Efficacy and Safety of Mirvetuximab Soravtansine in Patients With Platinum-Resistant Ovarian Cancer With High Folate Receptor Alpha Expression: Results From the SORAYA Study.

PURPOSE: Single-agent chemotherapies have limited activity and considerable toxicity in patients with platinum-resistant epithelial ovarian cancer (PROC). Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate targeting folate receptor α (FRα). SORAYA is a single-arm, phase II study evaluating efficacy and safety of MIRV in patients with PROC. METHODS: SORAYA enrolled FRα-high patients with PROC who had received one to three prior therapies, including required bevacizumab. The primary end point was confirmed objective response rate (ORR) by investigator; duration of response was the key secondary end point. RESULTS: One hundred six patients were enrolled; 105 were evaluable for efficacy. All patients had received prior bevacizumab, 51% had three prior lines of therapy, and 48% received a prior poly ADP-ribose polymerase inhibitor. Median follow-up was 13.4 months. ORR was 32.4% (95% CI, 23.6 to 42.2), including five complete and 29 partial responses. The median duration of response was 6.9 months (95% CI, 5.6 to 9.7). In patients with one to two priors, the ORR by investigator was 35.3% (95% CI, 22.4 to 49.9) and in patients with three priors was 30.2% (95% CI, 18.3 to 44.3). The ORR by investigator was 38.0% (95% CI, 24.7 to 52.8) in patients with prior poly ADP-ribose polymerase inhibitor exposure and 27.5% (95% CI, 15.9 to 41.7) in those without. The most common treatment-related adverse events (all grade and grade 3-4) were blurred vision (41% and 6%), keratopathy (29% and 9%), and nausea (29% and 0%). Treatment-related adverse events led to dose delays, reductions, and discontinuations in 33%, 20%, and 9% of patients, respectively. CONCLUSION: MIRV demonstrated consistent clinically meaningful antitumor activity and favorable tolerability and safety in patients with FRα-high PROC who had received up to three prior therapies, including bevacizumab, representing an important advance for this biomarker-selected population.

Breast cancer outcomes in a private hospital appear better than national outcomes in a country with a mixed public/private healthcare model.

BACKGROUND: Ireland has a mixed model of healthcare delivery with a public healthcare system funded by general taxation and a large private healthcare insurance system, covering 43% of the population in 2012 and 2016. We set out to examine disparities in outcomes among patients with breast cancer treated in a private hospital compared to national outcomes over a comparable period. METHODS: Medical records of patients diagnosed with early (Stage 1-3 as per AJCC version 5) breast cancer between 2010 and 2015 at Bon Secours Hospital, Cork, Ireland were reviewed. Staging was confirmed and 5-year disease specific survival (DSS) and overall survival (OS) were calculated. DSS was compared to 5-year net survival (NS) figures from the National Cancer Registry of Ireland (NCRI) for a comparable period (2010-2014). RESULTS: DSS (Bon Secours) and NS (NCRI) are summarized in Table 5 and Fig. 2. 5-year survival figures are numerically higher in the private hospital compared with national data for individual stage. Taking stages 1 to 3 combined, the 95% confidence intervals do not cross, indicating statistical significance. CONCLUSIONS: We found evidence of superior outcomes in patients with early breast cancer treated at a private hospital compared with national outcome figures. This was demonstrated in 'all comers' (stages 1-3 combined), and particularly in patients with stage 3 breast cancer. Potential reasons for this disparity include differences in socioeconomic status, health-seeking behaviours and/or underlying health status between the two populations included. Differences in extent or timeliness of access to therapies may also contribute.

Cancer-related fatigue and self-care agency: A multicentre survey of patients receiving chemotherapy.

