Curr. Oncol., Volume 25, Issue s1 (June 2018) – 20 articles

Cancer therapy has evolved significantly with increased adoption of biologic agents (“biologics”). That evolution is especially true for HER2 (human epidermal growth factor receptor-2)–positive breast cancer with the introduction of trastuzumab, a monoclonal antibody against the HER2 receptor, which, in combination with chemotherapy, significantly improves survival in both metastatic and early disease. Although the efficacy of biologics is undeniable, their expense is a significant contributor to the increasing cost of cancer care. Across disease sites and indications, biosimilar agents are rapidly being developed with the goal of offering cost-effective alternatives to biologics. Biosimilars are pharmaceuticals whose molecular shape, efficacy, and safety are similar, but not identical, to those of the original product. Although these agents hold the potential to improve patient access, complexities in their production, evaluation, cost, and clinical application have raised questions among experts. Here, we review the landscape of biosimilar agents in oncology, with a focus on trastuzumab biosimilars. We discuss important considerations that must be made as these agents are introduced into routine cancer care. Full article

Background: Life expectancy for women with metastatic breast cancer has improved since the early 2000s, in part because of the introduction of novel therapies, including chemotherapy, hormonal therapy, and targeted agents. However, those treatments can come at a cost for the patient (short- and long-term toxicities from treatment) and at a financial cost for the health care system. Given the increase in the number of costly anticancer agents being introduced into the clinical setting, the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) have developed a system to quantify the value of new cancer treatments in terms of benefit, toxicities, and costs. Methods: In our value-assessment analysis, we included drugs that were funded in Canada between 2012 and 2017 for metastatic breast cancer. We reviewed the clinical benefit of those agents (survival, progression, quality of life), their costs, their value according to the asco and esmo value frameworks, and their assessments from the pan-Canadian Oncology Drug Review [pcodr (in Canada, except Quebec)] and the Institut national d’excellence en santé et en services sociaux [iness (in Quebec)]. Results: Drugs funded in Canada showed variation in their asco net health benefit scores and esmo magnitude of clinical benefit scores, but all had a cost-effectiveness ratio greater than $100,000 per quality-adjusted life–year. The strength and magnitude of the clinical benefit (for example, overall survival benefit vs. progression-free survival benefit) was not necessarily associated with a higher value score. Conclusions: Although great progress has been made in developing value frameworks, use of those frameworks has to be refined to help patients and health care providers make informed decisions about the benefit of novel cancer therapies and to help policymakers make decisions about the societal benefit of funding those therapies. Full article

Background: A number of clinical practice guidelines (CPGS) concerning breast cancer (BCA) screening and management are available. Here, we review the strengths and weaknesses of CPGS from various professional organizations and consensus groups with respect to their methodologic quality, recommendations, and implementability. Methods: Guidelines from four groups were reviewed with respect to two clinical scenarios: adjuvant ovarian function suppression (OFS) in premenopausal women with early-stage estrogen receptor–positive BCA, and use of sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NAC) for locally advanced BCA. Guidelines from the American Society of Clinical Oncology (ASCO); Cancer Care Ontario’s Program in Evidence Based Care (CCO’s PEBC); the U.S. National Comprehensive Cancer Network (NCCN); and the St. Gallen International Breast Cancer Consensus Conference were reviewed by two independent assessors. Guideline methodology and applicability were evaluated using the AGREE II tool. Results: The quality of the CPGS was greatest for the guidelines developed by ASCO and CCO’s PEBC. The NCCN and St. Gallen guidelines were found to have lower scores for methodologic rigour. All guidelines scored poorly for applicability. The recommendations for OFS were similar in three guidelines. Recommendations by the various organizations for the use of SLNB after NAC were contradictory. Conclusions: Our review demonstrated that CPGS can be heterogeneous in methodologic quality. Low-quality CPG implementation strategies contribute to low uptake of, and adherence to, BCA CPGS. Further research examining the barriers to recommendations—such as intrinsic guideline characteristics and the needs of end users—is required. The use of BCA CPGS can improve the knowledge-to-practice gap and patient outcomes. Full article

