Current and future therapies for targeting HER2 mutations in gastrointestinal cancer

Introduction: Gastrointestinal (GI) cancers altogether represent the most common cancer type. HER2 is found to be present in nearly all histologic types of GI cancers in variable degrees of expression. Over the last decade, substantial advances have been made in targeting HER2-positive cancers.

Areas covered: The present review summarizes the current progress and future directions for HER2 targeted therapies in GI cancers, including esophagogastric, pancreaticobiliary, and colon cancers. To date trastuzumab is the only anti-HER2 therapy approved for metastatic esophagogastric adenocarcinoma. Efforts are ongoing to expand the therapeutic role of HER2 to other GI cancers and overcome mechanisms of drug resistance. Novel agents and combinations are being tested in most HER2 positive GI cancers including early stage disease. These are of recent interest in colorectal cancer with studies indicating that HER2 overexpression might increase resistance to anti-EGFR therapy and may be potentially targeted.

Expert commentary: With the current ability to sequence tumors and detect genetic alterations, emphasis should be put on genomically-selected pan-tumor targeted therapies. HER2 is a perfect example of a promising drug target in GI cancers.     

Opportunities and challenges of long term anti-estrogenic adjuvant therapy: treatment forever or intermittently?

Introduction: Extended adjuvant (5–10 years) therapy targeted to the estrogen receptor (ER) has

significantly decreased mortality from breast cancer (BC).

Areas covered: Translational research advanced clinical testing of extended adjuvant therapy with tamoxifen or aromatase inhibitors (AIs). Short term therapy or non-compliance increase

recurrence, but surprisingly recurrence and death does not increase dramatically after 5 years of adjuvant therapy stops.

Expert commentary: Compliance ensures optimal benefit from extended antihormone adjuvant therapy.Retarding acquired resistance using CDK4/6 or mTOR inhibitors is discussed. Preventing acquired resistance from mutations of ER could be achieved with Selective ER Downregulators (SERDs), eg fulvestrant. Fulvestrant is a depot injectable so oral SERDs are sought for extended use. In reality, a ‘super SERD’ which destroys ER but improves women’s health like a Selective ER Modulator (SERM), would aid compliance to prevent recurrence and death. Estrogen-induced apoptosis occurs in 30% of BC with antihormone resistance. The ‘one in three’ rule that dictates that one in three unselected patients respond to either hormonal or antihormonal therapy in BC occurs with estrogen or antiestrogen therapy and must be improved. The goal is to maintain patients for their natural lives by blocking cancer cell survival through precision medicine using short cycles of estrogen apoptotic salvage therapy, and further extended antihormone maintenance.     

Adjuvant therapeutic approaches of HER2-positive breast cancer with a focus on neratinib maleate

Introduction: Breast cancer (BC) is the most common cancer in women. Human epidermal growth factor receptor 2-positive (HER2-positive) BC represents up to 15% of all BC cases and is associated with a poor prognosis. Despite the substantial improvement obtained with the addition to the treatment of trastuzumab in this subtype of BC, disease recurrence can still occur.

Areas covered: Anti-HER2 targeting drugs such as trastuzumab, pertuzumab, and T-DM1 have shown significant results in (neo)adjuvant setting. In this article, we will focus on available data for neratinib to reduce BC recurrence based mainly on the results of the ExteNET trial. This trial aimed to investigate whether neratinib can further reduce the risk of recurrence of patients diagnosed with HER2-positive BC. This trial demonstrated a significant reduction in the risk of invasive disease-free survival, particularly in hormone receptor-positive population. In addition, this review provides an expert opinion and analysis of the current situation in the adjuvant HER2-positive BC setting and in particular the escalation strategy of HER2 targeting.

Expert opinion: The treatment landscape of HER2 positive BC in this setting will evolve in the coming years with a need for clinical and molecular perspective tools to guide therapy.     

Role of chemotherapy and targeted therapy in early-stage non-small cell lung cancer

Introduction: Adjuvant platinum based chemotherapy is accepted as standard of care in stage II and III non-small cell lung cancer (NSCLC) patients and is often considered in patients with stage IB disease who have tumors ≥ 4 cm. The survival advantage is modest with approximately 5% at 5 years.