AIMS AND OBJECTIVES: To measure cancer-related fatigue (CRF), self-care agency (SCA) and fatigue self-care strategies, and to explore the relationship between CRF and SCA. BACKGROUND: Cancer-related fatigue has been consistently rated as the most elusive, common and severe of symptoms that patients with cancer undergoing chemotherapy experience. Despite its frequency and severity, CRF is poorly managed. A renewed focus on supporting self-care among patients with cancer has been found to reduce symptom burden, empower patients and improve patient satisfaction. Understanding the link between self-care agency (i.e. capability and willingness to self-care) and CRF levels will help practitioners to better support individuals on the cancer journey. DESIGN: A descriptive, correlational survey design was employed. METHODS: Patients (n = 362) undergoing chemotherapy with a primary diagnosis of breast, colorectal, Hodgkin's and non-Hodgkin's lymphoma cancers were recruited from four oncology centres in one city in the South of Ireland. Participants completed the Piper Fatigue Scale-Revised, Appraisal of Self-care Agency Scale and a researcher-developed Fatigue Self-Care Survey. Multivariate logistic regression was used to examine the relationship between CRF and self-care agency using a dichotomous dependent variable score of four as the cut-off between those deemed to be fatigued (≥4) and those not fatigued (<4). As recommended by the EQUATOR Network, the STROBE checklist of items for cross-sectional studies is used to report the study. RESULTS: The incidence of CRF was high with 75% of participants scoring clinically relevant CRF. Higher SCA (OR = 0.96, 95% CI = 0.93-0.99, p = .011) was associated with decreased odds of developing CRF. Having non-Hodgkin's lymphoma (OR = 3.02, 95% CI = 1.29-7.07, p = .011) was associated with increased odds of developing CRF. CONCLUSIONS: Patient's undergoing chemotherapy experience significant fatigue. Higher capability for self-care is associated with lower fatigue. The promotion of SCA and self-care strategies can impact on CRF. RELEVANCE TO CLINICAL PRACTICE: Understanding the link between self-care abilities and fatigue can lead to more individualised and tailored approaches to CRF.

The Role of CDK4/6 Inhibitors in Breast Cancer.

OPINION STATEMENT: Oral inhibitors of CDK4/6 have been shown to increase response rates and prolong disease control when combined with endocrine therapy in hormone-responsive (HR+) HER2-negative advanced breast cancer. Palbociclib, ribociclib and abemaciclib are all approved in combination with non-steroidal aromatase inhibitors in first-line therapy for post-menopausal women, with a 40-45% improvement in progression-free survival seen with the addition of any of these CDK4/6 inhibitors. Additional approved indications, including first- and second-line combination therapy for pre-menopausal women, combination with fulvestrant and use as monotherapy, vary with each agent and are reviewed fully in the subsequent texts. These agents also differ in their toxicity profiles and monitoring requirements, and prescribers should be aware of the individual requirements for each agent. Current clinical trials are investigating the expanded use of these agents in other breast cancer subtypes, such as HER2-positive and triple-negative breast cancer, as well as in the adjuvant and neoadjuvant treatments of early breast cancer. Resistance to CDK4/6 inhibition can occur through multiple mechanisms. Rational combinations with other therapies, such as PI3K inhibitors, HER2-directed therapies and immunotherapy, are being explored.

Endocrine resistance in hormone-responsive breast cancer: mechanisms and therapeutic strategies.

The majority of breast cancers may be considered hormone responsive due to expression of hormone receptors (HR+). Although endocrine therapy is always considered for advanced HR+ breast cancer, the emergence of resistance is inevitable over time and is present from the start in a proportion of patients. In this review, we explore the mechanisms underlying de novo and acquired resistance to endocrine therapy. We comprehensively review newly approved and emerging therapies that have been developed to counteract specific mechanisms of resistance. We discuss the challenges pertinent to this therapeutic arena including the potential relief of negative regulatory feedback inhibition with compensatory pathway activation and the evolution of molecular changes in HR+ breast cancers during treatment. We discuss strategies to address these challenges in order to develop rational therapy approaches for patients with advanced HR+ breast cancer.

PARP Inhibitors in Clinical Use Induce Genomic Instability in Normal Human Cells.