Triple-negative breast cancer constitutes a heterogeneous group of malignancies that are often aggressive and associated with a poor prognosis. Molecular characterization, while not a standard of care, can further subtype triple-negative breast cancer and provide insight into prognostication and behaviour. Optimal chemotherapy regimens have yet to be established; however, there have been advances in the systemic treatment of triple-negative breast cancer in the neoadjuvant, adjuvant, and metastatic settings. In this review, we discuss evidence for the potential benefit of neoadjuvant platinum-based chemotherapy, adjuvant combination chemotherapy with weekly paclitaxel, and BRCA mutation–directed therapy in the metastatic setting. The role for adjuvant capecitabine in patients who do not achieve a pathologic complete response with neoadjuvant chemotherapy is reviewed. Future directions and data concerning novel targeted agents are reviewed, including the most recent data on parp [poly (ADP-RIBOSE) polymerase] inhibitors, antiandrogen agents, and immunotherapy. Full article

Estrogen receptor modulators and estrogen deprivation have become standards of care for hormone receptor– positive metastatic breast cancer. However, after traditional first-line endocrine monotherapy treatment, the disease typically progresses despite the initial high rate of clinical benefit. Multiple studies have aimed at optimizing treatment strategies to improve upon clinical benefit beyond the traditional single-agent endocrine treatment. With the availability of new data and novel therapies, the clinical practice challenge becomes how best to define the optimal treatment sequence to maximize clinical benefit. In this review, we present treatment options clinically relevant to the management of hormone-positive, her2-negative metastatic breast cancer, and we propose a treatment algorithm based on the current literature. Full article

Early-stage hormone receptor–positive breast cancer is the most common subtype and stage presenting in countries with organized screening programs. Standard clinical and pathologic factors are routinely used to support prognosis and decisions about adjuvant therapies. Hormone receptor and HER2 status are essential for decision-making about the use of adjuvant hormonal and anti-HER2 therapies respectively. Genomic assays are now commercially available to aid in either further prognostication or in refining the potential benefit of adjuvant chemotherapy. The current genomic assays all generally quantify estrogen receptor and proliferation gene sets (among others) by rna expression, although the specific genes assayed are quite discordant. The present review focuses on the pivotal studies in which each assay attempted to demonstrate clinical utility, with an emphasis on prospective trial data for each assay, if available. Using genomic assays, health care providers will increasingly be able to individualize therapy or de-escalate therapy, optimizing clinic benefit while minimizing toxicities from systemic therapies. Full article

Although screening mammography has delivered many benefits since its introduction in Canada in 1988, questions about perceived harms warrant an up-to-date review. To help oncologists and physicians provide optimal patient recommendations, the literature was reviewed to find the latest guidelines for screening mammography, including benefits and perceived harms of overdiagnosis, false positives, false negatives, and technologic advances. For women 40–74 years of age who actually participate in screening every 1–2 years, breast cancer mortality is reduced by 40%. With appropriate corrections, overdiagnosis accounts for 10% or fewer breast cancers. False positives occur in about 10% of screened women, 80% of which are resolved with additional imaging, and 10%, with breast biopsy. An important limitation of screening is the false negatives (15%–20%). The technologic advances of digital breast tomosynthesis, breast ultrasonography, and magnetic resonance imaging counter the false negatives of screening mammography, particularly in women with dense breast tissue. Full article

Significant progress has been made in the treatment of stage IV non-small-cell lung cancer (NSCLC); however, the prognosis of patients with brain metastases remains poor. Resection and radiation therapy remain standard options. This issue is an important one because 10% of patients with NSCLC have brain metastases at diagnosis, and 25%–40% develop brain metastases during their disease. Standard chemotherapy does not cross the blood–brain barrier. However, there is new hope that tyrosine kinase inhibitors (TKIS) used in patients with identified targetable mutations such as mutations of EGFR and rearrangements of ALK could have activity in the central nervous system (CNS). Furthermore, immunotherapy is increasingly becoming a standard option for patients with NSCLC, and interest about the intracranial activity of those agents is growing. This review presents current data about the CNS activity of the available major TKIS and immunotherapy agents. Full article