Areas covered: This review article presents relevant data regarding chemotherapy use in the perioperative setting for early stage NSCLC. A literature search was performed utilizing PubMed as well as clinical trial.gov. Randomized phase III studies in this setting including adjuvant and neoadjuvant use of chemotherapy as well as ongoing trials on targeted therapy and immunotherapy are also discussed.

Expert commentary: With increasing utilization of screening computed tomography scans, it is possible that the percentage of early stage NSCLC patients will increase in the coming years. Benefits of adjuvant chemotherapy in early stage NSCLC patients remain modest. There is a need to better define patients most likely to derive survival benefit from adjuvant therapy and spare patients who do not need adjuvant chemotherapy due to the toxicity of such therapy. Trials for adjuvant targeted therapy, including adjuvant EGFR-TKI trials and trials of immunotherapy drugs are ongoing and will define the role of these agents as adjuvant therapy.     

Adjuvant trastuzumab: a 10-year overview of its benefit

Introduction: Anti-HER2 targeted therapy is one of the key advances in the treatment of breast cancer that have occurred in the last 20 years. In the adjuvant setting, the use of trastuzumab has led to prolonged and sustained survival benefit with very little toxicity as also confirmed by the 10-year follow-up results from the pivotal trials. Despite the survival improvement, several key issues are not entirely resolved in this field. These issues have led to multiple research efforts in de-escalating or escalating the standard treatment with chemotherapy and 1 year of adjuvant trastuzumab.

Areas covered: In this paper, we present an in depth overview on the state of the art on these key issues of refining decision-making in adjuvant anti-HER2 therapy.

Expert commentary: Despite many important research efforts in the field, chemotherapy plus trastuzumab for a total duration of 1 year remains the standard of care. However, recent data showed that besides standard anthracycline- and taxane-based cytotoxic therapy, alternative chemotherapy regimens can now be proposed to patients with small tumors without nodal involvement and to women at high-risk of developing cardiotoxicity. Of note, besides HER2 itself, biomarkers predicting patients who may truly benefit from anti-HER2 agents are still lacking.     

Adjuvant therapy for advanced renal cell carcinoma

Introduction: Locally advanced, non-metastatic renal cell carcinoma (RCC) is conventionally managed with surgery. However, patients are at a high risk of RCC recurrence and have poor survival outcomes. An effective adjuvant systemic treatment is needed to improve on these outcomes. Targeted molecular and immune-based therapies have been investigated, or are under investigation, but their role in this setting remains unclear.

Areas covered: A comprehensive search of PubMed and ClinicalTrials.gov was performed for relevant literature. The following topics pertinent to adjuvant therapy in RCC were evaluated: strategies for patient selection, cytokine-based immunotherapy, vaccine therapy, VEGF and non-VEGF targeted molecular agents, and immune checkpoint inhibitors.

Expert commentary: Strong evidence for the incorporation of adjuvant therapy in high-risk RCC is lacking. Multiple targeted molecular therapies have been examined with only one approved for use. Genetic and molecular-based prognostic models are needed to determine who may benefit from adjuvant therapy. Developing adjuvant therapy strategies in the future depends on the results of important ongoing trials with immunotherapy and targeted agents.     

Combination therapies for the treatment of HER2-positive breast cancer: current and future prospects

Introduction: HER2-positive disease is an aggressive subtype of breast cancer that has been revolutionized by anti-HER2 directed therapies. Multiple drugs have been developed and are currently in clinical use, including trastuzumab, lapatinib, pertuzumab, T-DM1, and neratinib, alone or combined in ‘dual HER2-blockade’ regimens.

Areas covered: A comprehensive literature review was performed regarding the current state and the future of combination regimens containing anti-HER2 agents, focusing on their efficacy, toxicity, and cost-effectiveness.

Expert commentary: The combination of trastuzumab/pertuzumab is approved in all disease settings, while trastuzumab/neratinib is approved in the adjuvant setting and trastuzumab/lapatinib in metastatic disease. Meanwhile, as breast cancer biology and resistance mechanisms become clearer, combinations with drugs like PI3K/Akt/mTOR inhibitors, CDK4/6 inhibitors, anti-PD(L)1 antibodies, endocrine therapy, and new anti-HER2 agents (panHER and HER2 tyrosine kinase inhibitors, bispecific antibodies, anti-HER3 antibodies, and antibody-drug conjugates) are being extensively tested in clinical trials. More specific strategies for the ‘triple-positive’ (estrogen receptor-positive/HER2-positive) disease are also being explored. However, there is an urgent need for the development of predictive biomarkers for a better tailoring of anti-HER2 directed therapy. This is the only way to further improve clinical outcomes and quality of life and to decrease costs and toxicities of unnecessary treatments.     

