Michelle E. Melisko

Pretreatment fertility counseling and fertility preservation improve quality of life in reproductive age women with cancer.

The post‐treatment quality of life (QOL) impacts of receiving precancer‐treatment infertility counseling and of pursuing fertility preservation have not been described in large‐scale studies of reproductive age women with cancer.

Acute ovarian failure underestimates age‐specific reproductive impairment for young women undergoing chemotherapy for cancer

The authors sought to describe the age‐specific impact of infertility and early menopause after chemotherapy among reproductive age women with cancer.

Long-term Prognostic Role of Functional Limitations Among Women With Breast Cancer

BACKGROUND The long-term prognostic role of functional limitations among women with breast cancer is poorly understood. METHODS We studied a cohort of 2202 women with breast cancer at two sites in the United States, who provided complete information on body functions involving endurance, strength, muscular range of motion, and small muscle dexterity following initial adjuvant treatment. Associations of baseline functional limitations with survival were evaluated in delayed entry Cox proportional hazards models, with adjustment for baseline sociodemographic factors, body mass index, smoking, physical activity, comorbidity, tumor characteristics, and treatment. Difference in covariates between women with and without limitations was assessed with Pearson χ(2) and Student t tests. All statistical tests were two-sided. RESULTS During the median follow-up of 9 years, 112 deaths were attributable to competing causes (5% of the cohort) and 157 were attributable to breast cancer causes (7% of the cohort). At least one functional limitation was present in 39% of study participants. Proportionately, more breast cancer patients with functional limitations after initial adjuvant treatment were older, less educated, and obese (P < .001). In multivariable models, functional limitations were associated with a statistically significantly increased risk of death from all causes (hazard ratio [HR] = 1.40, 95% confidence interval [CI] = 1.03 to 1.92) and from competing causes (HR = 2.60, 95% CI = 1.69 to 3.98) but not from breast cancer (HR = 0.90, 95% CI = 0.64 to 1.26). The relationship between functional limitations and overall survival differed by tumor stage (among women with stage I and stage III breast cancer, HR = 2.02, 95% CI = 1.23 to 3.32 and HR = 0.74, 95% CI = 0.42 to 1.30, respectively). CONCLUSION In this prospective cohort study, functional limitations following initial breast cancer treatment were associated with an important reduction in all-cause and competing-cause survival, irrespective of clinical, lifestyle, and sociodemographic factors.

Treatment With Autologous Antigen-Presenting Cells Activated With the HER-2 –Based Antigen Lapuleucel-T: Results of a Phase I Study in Immunologic and Clinical Activity in HER-2–Overexpressing Breast Cancer

PURPOSE Lapuleucel-T (APC8024), an autologous active cellular immunotherapy, was prepared from peripheral-blood mononuclear cells, including antigen-presenting cells, that were activated in vitro with recombinant fusion protein BA7072. This antigen construct consisted of sequences from intracellular and extracellular domains of human epidermal growth factor receptor 2 (HER-2) linked to granulocyte-macrophage colony-stimulating factor. We conducted a phase I study to evaluate the safety and immunologic activity of lapuleucel-T in patients with HER-2-overexpressing metastatic breast cancer. PATIENTS AND METHODS Metastatic breast cancer patients whose tumors overexpressed or amplified HER-2 were eligible. Patients underwent leukapheresis and subsequent lapuleucel-T infusion 2 days later at weeks 0, 2, and 4. Patients who achieved a partial response (PR) or had stable disease (SD) lasting through week 48 were eligible for re-treatment using the same protocol and dose as their initial treatment. End points included safety, immunologic activity, and antitumor activity. RESULTS Nineteen patients were enrolled; 18 patients received treatment. Therapy was well tolerated, with no grade 3 or 4 adverse events associated with the treatment. Significant cellular immune responses specific for the immunizing antigen and HER-2 sequences were induced after treatment, as measured by lymphocyte proliferation and interferon gamma enzyme-linked immunospot assay. One patient experienced a PR lasting 6 months. Three additional patients had SD lasting more than 1 year. CONCLUSION Autologous active cellular immunotherapy with lapuleucel-T was feasible, safe, and well tolerated. The treatment stimulated significant immune responses, which were enhanced after boost infusions. Lapuleucel-T therapy was associated with tumor response or extended disease stabilization in some patients and warrants further investigation.