Poly(ADP-ribose) polymerases (PARPs) are the first proteins involved in cellular DNA repair pathways to be targeted by specific inhibitors for clinical benefit. Tumors harboring genetic defects in homologous recombination (HR), a DNA double-strand break (DSB) repair pathway, are hypersensitive to PARP inhibitors (PARPi). Early phase clinical trials with PARPi have been promising in patients with advanced BRCA1 or BRCA2-associated breast, ovary and prostate cancer and have led to limited approval for treatment of BRCA-deficient ovary cancer. Unlike HR-defective cells, HR-proficient cells manifest very low cytotoxicity when exposed to PARPi, although they mount a DNA damage response. However, the genotoxic effects on normal human cells when agents including PARPi disturb proficient cellular repair processes have not been substantially investigated. We quantified cytogenetic alterations of human cells, including primary lymphoid cells and non-tumorigenic and tumorigenic epithelial cell lines, exposed to PARPi at clinically relevant doses by both sister chromatid exchange (SCE) assays and chromosome spreading. As expected, both olaparib and veliparib effectively inhibited poly-ADP-ribosylation (PAR), and caused marked hypersensitivity in HR-deficient cells. Significant dose-dependent increases in SCEs were observed in normal and non-tumorigenic cells with minimal residual PAR activity. Clinically relevant doses of the FDA-approved olaparib led to a marked increase of SCEs (5-10-fold) and chromatid aberrations (2-6-fold). Furthermore, olaparib potentiated SCE induction by cisplatin in normal human cells. Our data have important implications for therapies with regard to sustained genotoxicity to normal cells. Genomic instability arising from PARPi warrants consideration, especially if these agents will be used in people with early stage cancers, in prevention strategies or for non-oncologic indications.

CDK4/6 inhibitors in breast cancer.

Deregulation of the cyclin-dependent kinase (CDK) 4/6-retinoblastoma (RB) axis can occur through a number of mechanisms and contributes towards the unrestrained growth witnessed in a variety of cancers including breast cancers. Recent years have seen the development of selective CDK4/6 inhibitors, which have delivered promising preclinical and clinical results in breast cancer and other tumours. A number of trials assessing antitumour efficacy in various disease settings and combinations are ongoing. The cyclin D1-CDK-Rb axis and its role in the cell cycle of normal and cancer cells are delineated. The early pan-CDK inhibitor flavopiridol and subsequent preclinical and clinical development of selective CDK4/6 inhibitors are described. Ongoing studies in breast cancer with novel CDK4/6 inhibitors (palbociclib, abemaciclib and ribociclib) are explored. A literature search of these topics was performed through PubMed. Abstracts from major oncology meetings were also reviewed. Selective CDK4/6 inhibitors, as represented by the competing compounds currently in clinical development, comprise a novel, safe and, thus far, promisingly efficacious group of drugs. Considerable resources are being devoted towards exploring the efficacy of these drugs in combination with endocrine therapies, an approach that has yielded encouraging results and accelerated approval by the US Food and Drugs Administration for one of these agents (palbociclib). The results of confirmatory phase 3 trials are, however, awaited. We discuss further therapy combinations in development and highlight potential areas for caution including the potential for antagonistic interactions with cytotoxic chemotherapies.

Prognostic significance of prospectively detected bone marrow micrometastases in esophagogastric cancer: 10-year follow-up confirms prognostic significance.

We have previously reported that most patients with esophagogastric cancer (EGC) undergoing potentially curative resections have bone marrow micrometastases (BMM). We present 10-year outcome data of patients with EGC whose rib marrow was examined for micrometastases and correlate the findings with treatment and conventional pathologic tumor staging. A total of 88 patients with localized esophagogastric tumors had radical en-bloc esophagectomy, with 47 patients receiving neoadjuvant (5-fluorouracil/cisplatin based) chemoradiotherapy (CRT) and the remainder being treated with surgery alone. Rib marrow was examined for cytokeratin-18-positive cells. Standard demographic and pathologic features were recorded and patients were followed for a mean 10.04 years. Disease recurrences and all deaths in the follow-up period were recorded. No patients were lost to follow-up. 46 EGC-related and 10 non-EGC-related deaths occurred. Multivariate Cox analysis of interaction of neoadjuvant chemotherapy, nodal status, and BMM positivity showed that the contribution of BMM to disease-specific and overall survival is significant (P = 0.014). There is significant interaction with neoadjvant CRT (P < 0.005), and lymph node positivity (P < 0.001) but BMM positivity contributes to increase in risk of cancer-related death in patients treated with either CRT or surgery alone. Bone marrow micrometastases detected at the time of surgery for EGC is a long-term prognostic marker. Detection is a readily available, technically noncomplex test which offers a window on the metastatic process and a refinement of pathologic staging and is worthy of routine consideration.