Adjuvant therapy for resected colon cancer 2017, including the IDEA analysis

Introduction: Oxaliplatin-based adjuvant chemotherapy has been the standard of care for resected early colon cancer for over a decade. Recent results from the IDEA meta-analysis attempt to address the question of whether 3 or 6 months of adjuvant chemotherapy is preferable in Stage III colon cancer.

Areas covered: A review of the literature and recent conference presentations was undertaken on the topic of adjuvant therapy for resected early colon cancers. This article reviews the current evidence for adjuvant treatment of Stage II and III colon cancer, as well as up-to-date data regarding optimal duration of therapy. This article reviews the evidence for lifestyle modifications in the management of early colorectal cancer and other future directions for research in early colon cancer.

Expert commentary: In recent years, there have been no advances in the development of novel agents for adjuvant therapy in colorectal cancer. Although the IDEA meta-analysis was negative for its primary non-inferiority endpoint, the detailed results provide valuable information that allows personalisation of treatment regimen and duration.     

Olaparib for the treatment of breast cancer

Introduction: Mutations in BRCA1 and BRCA2 genes account for around 2–3% of breast cancer events and more than 10% of triple negative breast cancers. Olaparib (Lynparza®), an orally administered PARP inhibitor, demonstrated clinical benefit in a phase III trial for mutated BRCA-positive HER2 negative metastatic breast cancer.

Areas covered: This review gives an overview of available preclinical and clinical data regarding olaparib, including its chemistry, mechanism of action, pharmacokinetics and pharmacodynamics, and evidence supporting antitumor efficacy and safety profile in breast cancer patients.

Expert commentary: Olaparib improves progression-free survival in germline BRCA mutated HER2 negative metastatic breast cancer patients as compared to standard chemotherapy, with a manageable toxicity profile. Efficacy is of clinical relevance especially in the context of triple negative breast cancer. However, several aspects, such as sequencing or combination of these agents with other anticancer agents and identification of appropriate biomarkers, still need to be clearly defined.     

The role of mTOR inhibition as second-line therapy in metastatic renal carcinoma: clinical evidence and current challenges

Introduction: Sequential treatment with targeted agents is the standard of care for patients with metastatic renal cell carcinoma (mRCC). Although first-line therapy with tyrosine kinase inhibitors (TKIs) is recommended for most patients, eventually all patients become resistant to them. Therefore, optimal selection of second-line therapy is crucial.

Areas covered: We have reviewed the recent literature through pubmed search and recent congress presentations to briefly describe the clinical evidence for mTOR inhibition as a valid strategy in the treatment of mRCC after progression during anti-VEGFR therapy. In addition, we outline the management of adverse events associated with these agents, highlighting the importance of switching to an alternative mechanism of action to overcome resistance to TKI and to decrease cumulative toxicity associated with sequential treatments of the same type.

Expert commentary: The choice of subsequent therapy after progression to first-line is not clear. Although the new drugs cabozantinib and nivolumab have shown to be superior that everolimus, still it is unknown which patients may benefit from these therapies in second-line, so treatment should be personalized to each patient and should consider approaches with different mechanisms of action.     

The use of systemic therapies to prevent progression of inflammatory breast cancer: which targeted therapies to add on cytotoxic combinations?

Introduction: Inflammatory breast cancer is a rare but frequently fatal disease, essentially because of its high ability to develop distant metastases. Even though the prognosis of IBC was significantly improved by multimodal management, including the systematic use of cytotoxic-based induction, the prognosis remains largely dismal.

Areas covered: This review presents the main achievements in the systemic treatment of IBC during the past 30 years. It focuses more specifically on recent results obtained with targeted therapies, including anti-HER2 and anti-angiogenic agents. Novel approaches under investigation are presented.

Expert commentary: Current management of IBC is subtype-specific and the largest benefit has been achieved in HER2-positive disease. The identification of breakthrough therapeutic advances is eagerly awaited and will require the development of IBC-specific clinical trials. Future clinical investigations should not only aim to increase the pathological response rate but also to eradicate distant metastases, which ultimately lead to patient death.     