EMERGE: A Randomized Phase II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Advanced Glycoprotein NMB–Expressing Breast Cancer

PURPOSE Glycoprotein NMB (gpNMB), a negative prognostic marker, is overexpressed in multiple tumor types. Glembatumumab vedotin is a gpNMB-specific monoclonal antibody conjugated to the potent cytotoxin monomethyl auristatin E. This phase II study investigated the activity of glembatumumab vedotin in advanced breast cancer by gpNMB expression. PATIENTS AND METHODS Patients (n = 124) with refractory breast cancer that expressed gpNMB in ≥ 5% of epithelial or stromal cells by central immunohistochemistry were stratified by gpNMB expression (tumor, low stromal intensity, high stromal intensity) and were randomly assigned 2:1 to glembatumumab vedotin (n = 83) or investigators choice (IC) chemotherapy (n = 41). The study was powered to detect overall objective response rate (ORR) in the glembatumumab vedotin arm between 10% (null) and 22.5% (alternative hypothesis) with preplanned investigation of activity by gpNMB distribution and/or intensity (Stratum 1 to Stratum 3). RESULTS Glembatumumab vedotin was well tolerated as compared with IC chemotherapy (less hematologic toxicity; more rash, pruritus, neuropathy, and alopecia). ORR was 6% (five of 83) for glembatumumab vedotin versus 7% (three of 41) for IC, without significant intertreatment differences for predefined strata. Secondary end point revealed ORR of 12% (10 of 83) versus 12% (five of 41) overall, and 30% (seven of 23) versus 9% (one of 11) for gpNMB overexpression (≥ 25% of tumor cells). Unplanned analysis showed ORR of 18% (five of 28) versus 0% (0 of 11) in patients with triple-negative breast cancer (TNBC), and 40% (four of 10) versus 0% (zero of six) in gpNMB-overexpressing TNBC. CONCLUSION Glembatumumab vedotin is well tolerated in heavily pretreated patients with breast cancer. Although the primary end point in advanced gpNMB-expressing breast cancer was not met for all enrolled patients (median tumor gpNMB expression, 5%), activity may be enhanced in patients with gpNMB-overexpressing tumors and/or TNBC. A pivotal phase II trial (METRIC [Metastatic Triple-Negative Breast Cancer]) is underway.

Translational breast cancer research consortium (TBCRC) 022: A phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases

PURPOSE Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. PATIENTS AND METHODS Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥ 50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression--the threshold for success was five of 40 responders. RESULTS Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. CONCLUSION Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.

A Phase I Trial of Immunotherapy with Lapuleucel-T (APC8024) in Patients with Refractory Metastatic Tumors that Express HER-2/neu

Purpose: This study aimed to evaluate the safety of, immune response induced by, and efficacy of treatment with lapuleucel-T (APC8024) in patients with HER-2/neu–expressing tumors. Lapuleucel-T is an investigational active immunotherapy product consisting of autologous peripheral blood mononuclear cells, including antigen presenting cells, which are cultured ex vivo with BA7072, a recombinant fusion antigen consisting of portions of the intracellular and extracellular regions of HER-2/neu linked to granulocyte-macrophage colony-stimulating factor. Experimental Design: Patients with metastatic breast, ovarian, or colorectal cancer whose tumors expressed HER-2 were eligible. Patients underwent leukapheresis in week 0 and received lapuleucel-T infusions in weeks 0, 2, and 4. Patients who achieved a partial response or had stable disease through week 48 were eligible for re-treatment using the same protocol and dose as their initial treatment. Results: Eighteen patients were enrolled and treated. Patients showed an immune response to the immunizing antigen (BA7072) at week 8 compared with week 0 as measured by T lymphocyte proliferation and IFN-γ enzyme-linked immunospot assay. Therapy was well tolerated. The majority (94.7%) of adverse events associated with treatment were grade 1 or 2. Two patients experienced stable disease lasting >48 weeks. Conclusions: Autologous active cellular immunotherapy with lapuleucel-T stimulated an immune response specific to the immunizing antigen and seemed to be well tolerated. Further clinical studies to assess the clinical benefit for patients with HER/2-neu–expressing breast, ovarian, and colorectal cancer are warranted. (Clin Cancer Res 2009;15(18):5937–44)

Disease and treatment characteristics do not predict symptom occurrence profiles in oncology outpatients receiving chemotherapy

A large amount of interindividual variability exists in the occurrence of symptoms in patients receiving chemotherapy (CTX). The purposes of the current study, which was performed in a sample of 582 oncology outpatients who were receiving CTX, were to identify subgroups of patients based on their distinct experiences with 25 commonly occurring symptoms and to identify demographic and clinical characteristics associated with subgroup membership. In addition, differences in quality of life outcomes were evaluated.

The Neoadjuvant Model is Still the Future for Drug Development in Breast Cancer

The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDAs draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach. Clin Cancer Res; 21(13); 2911–5. ©2015 AACR.

New challenges and opportunities in the management of brain metastases in patients with ErbB2-positive metastatic breast cancer.

The introduction of trastuzumab for the treatment of tumors that overexpress ErbB2 (also known as HER2) has contributed significantly to recent improvements in systemic therapy for advanced breast cancer. The advances in systemic therapy have highlighted an increasing prevalence of central nervous system involvement in patients with ErbB2-positive breast cancer and a consequent need for new treatment options for brain metastases. Just as ErbB2-targeted systemic therapy has given rise to this challenge, so too could targeted therapy represent an opportunity to meet it. This Review considers the potential for targeted therapy to facilitate effective management of brain metastases in patients with ErbB2-positive breast cancer, and discusses in particular the data currently available in this setting for lapatinib, an orally available small-molecule tyrosine kinase inhibitor of ErbB1 and ErbB2.