For patients with advanced non-small-cell lung cancer (NSCLC) lacking a targetable molecular driver, the mainstay of treatment has been cytotoxic chemotherapy. The survival benefit of chemotherapy in this setting is modest and comes with the potential for significant toxicity. The introduction of immunotherapeutic agents targeting the programmed cell death 1 protein (PD-1) and the programmed cell death ligand 1 (PD-L1) has drastically changed the treatment paradigms for these patients. Three agents—atezolizumab, nivolumab, and pembrolizumab—have been shown to be superior to chemotherapy in the second-line setting. For patients with tumours strongly expressing PD-L1, pembrolizumab has been associated with improved outcomes in the first-line setting. Demonstration of the significant benefits of immunotherapy in NSCLC has focused attention on new questions. Combination checkpoint regimens, with acceptable toxicity and potentially enhanced efficacy, have been developed, as have combinations of immunotherapy with chemotherapy. In this review, we focus on the published trials that have changed the treatment landscape in advanced NSCLC and on the ongoing clinical trials that offer hope to further improve outcomes for patients with advanced NSCLC. Full article

Background: Neuroendocrine tumours (NETS) are classified by site of origin, with lung being the second most common primary site after the gastrointestinal tract. Lung nets are rare and heterogeneous, with varied pathologic and clinical features. Typical and atypical carcinoid tumours are low-grade lung nets which, compared with the more common high-grade nets, are associated with a more favourable prognosis. Still, optimal treatment strategies are lacking. Methods: This review concentrates on classification and treatment strategies for metastatic low-grade lung nets, considering both typical and atypical carcinoids. The terminology can be confusing, and an attempt is made to simplify it. Promising results from recent trials that included lung nets are presented and discussed. Finally, guidelines from Europe and North America are discussed, and differences are noted. Results: Even within the group of patients with low-grade nets, the presentation, the locations of metastasis, and the speed of progression can be very different. The initial work-up and an understanding of the tumour’s biology are key in making management decisions. Various treatment options—including somatostatin analogs, peptide receptor radioligand therapy, and biologic systemic therapy, specifically with the mtor (mechanistic target of rapamycin) inhibitor everolimus—are now available and are presented in a treatment algorithm. Summary: Although lung nets are rare and evidence supporting optimal treatment strategies is lacking, the recent publication of trials that have included patients with lung nets advances evidence-based therapy for these tumours. Many variables have to be considered in managing these tumours that have received little attention. Education for treating physicians is needed. Full article

The treatment of squamous non-small-cell lung cancer (NSCLC) is evolving. In the past, the backbone of treatment was chemotherapy, with very few other options available. Fortunately, that situation is changing, especially with a better understanding of tumour biology. Various strategies have been tried to improve patient outcomes. The most notable advance must be immunotherapy, which has revolutionized the treatment paradigm for lung cancer in patients without a driver mutation. Immunotherapy is now the treatment of choice in patients who have progressed after chemotherapy and is replacing chemotherapy as upfront therapy in a selected population. Other strategies have also been tried, such as the addition of targeted therapy to chemotherapy. Targeted agents include ramucirumab, an inhibitor of vascular endothelial growth factor receptor 2, and necitumumab, a monoclonal antibody against epithelial growth factor receptor. Recently, advances in molecular profiling have also been applied to tumours of squamous histology, in which multiple genetic alterations, including mutations and amplifications, have been described. Research is actively seeking targetable mutations and testing various therapies in the hopes of further improving prognosis for patients with squamous NSCLC. Here, we review the various advances in the treatment of squamous nsclc and present a proposed treatment algorithm based on current evidence. Full article