Multimodality treatment of operable gastric and oesophageal adenocarcinoma: evaluating neoadjuvant,adjuvant and perioperative approaches

Introduction: Treatment patterns for locally advanced operable gastric and oesophageal adenocarcinoma vary, with the optimal approach an area of debate within oncology. Strategies for treatment include a variety of neo-adjuvant, adjuvant and peri-operative regimens involving differing chemotherapy and radiotherapy combinations.

Areas covered: This review will critically appraise the evidence base underpinning the main treatment approaches in operable oesophagogastric adenocarcinoma, highlighting variations in treatment by factors such as geographical area and primary tumor site.

Expert commentary: The expert commentary will focus on the optimal evidence-based approaches for clinicians at the present time and explore how increased understanding of the molecular and genetic determinants of the disease may lead to refinements in treatment through the development of both biomarker-driven approaches and the application of novel targeted and immune-modulating agents to early treatment.     

Predictive biomarkers along gastric cancer pathogenetic pathways

Introduction: Gastric cancer is the second leading cause of cancer all over the world. Unfortunately, several gastric cancers are diagnosed in an advanced stage and chemotherapy and/or target therapies remain the only options to treat patients.

Areas covered: Herein we evaluate the new molecular proposal of gastric cancer classification, offering the possibility to recognize different pathogenetic mechanisms and molecular biomarkers potentially useful for target therapies.

Expert commentary: The possibility of introducing new specific tests for identification of molecular biomarkers critical for targeted therapies response represents the new frontier in the selection of gastric cancer patients to improve their survival. Besides HER2, already used in clinical settings as a target biomarker for biological therapy in gastric cancer patients with tissue cancer cells overexpressing HER2, other promising target biomarkers which are deregulated in gastric cancer, such as MET and FGFR, could be identified in tissue and then used for therapeutic purposes. In addition immunotherapy represents the most promising possibility of advanced gastric cancer treatment. In particular, as in other solid tumors, PD-1/PDL1 pathway has emerged in several clinical trials as an interesting therapeutic target.     

Recent advances in the management of pancreatic adenocarcinoma

Introduction: Pancreatic cancer (PC) demonstrates very poor prognosis and its incidence continues to increase, despite developments in chemotherapy, radiotherapy, and targeted therapies. Surgical resection is currently the only curative approach for PC. The role of radiotherapy in adjuvant and locally advanced PC continues to be increasingly controversial. This review article aims to explore the current knowledge of pancreatic adenocarcinoma, focusing on diagnosis, treatment strategies, and the best supportive care.

Areas covered: The current literature on pancreatic adenocarcinoma treatment modalities has been summarized, with a focus on clinical trials and reviews. New treatment strategies and their impact on clinical practice have also been discussed.

Expert commentary: Despite many therapeutic developments, only modest improvements in survival rates have been achieved. There is an essential need to increase survival by developing more innovative treatment approaches for patients with PC.     

Second-line treatments of small-cell lung cancers

Introduction: Second-line therapies for relapsed small cell lung cancer (SCLC) patients remain a challenge, with limited clinical benefit because of rapid tumor growth, early dissemination and the development of drug resistance during the disease. Recent developments in genomic sequencing have provided further insight into the biology of the disease, identifying new targets and new pathways.

Areas covered: This review details chemotherapy, targeted therapies and immune-checkpoint blockades that have been investigated as second-line treatments for SCLC patients using a PubMed search (period 1990 – 2016, terms used: SCLC, treatments, second line, therapy).

Expert commentary: Recent genomic, proteomic and preclinical studies have identified novel therapeutic strategies currently being evaluated in clinical trials. Promising approaches for SCLC management include delta-like ligand-3 (DLL3)-targeted antibody–drug conjugate, combination targeted therapies, or targeted therapy–chemotherapy with an additive effect superior to the efficacy of single agents. The blockade of immune checkpoints has yielded promising preliminary results and is being investigated in ongoing trials. The inclusion of SCLC patients relapsing after platin-doublet induction in well-designed clinical trials remains a major challenge.     

Targeted therapy for metastatic colorectal cancer

Introduction: Outcomes in metastatic colorectal cancer are improving, with better understanding and use of targeted therapies.

Areas covered: A review of the literature and recent conference presentations was undertaken on the topic of systemic treatment of metastatic colorectal cancer. This article reviews the current evidence for targeted therapies in advanced colorectal cancer, including up-to-date data regarding anti-epidermal growth factor receptor (EGFR) and anti-vascular endothelial growth factor (VEGF) agents, the relevance of primary tumor location and novel subgroups such as BRAF mutated, HER2 amplified, and mismatch-repair-deficient cancers.

