Reshma L. Mahtani

Phase IIa Trial of Trastuzumab Emtansine With Pertuzumab for Patients With Human Epidermal Growth Factor Receptor 2–Positive, Locally Advanced, or Metastatic Breast Cancer

PURPOSE Our phase IIa study characterized the safety and efficacy of two human epidermal growth factor receptor 2 (HER2) -targeted agents, trastuzumab emtansine (T-DM1) and pertuzumab, in patients with HER2-positive metastatic breast cancer (MBC). PATIENTS AND METHODS Patients with HER2-positive locally advanced breast cancer or MBC were treated with 3.6 mg/kg T-DM1 plus pertuzumab (840-mg loading dose, then 420 mg subsequently) once every 3 weeks. The primary efficacy end point was investigator-assessed objective response rate (ORR). RESULTS Sixty-four patients (43 patients in the second-line or greater setting [advanced MBC]; 21 patients in the first-line setting [first-line MBC]) were enrolled. Patients with advanced MBC had received trastuzumab and a median of six prior nonhormonal treatments for MBC; 86% of first-line MBC patients had received trastuzumab in the (neo)adjuvant setting. The ORR was 41% overall, 33% in patients with advanced MBC, and 57% in first-line patients. Median progression-free survival was 6.6, 5.5, and 7.7 months, respectively. The most common adverse events were fatigue (61%), nausea (50%), and diarrhea (39%). The most frequent grade ≥ 3 adverse events were thrombocytopenia (13%), fatigue (11%), and liver enzyme elevations (increased ALT: 9%; increased AST: 9%). One patient had left ventricular ejection fraction of less than 40% after study drug discontinuation. Exploratory biomarker analyses demonstrated that patients with above-median tumor HER2 mRNA levels had a numerically higher ORR than patients with below-median levels (44% v 33%, respectively). CONCLUSION T-DM1 and pertuzumab can be combined at full doses with no unexpected toxicities. The preliminary efficacy in patients in the first-line and advanced MBC settings warrants further investigation.

High-dose estrogen as salvage hormonal therapy for highly refractory metastatic breast cancer: A retrospective chart review

BACKGROUND High-dose estrogens (HDEs) are an efficacious but widely overlooked treatment option for patients with metastatic breast cancer (MBC). This is due in part to the introduction of tamoxifen in the 1970s, which was proven to be equivalent in efficacy and associated with fewer adverse events (AEs). OBJECTIVE The aim of this study was to report our experience with the use of HDE in postmenopausal women with advanced breast cancer. METHODS Local institutional review board approval was obtained to conduct a retrospective chart review of patients with MBC treated with HDEs at the Boca Raton Comprehensive Cancer Center, Boca Raton, Florida, from 2001 through March 2009. Demographic information, response rates, and tolerability profiles were collected. RESULTS Of the 426 patients with MBC identified, we found 26 patients with MBC who were prescribed HDEs as a treatment in any line of therapy for advanced breast cancer. The median age at the start of HDE therapy was 59 years (range, 42-92 years). Three of the 26 patients (11.5%) were human epidermal growth factor receptor 2-positive determined via fluorescent in situ hybridization analysis. With the exception of 1 patient who had received no prior systemic treatment for metastatic disease, all patients received multiple lines of treatment (both chemotherapy and hormonal treatments) in the advanced setting (median, 7 lines; range, 0-12) prior to the initiation of HDE. Five of 20 patients (25%) with measurable metastatic disease (visceral and/or soft tissue metastases) had objective antitumor responses defined as either a partial response (PR) or a complete response (CR). Four additional patients (20%) had prolonged stable disease (SD) for > or =6 months. Three of 6 patients (50%) with nonmeasurable metastatic disease (bone-only) had prolonged SD for > or =6 months. Clinical benefit rate (defined as CR + PR + SD > or =6 months) for all patients was 46% (12/26), with a median duration of 10 months. Overall median progression-free survival for the 26 subjects was 5 months. Median survival from the start of HDE was 17 months (range, 3-54 months). AEs included fluid retention (8 [31%]), vaginal bleeding (7 [27%]), and nausea (4 [15%]). Two patients discontinued therapy after 1 month. Three of the remaining 24 patients discontinued estrogen therapy due to AEs. CONCLUSIONS This retrospective chart review details our facilitys experience with the use of HDE in patients with advanced breast cancer, most of whom had received multiple prior treatments. Our data suggest that this treatment is another option for heavily-treated patients in whom further endocrine manipulation might still be appropriate.