The Role of CDK4/6 Inhibition in Breast Cancer.

Imbalance of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer cells may result in diversion away from a pathway to senescence and toward a more proliferative phenotype. Cancer cells may increase cyclin D-dependent activity through a variety of mechanisms. Therapeutic inhibition of CDKs in tumors to negate their evasion of growth suppressors has been identified as a key anticancer strategy. In this review, we outline the development of CDK inhibitory therapy in breast cancer, including the initial experience with the pan-CDK inhibitor flavopiridol and the next generation of oral highly selective CDK4 and CDK6 inhibitors PD0332991 (palbociclib), LEE011 (ribociclib), and LY2835219 (abemaciclib). Data from phase I and II studies in estrogen receptor-positive (ER+) breast cancer demonstrate promising efficacy with manageable toxic effects, chiefly neutropenia. We discuss these studies and the phase III studies that are accruing or nearing completion. We describe the application of such therapy to other breast cancer settings, including HER2-positive breast cancer and the adjuvant treatment of early breast cancer. We also discuss potential concerns surrounding the combination of CDK inhibitors with chemotherapy and their effects on repair of double-strand DNA breaks in cancer cells. Oral highly selective CDK inhibitors show great promise in improving the outcomes of patients with ER+ breast cancer, although caution must apply to their combination with other agents and in the early breast cancer setting.

Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study.

BACKGROUND: Breast cancer brain metastases (BCBM) are challenging complications that respond poorly to systemic therapy. The role of the blood-tumor barrier in limiting BCBM drug delivery and efficacy has been debated. Herein, we determined tissue and serum levels of capecitabine, its prodrug metabolites, and lapatinib in women with BCBM resected via medically indicated craniotomy. METHODS: Study patients with BCBM requiring surgical resection received either single-dose capecitabine (1250 mg/m(2)) 2-3 h before surgery or 2-5 doses of lapatinib (1250 mg) daily, the last dose 2-3 h before surgery. Serum samples were collected serially on the day of surgery. Drug concentrations were determined in serum and BCBM using liquid chromatography tandem mass spectrometry. RESULTS: Twelve patients were enrolled: 8 for capecitabine and 4 for lapatinib. Measurable drug levels of capecitabine and metabolites, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil, were detected in all BCBM. The ratio of BCBM to serum was higher for 5-fluorouracil than for capecitabine. As for lapatinib, the median BCBM concentrations ranged from 1.0 to 6.5 µM. A high variability (0.19-9.8) was noted for lapatinib BCBM-to-serum ratio. CONCLUSIONS: This is the first study to demonstrate that capecitabine and lapatinib penetrate to a significant though variable degree in human BCBM. Drug delivery to BCBM is variable and in many cases appears partially limiting. Elucidating mechanisms that limit drug concentration and innovative approaches to overcome limited drug uptake will be important to improve clinical efficacy of these agents in the central nervous system. Trial registration ID: NCT00795678.

Recent advances in novel targeted therapies for HER2-positive breast cancer.