Expert commentary: EGFR-targeted and VEGF-targeted antibodies are now routinely incorporated into treatment strategies for metastatic colorectal cancer (mCRC). The use of EGFR-targeted antibodies should be restricted to patients with extended RAS wild-type profiles, and there is evidence that they should be further restricted to patients with left-sided tumors. Clinically, mCRC can be divided into subgroups based on RAS, BRAF, HER2, and MMR status, each of which have distinct treatment pathways.     

Novel agents in mantle cell lymphoma

Introduction: Mantle cell lymphoma (MCL) usually takes an aggressive clinical course and carries a poor prognosis. Recently, progress has been made in the treatment of MCL including the development of a number of novel agents which target intracellular pathways and the extracellular microenvironment. These agents have transformed the landscape of available therapeutic options.

Areas covered: The current literature on the novel agents which currently hold a licence for the treatment of MCL in the context of front-line therapy and in the relapsed/refractory setting is summarized. In addition, targeted therapies showing promise at an earlier stage of development will also be discussed. A literature search was performed using the terms ‘mantle cell lymphoma’, ‘bortezomib’, ‘temsirolimus’, ‘lenalidomide’, ‘ibrutinib’, ‘novel agents’, ‘targeted molecular therapies’ and derivations thereof.

Expert commentary: In addition to improvements in immunochemotherapy, a succession of new molecular targets and corresponding drugs has revolutionised MCL therapy. The discovery of a novel agent which disrupts external signalling pathways through inhibition of Bruton’s tyrosine kinase has been a particularly exciting breakthrough. The best way to sequence and combine these agents with existing regimens and how to overcome the problem of drug resistance represent new challenges in this rapidly developing field.     

Total pathological complete response versus breast pathological complete response in clinical trials of reference and biosimilar trastuzumab in the neoadjuvant treatment of breast cancer

Introduction: Trastuzumab is a key drug in the neoadjuvant treatment of breast cancers that overexpress the human epidermal growth factor receptor 2 (HER2). Pathological complete response (pCR) is commonly used as an endpoint in neoadjuvant clinical trials of trastuzumab as evidence suggests it may be a surrogate for long-term survival. Several biosimilar candidates of originator or ‘reference’ trastuzumab are in development and have used pCR as a primary endpoint to assess therapeutic equivalence between treatments. The exact definition of pCR has varied across studies.

Areas covered: Here we look at the clinical relevance of pCR and compare rates of total pCR (defined as ypT0/is ypN0) and breast pCR (defined as ypT0/is) in clinical trials of reference and biosimilar trastuzumab.

Expert commentary: In order to evaluate the efficacy of neoadjuvant systemic therapies in a uniform way, standardization of trial endpoints is necessary. Future studies in HER2-positive breast cancer should include full assessment of the breast and lymph node basin before and after neoadjuvant systemic therapy, and the use of total pCR as the primary outcome.     

New advances in focal therapy for early stage prostate cancer

Introduction: Prostate focal therapy offers men the opportunity to achieve oncological control while preserving sexual and urinary function. The prerequisites for successful focal therapy are to accurately identify, localize and completely ablate the clinically significant cancer(s) within the prostate. We aim to evaluate the evidence for current and upcoming technologies that could shape the future of prostate cancer focal therapy in the next five years.

Areas covered: Current literature on advances in patient selection using imaging, biopsy and biomarkers, ablation techniques and adjuvant treatments for focal therapy are summarized. A literature search of major databases was performed using the search terms ‘focal therapy’, ‘focal ablation’, ‘partial ablation’, ‘targeted ablation’, ‘image guided therapy’ and ‘prostate cancer’.

Expert commentary: Advanced radiological tools such as multiparametric magnetic resonance imaging (mpMRI), multiparametric ultrasound (mpUS), prostate-specific-membrane-antigen positron emission tomography (PSMA-PET) represent a revolution in the ability to understand cancer function and biology. Advances in ablative technologies now provide a menu of modalities that can be rationalized based on lesion location, size and perhaps in the near future, pre-determined resistance to therapy. However, these need to be carefully studied to establish their safety and efficacy parameters. Adjuvant strategies to enhance focal ablation are under development.