Biosimilars: Here and Now.

Congress passed the Biologics Price Competition and Innovation Act (BPCI Act) as part of the Affordable Care Act on March 23, 2010. The BPCI Act authorized an approval pathway for biosimilar and interchangeable products. It defines biosimilarity to mean "that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components" and that "there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency of the product." The biosimilar pathway has the potential to facilitate access to biologic products through increased competition, in the same manner as biosimilars have done for almost 10 years in Europe. The goal of a biosimilar program is not to independently establish safety and effectiveness for each condition of use. Rather, the goal is to demonstrate biosimilarity through an extensive analytical characterization and a targeted clinical program designed to assess for clinically meaningful differences, if they exist. The regulatory approaches in both the United States and Europe involve a totality-of-the-evidence approach to demonstrate biosimilarity. Importantly, the biosimilar pathway allows for extrapolation of data across indications so that a sponsor, with adequate scientific justification, need not conduct clinical studies in each intended condition of use. Without extrapolation, development may not be feasible for many products, and patients and resources could be diverted from clinical studies of newer agents for cancer.

Genome-based risk prediction for early stage breast cancer.

Tests to better characterize tumor genomic architecture are quickly becoming a standard of care in oncology. For breast cancer, the use of gene expression assays for early stage disease is already common practice. These tests have found a place in risk stratifying the heterogeneous group of stage I-II breast cancers for recurrence, for predicting chemotherapy response, and for predicting breast cancer-related mortality. In the last 5 years, more assays have become available to the practicing oncologist. Given the rapidity with which this field has evolved, it is prudent to review the tests, their indications, and the studies from which they have been validated. We present a comprehensive review of the available gene expression assays for early stage breast cancer. We review data for several individual tests and comparative studies looking at risk prediction and cost-effectiveness.

Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline.

PURPOSE: To provide evidence-based recommendations to practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer. METHODS: The American Society of Clinical Oncology convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts and conducted a systematic literature review from January 2009 to October 2012. Outcomes of interest included overall survival, progression-free survival (PFS), and adverse events. RESULTS: A total of 16 trials met the systematic review criteria. The CLEOPATRA trial found survival and PFS benefits for docetaxel, trastuzumab, and pertuzumab in first-line treatment, and the EMILIA trial found survival and PFS benefits for trastuzumab emtansine (T-DM1) in second-line treatment. T-DM1 also showed a third-line PFS benefit. One trial reported on duration of HER2-targeted therapy, and three others reported on endocrine therapy for patients with HER-positive advanced breast cancer. RECOMMENDATIONS: HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. Trastuzumab, pertuzumab, and taxane for first-line treatment and T-DM1 for second-line treatment are recommended. In the third-line setting, clinicians should offer other HER2-targeted therapy combinations or T-DM1 (if not previously administered) and may offer pertuzumab, if the patient has not previously received it. Optimal duration of chemotherapy is at least 4 to 6 months or until maximum response, depending on toxicity and in the absence of progression. HER2-targeted therapy can continue until time of progression or unacceptable toxicities. For patients with HER2-positive and estrogen receptor-positive/progesterone receptor-positive breast cancer, clinicians may recommend either standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy or endocrine therapy alone.

Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline.

PURPOSE: To provide formal expert consensus-based recommendations to practicing oncologists and others on the management of brain metastases for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer. METHODS: The American Society of Clinical Oncology (ASCO) convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts and conducted a systematic review of the literature. When that failed to yield sufficiently strong quality evidence, the Expert Panel undertook a formal expert consensus-based process to produce these recommendations. ASCO used a modified Delphi process. The panel members drafted recommendations, and a group of other experts joined them for two rounds of formal ratings of the recommendations. RESULTS: No studies or existing guidelines met the systematic review criteria; therefore, ASCO conducted a formal expert consensus-based process. RECOMMENDATIONS: Patients with brain metastases should receive appropriate local therapy and systemic therapy, if indicated. Local therapies include surgery, whole-brain radiotherapy, and stereotactic radiosurgery. Treatments depend on factors such as patient prognosis, presence of symptoms, resectability, number and size of metastases, prior therapy, and whether metastases are diffuse. Other options include systemic therapy, best supportive care, enrollment onto a clinical trial, and/or palliative care. Clinicians should not perform routine magnetic resonance imaging (MRI) to screen for brain metastases, but rather should have a low threshold for MRI of the brain because of the high incidence of brain metastases among patients with HER2-positive advanced breast cancer.