Background: The treatment paradigm for metastatic nonsquamous non-small-cell lung cancer (NSCLC) continues to change. Algorithms published only 6 months ago are outdated today and are dramatically different from those published a few years ago. New driver mutations continue to be identified, and the development of therapies to inhibit oncogenic addiction is ongoing. Patient survival is improving as treatments become more personalized and effective. Methods: This review looks at the outcomes of recent trials and discusses treatment options for patients with metastatic NSCLC of nonsquamous histology. Algorithms continue to change quickly, and an attempt is made to keep the paradigm current and applicable into the near future. Results: Treatment algorithms for nsclc tumours with EGFR mutations, ALK rearrangements, and ROS1 rearrangements, and for wild-type tumours are presented. A future algorithm based on new immunotherapy data is proposed. The treatment algorithm for EGFR mutation is changing with the proven efficacy of osimertinib for the acquired T790M mutation. All patients taking first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors must be tested. Conclusions: The treatment algorithm for ALK rearrangement has changed with the proven superiority of alectinib compared with crizotinib in the first-line setting. The approval of crizotinib for ROS1 rearrangements now means that patients also must be tested for that mutation. The biomarker for checkpoint inhibitors continues to be PD-L1 by immunohistochemistry stain, but whether testing will be necessary for patient selection if chemotherapy combinations are implemented will be determined soon. Full article

The treatment of advanced non-small-cell lung cancer (NSCLC) has undergone a paradigm shift since the early 2000s. The identification of molecular subtypes of the disease, based on oncogenic drivers, has led to the development of personalized medicine and the ability to deliver molecularly targeted therapies to patients. In the 10 years that have elapsed since the discovery of the ALK gene in a patient with NSCLC, several active drugs have moved rapidly from bench to bedside, and multiple others are currently in clinical trials. Those developments have led to important improvements in patient outcomes, while simultaneously raising key questions about the optimal treatment for ALK-positive NSCLC. The inevitable emergence of resistance to ALK-directed therapy is central to ongoing research and daily clinical practice for affected patients. In the present review, we highlight the current treatment landscape, the available and emerging clinical trials, and the evolving clinical decision-making in ALK-positive NSCLC, with a focus on Canadian practice. Full article

Angiogenesis is frequent in non-small-cell lung cancer (NSCLC) and is associated with more aggressive disease. Many clinical trials have evaluated the addition of antiangiogenic therapy to standard therapies for patients with NSCLC. Bevacizumab, a monoclonal antibody directed against serum vascular endothelial growth factor, in combination with carboplatin–paclitaxel chemotherapy, has been shown to improve survival for patients with NSCLC. However, bevacizumab-based therapy is not suitable for many NSCLC patients, including those with squamous histology, poor performance status, brain metastases, and the presence of bleeding or thrombotic disorders. Similar efficacy has also been seen with carboplatin–pemetrexed followed by maintenance pemetrexed chemotherapy. In the second-line setting, the addition of ramucirumab to docetaxel—or the addition of bevacizumab to paclitaxel—has resulted in a modest improvement in efficacy, although the clinical importance of those findings is questionable. Many trials in NSCLC have also evaluated oral antiangiogenic compounds, both in the first line in combination with chemotherapy and upon disease progression either as combination or single-agent therapy. No clear improvements in overall survival have been observed, although a subgroup analysis of a trial evaluating the addition of nintedanib to docetaxel showed improved survival that was limited to patients with adenocarcinoma. Those findings require validation, however. All of the oral antiangiogenic agents result in added toxicities. Some agents have resulted in an increased risk of death, limiting their development. Available evidence supports a limited number of antiangiogenic therapies for patients with NSCLC, but no biomarkers to help in patient selection are currently available, and additional translational research is needed to identify predictive biomarkers for antiangiogenic therapy. Full article

