therapy includes hyperthermia (HT), an efficient way to improve drug delivery, however, more costly and time consuming. There is data showing that this goal can be achieved using magnetic resonance imaging (MRI) with contrast agent (CA) enhancement. This work for the first time proposes combining the information extracted from pre-treatment MR imaging into a morpho-physiological tumour score (MPTS) with the hypothesis that this score will increase the prognostic efficacy, compared to each of its MR-derived components: morphological (derived from the shape of the tumour enhancement) and physiological (derived from the CA enhancement variance dynamics parameters). The MPTS was correlated with response as determined by both pathologic residual tumour and MRI imaging, and was shown to have potential to predict response. The MPTS was extracted from pre-treatment MRI parameters, so independent of the combined therapy used. PURPOSE: To use a novel morpho-physiological tumour score (MPTS) generated from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict response to treatment. MATERIALS AND METHODS: A protocol was designed to acquire DCE-MRI images of 20 locally advanced breast cancer (LABC) patients treated with neoadjuvant chemotherapy (NA ChT) and hyperthermia (HT). Imaging was done over 30 min following bolus injection of gadopentetate-based contrast agent. Parametric maps were generated by fitting the signal intensity to a double exponential curve and were used to derive a morphological characterisation of the lesions. Enhancement-variance dynamics parameters, wash-in and wash-out parameters (WiP, WoP), were extracted. The morphological characterisation and the WiP and WoP were combined into a MPTS with the intent of achieving better prognostic efficacy. The MPTS was correlated with response to NA therapy as determined by pathological residual tumour and MRI imaging. RESULTS: The contrast agent in all tumours typically peaked in the first 1-4 min. The tumours' WiP and WoP varied considerably. The MPTS was highly correlated with whether the patients had a pathological response. This scoring system has a specificity of 78% and a sensitivity of 91% for predicting response to NA chemotherapy. The kappa was 0.69 with a 95% confidence interval of [0.38, 1] and a p-value of 0.002. CONCLUSIONS: This pilot study shows that the MPTS derived using pre-treatment MRI images has the potential to predict response to NA ChT and HT in LABC patients. Further prospective studies are needed to confirm the validity of these results.

Fulvestrant-Based Combination Therapy for Second-Line Treatment of Hormone Receptor-Positive Advanced Breast Cancer.

Fulvestrant is recommended for patients with hormone receptor-positive (HR+) advanced breast cancer (ABC) who progress after aromatase inhibitor therapy. As most patients in this setting have already developed mechanisms of resistance to endocrine therapy, targeting biological pathways associated with endocrine resistance in combination with fulvestrant may improve outcomes. Therefore, evidence supporting a combinatorial treatment approach in the second-line setting was investigated based on a search of PubMed and ClinicalTrials.gov . Twenty-eight studies of targeted therapies plus fulvestrant as second-line treatment for HR+ ABC were identified, including three and six key randomized trials exploring cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors plus fulvestrant respectively. Additional combinations with fulvestrant included inhibitors of epidermal growth factor receptors, androgen receptor, and the bromodomain and extra-terminal family of proteins. Across the studies reviewed with available data, the addition of targeted therapies to fulvestrant resulted in clinically meaningful improvements in progression-free survival compared with fulvestrant alone. While some challenging toxicities were observed, most adverse events could be effectively managed. Selection of second-line targeted therapy for use with fulvestrant should consider prior treatment as well as the mutation status of the tumor. In conclusion, available data indicate that fulvestrant combined with agents targeting mechanisms of endocrine resistance is a promising approach. The ongoing trials identified in this review will help further inform the selection of combination treatments with fulvestrant for HR+ ABC.

Correction to: Fulvestrant-Based Combination Therapy for Second-Line Treatment of Hormone Receptor-Positive Advanced Breast Cancer.

The article Fulvestrant-Based Combination Therapy for Second-Line Treatment of Hormone Receptor-Positive Advanced Breast Cancer, written by Sarah Sammons, Noah S. Kornblum and Kimberly L. Blackwell, was originally published electronically on the publisher's internet portal (currently SpringerLink).