Incidence, risk factors, and management of infusion-related reactions in breast cancer patients receiving trastuzumab.

BACKGROUND: Trastuzumab has become a mainstay of therapy for human epidermal growth factor receptor-2 overexpressed breast cancer in nearly all stages of the disease. Like many monoclonal antibodies, trastuzumab is associated with infusion-related reactions (IRRs) that are not well described, and incidence varies widely between reports (0.7%-40% of patients). MATERIALS AND METHODS: A retrospective chart review of breast cancer patients who received trastuzumab was conducted. The primary objective was to describe the incidence, risk factors, and management of IRRs during the first 12 weeks of trastuzumab therapy in a general population of breast cancer patients. RESULTS: A total of 197 patients who received trastuzumab (1,788 doses) were evaluated. Thirty-three IRRs were identified in 32 patients, resulting in an incidence of 16.2% of patients and 1.8% of doses. All IRRs were mild or moderate in severity and were successfully managed with supportive medications and/or by temporarily stopping the infusion. All patients received subsequent cycles of trastuzumab, with only one patient experiencing a subsequent reaction. Body mass index, stage of disease, and use of premedications were significantly associated with IRRs by multivariate logistic regression analysis. CONCLUSION: Overall, these results support that the vast majority of IRRs occur with the first infusion, are mild in severity, and are easily managed. In addition, risk factors were identified that may help to identify a population of patients at increased risk of IRRs who may benefit from premedication.

Assessment of an RNA interference screen-derived mitotic and ceramide pathway metagene as a predictor of response to neoadjuvant paclitaxel for primary triple-negative breast cancer: a retrospective analysis of five clinical trials.

BACKGROUND: Addition of taxanes to preoperative chemotherapy in breast cancer increases the proportion of patients who have a pathological complete response (pCR). However, a substantial proportion of patients do not respond, and the prognosis is particularly poor for patients with oestrogen-receptor (ER)/progesterone-receptor (PR)/human epidermal growth factor receptor 2 (HER2; ERBB2)-negative (triple-negative) disease who do not achieve a pCR. Reliable identification of such patients is the first step in determining who might benefit from alternative treatment regimens in clinical trials. We previously identified genes involved in mitosis or ceramide metabolism that influenced sensitivity to paclitaxel, with an RNA interference (RNAi) screen in three cancer cell lines, including a triple-negative breast-cancer cell line. Here, we assess these genes as a predictor of pCR to paclitaxel combination chemotherapy in triple-negative breast cancer. METHODS: We derived a paclitaxel response metagene based on mitotic and ceramide genes identified by functional genomics studies. We used area under the curve (AUC) analysis and multivariate logistic regression to retrospectively assess the metagene in six cohorts of patients with triple-negative breast cancer treated with neoadjuvant chemotherapy; two cohorts treated with paclitaxel (n=27, 30) and four treated without paclitaxel (n=88, 28, 48, 39). FINDINGS: The metagene was associated with pCR in paclitaxel-treated cohorts (AUC 0.79 [95% CI 0.53-0.93], 0.72 [0.48-0.90]) but not in non-paclitaxel treated cohorts (0.53 [0.31-0.77], 0.59 [0.22-0.82], 0.53 [0.36-0.71], 0.64 [0.43-0.81]). In multivariate logistic regression, the metagene was associated with pCR (OR 19.92, 2.62-151.57; p=0.0039) with paclitaxel-containing chemotherapy. INTERPRETATION: The paclitaxel response metagene shows promise as a paclitaxel-specific predictor of pCR in patients with triple-negative breast cancer. The metagene is suitable for development into a reverse transcription-PCR assay, for which clinically relevant thresholds could be established in randomised clinical trials. These results highlight the potential for functional genomics to accelerate development of drug-specific predictive biomarkers without the need for training clinical trial cohorts. FUNDING: UK Medical Research Council; Cancer Research UK; the National Institute for Health Research (UK); the Danish Council for Independent Research-Medical Sciences (FSS); Breast Cancer Research Foundation (New York); Fondation Luxembourgeoise contre le Cancer; the Fonds National de la Recherche Scientifique; Brussels Region (IRSIB-IP, Life Sciences 2007) and Walloon Region (Biowin-Keymarker); Sally Pearson Breast Cancer Fund; and the European Commission.

