The Heterogeneous Landscape of Head & Neck Squamous Cell Carcinomas, Head & Neck Squamous Cell Carcinomas Head and neck squamous cell carcinomas can be highly aggressive tumors in some cases, while other prognoses can be very good. The tumors present in different anatomical regions of the upper airways and digestive tract, and they present with very different mutation profiles, molecular characteristics, and immune landscapes, as well as prognoses. Recognizing that differences in these head and neck cancers exist is important. But, the heterogeneity in head and neck squamous cell carcinomas has made it difficult to map out the immunological characteristics of these tumors in a way that will improve treatment and therefore improve patients' outcomes. That's the bottom line from a recent review on the topic, published earlier this year online ahead of print in the journal Frontiers in Cell and Developmental Biology (2019; doi.org/10.3389/fcell.2019.00052). “Over the past decade, despite the marked improvement in clinical outcome of many tumor types, the overall 5-year survival rate of [head and neck squamous cell carcinomas] remained [approximately] 40-50 percent largely due to poor availability of effective therapeutic options for [head and neck squamous cell carcinoma] patients with recurrent disease,” the coauthors note in the paper. While there have been gains in better understanding the molecular characterization of head and neck squamous cell carcinomas (in terms of somatic mutations and alterations in gene expression and rearrangement), those insights have not yet been used to change treatment paradigms for these patients, according to the paper. “There is an urgent and unmet need for the identification of specific molecular signatures that better predict the clinical outcomes and markers that serve as better therapeutic targets,” the coauthors noted. Here are some of the points made in the paper. Classification beyond anatomical region is important, but that doesn't mean genomic analysis alone should be considered. Conventional classification of these cancers is based on anatomic location and tumor characteristics (like stage, depth of tumor invasion, and tumor-node metastasis). But those factors alone are not enough to accurately predict prognoses, suggesting that other factors should be taken into account, according to the new review. HPV status should be considered in these tumors. But one challenge is that HPV status has not always been considered in existing literature. “Most of the molecular classification studies were performed using total [head and neck squamous cell carcinoma] specimens regardless of HPV statuses,” the coauthors noted. HPV Genomic expression needs to be taken into account, as that information may inform new therapeutic targets. But classical molecular subtypes are important, too, including classical, basal, mesenchymal, and atypical subtypes, which exist across all tumor subtypes and anatomical locations. Combining that information with gene expression profiles will be important. “Integrative genomic analyses in association with functional annotation provides valuable information for identifying molecular drivers of carcinogenesis, potential markers for prognosis, and [head and neck squamous cell carcinoma] classification based on molecular signatures that may facilitate a better prediction for responsiveness to therapy,” the review's coauthors noted. Immune landscape of the tumor microenvironment matters, too. Another point in the review: It's not enough to just look at what's happening in the tumor; what's happening in the immune system and how the molecules in the immune system are responding to the tumor needs to be considered, too. There's evidence to support the significance of the immunosurveillance hypothesis that there are dynamic and bidirectional interactions between the tumor cells and the immune system that contribute to a tumor's growth and survival, according to the paper's coauthors. “The immunosurveillance concept has been well appreciated to relay an important physiological process during carcinogenesis and tumor progression, and has provided invaluable insight into potential targets for immunotherapy intervention,” they noted, adding that bolstering immune defense is significant to improving anticancer therapy. Checkpoint inhibitor therapy will be important, but research needs to discriminate more heavily on tumor characteristics. Checkpoint inhibitor therapies, like anti-PD-1 and anti-CTLA4 antibodies, hold a lot of promise for improving outcomes for patients with head and neck squamous cell carcinomas (specifically many tumors are known to express PD-L1, PD-1, and CTLA-4 molecules). But previous studies may have underestimated the benefits of those studies by not classifying patients into subtypes that were discriminatory enough to show who the therapies worked for and who they did not work for. “Early checkpoint inhibitor clinical trials for [head and neck squamous cell carcinoma] treatment did not discriminate patients based on their HPV status,” the review's coauthors noted in the paper. “As we now appreciate the high level of heterogeneity in the [tumor microenvironment] of [head and neck squamous cell carcionomas] concerning the HPV status and tumor types, it becomes clear that analyzing and presenting the [head and neck squamous cell carcinoma] clinical trial results by segregating HPV (+) patients from HPV (-) cases will be more informative.” Recent FDA approval of pembrolizumab for some HNSCC is a step forward. Head and neck cancers are no longer thought of as a homogeneous disease, Cristina Rodriguez, MD, an oncologist specializing in the treatment of people with head and neck, salivary gland, thyroid, and lung cancers at Seattle Cancer Care, shared with Oncology Times. Rodriguez was not involved in writing the recent review paper. “Looking at the entire population without recognizing these differences may lead to misleading assumptions,” added Rodriguez, who is also Associate Professor at University of Washington School of Medicine and Associate Member of the Clinical Research Division at Fred Hutchinson Cancer Research Center. (Her research at Fred Hutch focuses on integrating targeted and biological therapies into multimodal therapy of locally advanced head and neck squamous cell carcinomas and optimizing functional outcomes after therapy for advanced head and neck malignancies). One step in the right direction, Rodriguez said, is the FDA's approval of pembrolizumab either used as a monotherapy in patients with head and neck squamous cell carcinomas whose tumors express PD-L1 or in combination with a platinum and fluorouracil chemotherapy regimen for first-line treatment of patients with metastatic or unresectable tumors. Pembrolizumab is a PD-1 inhibitor, a type of immunotherapy, and has previously been approved for the treatment of other cancers, including lung and skin cancers. “Since the great majority of patients with head and neck squamous cell carcinomas are diagnosed with locally advanced, potentially curable disease, investigating the incorporation of immune checkpoint inhibitors in the curative-intent setting would have a major impact on the treatments we offer our patients,” she stated. “The landscape of treatment is rapidly shifting.” The bottom line she believes oncologists should know about treating patients with head and neck cancers is that, to provide treatment with the best oncologic and functional outcomes, tailoring therapy to the individual and the characteristics of his or her disease is increasingly important. “One of the most important aspects of formulating these treatment plans is the multidisciplinary clinic, and I cannot emphasize how important the input of the many specialists who treat head and neck cancer is to ensure the best treatment outcomes for our patients,” she said. Sarah DiGiulio is a contributing writer. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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