The advent of targeted therapy in non-small-cell lung cancer (NSCLC) has made the routine molecular diagnosis of EGFR mutations crucial for optimal patient management. Obtaining tumour tissue for biomarker testing, especially in the setting of re-biopsy, can present many challenges. A potential alternative source of tumour dna is circulating cell-free tumour-derived DNA (CTDNA). Although CTDNA is present in low quantities in plasma, the convenience of sample acquisition and the increasing reliability of detection methods make this approach a promising one. The various performance characteristics of both digital and nondigital platforms are still variable, and a standardized approach is needed that will make those platforms reliable clinical tools for the detection of EGFR sensitizing mutations and resistance mutations, including the T790M resistance mutation. Information derived from ctdna can be used to assess tumour burden, to identify genomic-based resistance mechanisms, and to track dynamic changes during therapy. Full article

Tumours with sensitizing mutations in the EGFR gene constitute a distinct molecular subgroup of non-small-cell lung cancers (NSCLCS) that benefit from precision medicine. First- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIS) are recommended as upfront therapy for EGFR-mutated advanced NSCLC and, compared with chemotherapy, have resulted in superior progression-free survival, improved tumour response rates, and improved quality of life. However, resistance inevitably develops, and the third-generation tki osimertinib has been approved to target the gatekeeper EGFR mutation T790M, which is responsible for resistance in 60% of cases. Multiple drivers of tki resistance have now been identified, and many new drugs are in development. With respect to this rapidly evolving field, our review highlights the current status of treatment options for patients with EGFR-mutated advanced nsclc, focusing especially on identified causes of resistance, challenges, and clinical trials aiming to improve outcomes in this patient population. Full article

Endocrine therapy, a major modality in the treatment of hormone receptor (HR)–positive breast cancer (BCA), has improved outcomes in metastatic and nonmetastatic disease. However, a limiting factor to the use of endocrine therapy in BCA is resistance resulting from the development of escape pathways that promote the survival of cancer cells despite estrogen receptor (er)–targeted therapy. The resistance pathways involve extensive cross-talk between ER and receptor tyrosine kinase growth factors [epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER2), and insulin-like growth factor 1 receptor] and their downstream signalling pathways—most notably pi3k/akt/mtor and mapk. In some cases, resistance develops as a result of genetic or epigenetic alterations in various components of the signalling pathways, such as overexpression of HER2 and ERα co-activators, aberrant expression of cell-cycle regulators, and PIK3CA mutations. By combining endocrine therapy with various molecularly targeted agents and signal transduction inhibitors, some success has been achieved in overcoming and modulating endocrine resistance in HR-positive BCA. Established strategies include selective ER downregulators, anti-HER2 agents, mtor (mechanistic target of rapamycin) inhibitors, and inhibitors of cyclin-dependent kinases 4 and 6. Inhibitors of pi3ka are not currently a treatment option for women with HR-positive BCA outside the context of clinical trial. Ongoing clinical trials are exploring more agents that could be combined with endocrine therapy, and biomarkers that would help to guide decision-making and maximize clinical efficacy. In this review article, we address current treatment strategies for endocrine resistance, and we highlight future therapeutic targets in the endocrine pathway of BCA. Full article

Despite recent advances in the systemic therapy of non-small-cell lung cancer (NSCLC), the prognosis for stage IV disease remains poor. The discovery of targetable mutations has led to new treatment options. The most common mutations, the EGFR activating mutations, are present in about 50% of Asian patients and up to 15% of white patients. First-generation reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIS) have led to improved survival in patients positive for EGFR activating mutations, but resistance eventually leads to disease progression. The irreversible EGFR TKI afatinib was developed to counter such resistance. The clinical efficacy of afatinib has been shown in first-line studies comparing it with both cytotoxic chemotherapy and first-generation EGFR TKIS. Afatinib has also shown continued benefit beyond progression while a patient is taking an EGFR inhibitor. Furthermore, its toxicity profile is both predictable and manageable. The results of the principal clinical trials assessing afatinib are reviewed here. Full article