Pathologic changes in breast cancer following neoadjuvant chemotherapy: implications for the assessment of response.

Neoadjuvant chemotherapy (also known as preoperative or primary chemotherapy) is the treatment of choice for patients with locally advanced breast cancer. One of the main advantages of neoadjuvant chemotherapy is that it allows for assessment of pathologic response to treatment. Clinical and radiologic evaluations of response to neoadjuvant chemotherapy are based on change in tumor size, and the correlation with pathologic response is often inaccurate. Pathologic evaluation of tumor size remains the gold standard for evaluation of residual tumor after chemotherapy. Chemotherapy-induced histomorphologic change is commonly observed in posttreatment resection specimens and can contribute to the less-than-perfect correlation between the clinical assessment of tumor size and the pathologic measurement. Therefore, accurate histologic mapping to the macroscopic and radiologic appearance of the tumor bed is necessary. Cytopathologic changes are also common in residual cancer cells after neoadjuvant chemotherapy and have uncertain clinical relevance. There is a role for the development of new histologic approaches to augment the pathologic and clinical assessment and provide information on the differential response, particularly for tumors in which less than pathologic complete response is achieved.

Assessment of histologic features and expression of biomarkers in predicting pathologic response to anthracycline-based neoadjuvant chemotherapy in patients with breast carcinoma.

BACKGROUND: There is significant variability in the response of tumors to neoadjuvant chemotherapy, and the underlying mechanism for this variability is unknown. In this study, the authors investigated the roles of tumor nuclear grade, mitotic activity, and biomarker expression profiles in predicting the pathologic response of breast tumors to preoperative chemotherapy. METHODS: Eighty-two patients with breast carcinoma participated in two clinical trials and were treated with neoadjuvant chemotherapy, which consisted of either a conventional dose of fluorouracil, doxorubicin, and cyclophosphamide (FAC) or dose-escalated FAC. The mean age of the patients was 46 years (range, 24-69 years). Nuclear grade, mitotic activity, and biomarker profile (Her2-neu and mitosin expression patterns) in pretreatment tumors were correlated with the postchemotherapy pathologic response. RESULTS: Twelve patients (15%) had a complete pathologic response (CPR), 23 patients (28%) had a near complete response (NCR), and 47 patients (57%) had significant residual disease present either at the primary site or in the axillary lymph nodes. The authors found that the nuclear grade and mitotic activity of pretreatment tumors were correlated significantly with CPR and NCR (P = 0.002 and P = 0.004). Mitosin also was correlated significantly with CPR and NCR (P = 0.028). A higher percentage of patients with Her2-neu-positive tumors had a CPR or an NCR (P = 0.152). CPR and NCR were not correlated significantly with disease stage (P = 0.186) or lymph node positivity (P = 0.498). CONCLUSIONS: The current results indicate that tumor nuclear grade and tumor proliferative activity (mitotic activity and mitosin immunostaining) of pretreatment tumors in patients with breast carcinoma may serve as important indicators for the pathologic responsiveness of tumors to neoadjuvant, anthracycline-based chemotherapy.