The monoclonal antibody trastuzumab has improved the outcomes of patients with breast cancer that overexpresses the human epidermal growth factor receptor 2 (HER2). However, despite this advancement, many tumors develop resistance and novel approaches are needed. Recently, a greater understanding of cellular biology has translated into the development of novel anti-HER2 agents with varying mechanisms of action. The small molecule tyrosine kinase inhibitor lapatinib has demonstrated activity in HER2-positive metastatic breast cancer (MBC) and in the preoperative setting. Pertuzumab is a monoclonal antibody with a distinct binding site from trastuzumab, which inhibits receptor dimerization. In recent studies, the addition of pertuzumab to combination therapy has led to improvements in progression-free survival in patients with HER2-positive MBC and higher response rates in the preoperative setting. An alternative approach is the use of novel antibody-drug conjugates such as trastuzumab-emtansine, which recently demonstrated activity in MBC. Neratinib, a pan-HER tyrosine kinase inhibitor, which irreversibly inhibits HER1 and HER2, also has proven activity in MBC. A range of compounds is being developed to attempt to overcome trastuzumab resistance by targeting heat shock protein 90, a molecular chaperone required for the stabilization of cellular proteins. Furthermore, agents are being developed to inhibit the mammalian target of rapamycin, a downstream component of the PTEN/PI3K pathway, which has been implicated in trastuzumab resistance. Finally, there are emerging data indicating that combinations of anti-HER2 agents may circumvent resistance mechanisms and improve patient outcomes. In this review, recent data on these emerging agents and novel combinations for HER2-positive breast cancer are discussed.

Limited overall survival in patients with brain metastases from triple negative breast cancer.

Patients with breast cancer, which lacks ER, PR, and HER2; "triple negative" (TNBC), are at increased risk of brain metastases (BMs). However, the impact of modern therapy on the risk of BMs and outcomes remains largely unknown. In this retrospective, single-institution study we assessed the incidence of BMs, the therapeutic options, and overall survival, in a recent cohort of patients with TNBC. Women diagnosed with early stage TNBC from January 1, 1998 to December 31, 2007 were identified through institutional databases. Electronic medical records were reviewed to assess patterns of recurrence, treatment, and survival. In total, 1,323 patients, median age 53 years (range 20-91), were identified. There were 298 patients (23%) who developed metastatic disease, of whom, 99 (33%) developed BMs, representing 7.5% of the entire cohort. Following BM diagnosis, treatment consisted of: radiotherapy 87 (88%) patients, resection 26 (26%) patients, and systemic chemotherapy 70 (71%) patients, with a median of 1.0 (range 0-8) chemotherapy regimens. The actuarial median survival from diagnosis of BMs is 5 months (95% CI 4-7 months). This single-institution, retrospective study confirms that the prognosis for patients with BMs from TNBC remains poor. This group of patients urgently needs improved therapies.

Current or recent pregnancy is associated with adverse pathologic features but not impaired survival in early breast cancer.

BACKGROUND: Pregnancy-associated breast cancer (PABC) may be defined as breast cancer diagnosed during pregnancy or within 1 year of giving birth. Conflicting data exist regarding the impact of pregnancy on clinical features and prognosis of breast cancer. METHODS: A single-institution retrospective chart review was performed of 99 patients identified with PABC between 1992 and 2007. Non-PABC controls were matched 2:1 to PABC cases by year of diagnosis and age. The differences in clinical features were compared between cases and controls using chi-square tests. Univariate and multivariate analyses were performed to assess the effect of PABC on survival. RESULTS: Of the 99 PABC cases, breast cancer was diagnosed during pregnancy in 36 patients, and after delivery in 63. PABC cases were more likely than controls to be negative for estrogen receptor (59% vs 31%, P < .0001) and negative for progesterone receptor (72% vs 40%, P < .0001). Cases were also more likely to have advanced T class (P = .0271) and N class (P = .0104) and higher grade tumors (P = .0115). With a median follow-up of 6.3 years for cases and 4.7 years for controls, overall survival did not differ between cases and controls (P = .0787). On multivariate analysis, the independent prognostic factors for overall survival were estrogen receptor status (P = .0031) and N class (P = .0003). The diagnosis of PABC was not an independent prognostic factor (P = .1317). CONCLUSIONS: PABC is associated with more adverse tumor features than non-PABC matched for age and year of diagnosis. After correcting for pathologic features, the diagnosis of PABC is not in itself an adverse prognostic factor for survival.

HER2-positive breast cancer: beyond trastuzumab.