The Potential Application of Zoledronic Acid as Anticancer Therapy in Patients With Non–Small-Cell Lung Cancer

Non-small-cell lung cancer (NSCLC) is frequently characterized by metastases to bone. Bisphosphonates have demonstrated efficacy in reducing the risk of skeletal-related events in cancer patients with bone metastases, including those with NSCLC. Zoledronic acid (ZA) is one of the most potent bisphosphonates and is approved for the first-line treatment of patients with multiple myeloma and bone metastases from solid tumors. Recent preclinical and clinical data suggest that ZA may also have direct and indirect anticancer effects. Several preclinical studies have provided insight into the potential mechanisms responsible for the anticancer activity of ZA, including inhibiting farnesyl pyrophosphate or geranylgeranyl pyrophosphate and activation of immune-mediated anticancer response by γδ T cells. In patients with NSCLC, ZA has been shown to reduce vascular endothelial growth factor levels with a direct correlation to clinical response. Clinical studies in this setting have shown that ZA may also provide a survival benefit and prolong time to progression. Ongoing studies are evaluating the efficacy of ZA for anticancer activity and prevention of bone metastases. Bisphosphonates, particularly ZA, are generally well tolerated and may likely offer an adjunct therapeutic option for patients with NSCLC.

Bisphosphonates as anticancer therapy for early breast cancer.

Bisphosphonates (BPs) are approved for preventing the skeletal-related events associated with malignant bone disease. Several studies indicate that they may also prevent cancer therapy-induced bone loss. Multiple preclinical and early clinical studies provide evidence of the anticancer activity of BPs, including an inhibition of tumor cell proliferation and survival, a reduction of angiogenesis, and a stimulation of innate anticancer immunity. In addition to their evident single-agent activity, BPs may also act synergistically with other antineoplastic agents. Translational studies corroborate the effects of bisphosphonates on angiogenesis and innate immunity. Moreover, many of these anticancer effects occur at clinically relevant drug concentrations. Indeed, clinical data suggest that in addition to being well-tolerated and efficacious in maintaining bone health, BPs including clodronate, pamidronate, and zoledronic acid also improve cancer-related outcomes such as tumor response, disease-free survival, and overall survival in patients with breast cancer. Among the BPs, zoledronic acid is the most extensively studied in the adjuvant and neoadjuvant settings and has accumulated the most data pointing to anticancer activity, although a survival benefit has not been documented. Future studies are necessary to elucidate the anticancer activity of BPs. Other aspects of BP therapy that require further study include the optimization of dosing regimens for single agents and combinations in various clinical settings and the identification of prognostic factors that predict treatment outcomes. This review summarizes the preclinical and clinical evidence of anticancer activity of BPs, with a focus on zoledronic acid.

Pleomorphic Lobular Carcinoma of the Breast: Four Long-Term Responders to Trastuzumab—Coincidence or Hint?

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Defining the Survival Benchmark for Breast Cancer Patients with Systemic Relapse

Background Our original paper, published in 1992, reported a median overall survival after first relapse in breast cancer of 26 months. The current retrospective review concentrates more specifically on patients with first systemic relapse, recognizing that subsets of patients with local recurrence are potentially curable. Methods Records of 5,168 patients from a largely breast-cancer-specific oncology practice were reviewed to identify breast cancer patients with their first relapse between 1996 and 2006 after primary treatment. There were 189 patients diagnosed with metastatic disease within 2 months of being seen by our therapeutic team and 101 patients diagnosed with metastatic disease greater than 2 months. The patients were divided in order to account for lead-time bias than could potentially confound the analysis of the latter 101 patients. Results Median survival for our primary study population of 189 patients was 33 months. As expected, the median survival from first systemic relapse (MSFSR) for the 101 patients excluded because of the potential for lead-time bias was better at 46 months. Factors influencing prognosis included estrogen receptor (ER) status, disease-free interval (DFI), and dominant site of metastasis. Compared with our original series, even with elimination of local-regional recurrences in our present series, the median survival from first relapse has improved by 7 months over the past two decades. Conclusion The new benchmark for MSFSR approaches 3 years.

Comparative effectiveness of early-line nab -paclitaxel vs. paclitaxel in patients with metastatic breast cancer: a US community-based real-world analysis

Background Real-world analyses of treatments for patients with metastatic breast cancer are limited. We evaluated the comparative effectiveness of nab-paclitaxel vs. paclitaxel in patients with metastatic breast cancer using data from an electronic medical record database from community practices across the USA. Methods We performed a retrospective cohort study using fully de-identified data from an independent US electronic medical record platform of patients with metastatic breast cancer initiating single-agent nab-paclitaxel or paclitaxel as a first- or second-line treatment from December 1, 2010 to October 6, 2014. The clinical efficacy objectives were time to treatment discontinuation (TTD) and time to next treatment (TTNT). Subgroup analyses were performed in patients with 2 types of metastatic breast cancer as follows: 1) hormone receptor-positive and human epidermal growth factor receptor 2 negative, and 2) triple-negative disease. Results This analysis included 925 patients. Patients receiving nab-paclitaxel vs. paclitaxel had significantly longer TTD (median 4.2 vs. 2.8 months, P<0.0001) and TTNT (median 6.0 vs. 4.2 months, P<0.0001); similar outcomes were observed for patients with hormone receptor-positive/human epidermal growth factor receptor 2 negative disease. Compared with paclitaxel, nab-paclitaxel was associated with significantly longer TTD in patients with triple-negative disease. nab-Paclitaxel was associated with significantly less all-grade neuropathy, anemia, pain, and diarrhea than paclitaxel. Antiemetic and antihistamine use were significantly less frequent with nab-paclitaxel vs. paclitaxel, whereas use of granulocyte colony-stimulating factor, hydrating agents, and bone-directed therapy to decrease skeletal-related events were more frequent. Conclusion nab-Paclitaxel demonstrated improved clinical effectiveness compared with paclitaxel when examining TTD and TTNT in patients with metastatic breast cancer in a real-world setting.

Insomnia in the Cancer Patient: A Complex Problem

Insomnia, which can manifest as difficulty falling asleep, multiple awakenings during the night, or difficulty staying asleep, is reported in up to 50% of cancer patients as compared to 15% of the general population (1). Although the full impact of sleep deprivation in cancer patients is not known, the consequences of this issue are reported to be similar or worse than in noncancer patients. Specifically, poor sleep reduces quality of life, immune function, and ability to function daily. Despite the prevalence of this problem, it tends to be under-treated. This is likely due to the perception insomnia is a normal and transient reaction to a cancer diagnosis and associated treatments, and also as a consequence of under-reporting by patients. However, such problems can become chronic in some patients, persisting for months or years after completing cancer therapy. The persistence of insomnia even after patients are in remission suggests a possible interaction between behavioral factors and disease-related factors (2). The interactions between insomnia and various other factors including level of fitness, pain, depression/anxiety, types of treatments for cancer and side effects of these treatments, are complex and have not been the subject of extensive study. Many studies have focused on the relationship between cancer-related fatigue (CRF) and cancer-related sleep disorders, and have been correlative in nature. The summary of most of these studies indicates: insomnia is positively correlated with fatigue, more severe in fatigued patients, and is a significant predictor of fatigue (2). However, predictive models which identify risk factors for the development on insomnia (and subsequent CRF) are lacking. Treatment strategies to combat CRF include pharmacologic as well as nonpharmacologic interventions. At present, exercise as a treatment for CRF has the most compelling data, with several meta-analyses concluding that physical activity has a moderate beneficial effect (effect sizes in the range of 0.30 to 0.38) (3–9). There is also some support for psychological interventions, with meta-analyses showing small to moderate beneficial effects (effect sizes in the range of 0.10 to 0.30) (3,8,10,11). Finally, although pharmacologic intervention is certainly widely used, long-term treatment with medication alone is not the optimal treatment plan for cancer patients with insomnia. In the article which accompanies this editorial, Galiano-Castillo et al. (12) address a gap in the literature, by attempting to identify a predictive model for the development of insomnia in cancer patients. This was a cross-sectional study in which 123 breast cancer patients were assessed. The primary variable was insomnia assessed by The European Organization for Research and Treatment of Cancer Quality of Life Questionairre. Patient and disease-related characteristics were collected including: age, menopausal status, stage of cancer, and type(s) of treatment (chemotherapy/hormonal therapy, radiotherapy). Pain levels were assessed using The Brief Pain Inventory Short Form (BPI-SF) and anxiety/depression levels were captured using The Hospital Anxiety and Depression Scale (HADS). Finally, patients were given physical assessments in a Physical Therapy laboratory where they were evaluated for lower body endurance (using multiple sit to stand test), endurance of abdominal flexors (using the trunk curl test), functional capacity (using the 6-minute walk test), and finally for back muscle strength. Insomnia was negatively associated with treatment stage, functional capacity, and back muscle strength. It was positively associated with the type of treatment and lower body endurance. In addition, higher levels of insomnia were associated with higher scores on the BPI-SF and HADS. When combining all positively correlated variables, the authors were able to explain 51.2% of insomnia in the study sample. This study is a useful starting point to further identify factors related to the development of insomnia in cancer patients. As mentioned previously, this topic has not been extensively studied, and predictive models are needed. There are inherent difficulties with conducting Address correspondence and reprint requests to: Dr. Reshma L. Mahtani, Division of Hematology/Oncology, Sylvester Comprehensive Cancer Center, University of Miami Health System, 1192 East Newport Center Drive, Deerfield Beach, FL 33442, USA, or e-mail: rmahtani@miami.edu

Cutaneous Reactions to Chemotherapy

Patients undergoing cancer chemotherapy are often challenging to physicians from a management standpoint due to an unfortunate combination of general poor health, immunosuppression, and multi-drug regimens. Several chemotherapeutic agents are associated with well-described mucocutaneous toxicities.