The outlook for patients with HER2-positive breast cancer was revolutionized by the development of trastuzumab (Herceptin), a humanized murine monoclonal antibody. Use of this agent led to improved overall survival when it was added to chemotherapy for the treatment of metastatic breast cancer. Improved understanding of mechanisms of resistance to trastuzumab has facilitated the development of novel agents for HER2-positive breast cancer, and also resulted in superior outcomes when added to chemotherapy in the adjuvant setting. This review explores the use of several such agents, including lapatinib (Tykerb), HSP90 inhibitors, T-DM1, and other tyrosine kinase inhibitors. Emerging data from trials of these agents indicate that the HER2 pathway remains a valid therapeutic target following disease progression on trastuzumab, and suggest a promising role for combined HER2 blockade with two or more agents.

BRCA gene structure and function in tumor suppression: a repair-centric perspective.

Germline mutations in the BRCA1 and BRCA2 genes are characterized by deficient repair of DNA double-strand breaks by homologous recombination. Defective DNA double-strand break repair has been not only implicated as a key contributor to tumorigenesis in mutation carriers but also represents a potential target for therapy. The transcriptional similarities between BRCA1-deficient tumors and sporadic tumors of the basal-like subtype have led to the investigation of homologous recombination repair-directed therapy in triple-negative tumors, which demonstrates overlap with the basal-like subtype. We broaden the scope of this topic by addressing a "repair-defective" rather than "BRCA1-like" phenotype. We discuss structural and functional aspects of key repair proteins including BRCA1, BRCA2, BRCA1 interacting protein C-terminal helicase 1, and partner and localizer of BRCA2 and describe the phenotypic consequences of their loss at the cellular, tissue, and organism level. We review potential mechanisms of repair pathway dysfunction in sporadic tumors and address how the identification of such defects may guide the application of repair-directed therapies.

HER2 breast cancer therapies: a review.

Amplification of the HER2 gene and/or overexpression of its protein product have been found in up to 25% to 30% of human breast cancers and have been shown to be associated with poorer outcomes compared to 'HER2 normal' breast cancer. Research has focused on developing therapies directed to the HER2 receptor and its pathway. These include the monoclonal antibody trastuzumab, which has improved outcomes when used in patients with both advanced and early breast cancer. Lapatinib is a small-molecule tyrosine kinase inhibitor which has demonstrated activity in advanced breast cancer and is currently being evaluated in early stage disease. We discuss the therapeutic rationale and clinical trial experience with these agents. Other novel and emerging strategies targeting the HER2 receptor and its pathway are also discussed. These strategies include novel HER2 antibodies and small-molecule inhibitors, antibody-drug conjugates, agents targeting downstream components of the HER2 signaling pathway, and heat shock protein 90 (HSP90) inhibitors.

Evolving approaches to metastatic breast cancer previously treated with anthracyclines and taxanes.

Despite major advances in the adjuvant treatment of breast cancer, many women will develop metastatic disease, either de novo or following optimal adjuvant therapy. Further effective therapeutic options are needed for women who progress following anthracycline- and taxane-containing regimens. Capecitabine is approved by the US Food and Drug Administration as monotherapy in this setting. Other agents such as gemcitabine or vinorelbine might be considered based on multiple phase II studies. Combination therapies generally increase response rates but with a concomitant increase in toxicity. Other agents that have been studied in this setting include etoposide, irinotecan, and pemetrexed. Novel agents undergoing testing include the fluorinated vinca alkaloid vinflunine and the halichondrin B analogue eribulin. Responses have been seen in taxane-pretreated patients with the use of another conventional taxane, novel formulations, or alternative schedules. Pegylated liposomal doxorubicin might be considered in some patients for whom there is a concern regarding cardiac toxicity with the conventional preparation. The epothilones are a novel group of microtubule-stabilizing agents. Ixabepilone is a member of this class that has been approved as monotherapy in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine. It is also approved with capecitabine in patients whose cancer is resistant to treatment with anthracyclines and taxanes. Decision-making regarding treatment selection must take into account multiple patient and tumor factors. The therapeutic indices of the available treatments should be considered in the context of the individual patient.