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SQUAMOUS, SMALL CELL, AND RARE LUNG CANCERS
Beyond Adenocarcinoma: Current Treatments and Future
Directions for Squamous, Small Cell, and Rare Lung
Cancer Histologies
David E. Gerber, MD, Paul K. Paik, MD, and Afshin Dowlati, MD
OVERVIEW
Lung cancer encompasses a diverse spectrum of histologic subtypes. Until recently, the majority of therapeutic advances were limited
to the minority of patients with adenocarcinoma. With the advent of comprehensive genomic profiling of squamous and small cell lung
cancers, new therapeutic targets have emerged. For squamous tumors, the most promising of these include fibroblast growth factor
receptor (FGFR), the phosphatidylinositol 3-kinase (PI3K) pathway, discoidin domain receptor 2 (DDR2), and G1/S checkpoint regulators.
In 2014, the antiangiogenic agent ramucirumab was approved for all non–small cell lung cancer (NSCLC) histologies, including squamous
tumors. Immunotherapeutic approaches also appear to be promising for these cases. Genomic analysis of small cell lung cancer has
revealed a high mutation burden, but relatively few druggable driver oncogenic alterations. Current treatment strategies under
investigation are focusing on targeting mitotic, cell cycle, and DNA repair regulation, as well as immunotherapy. Pulmonary neuroendocrine
tumors represent a diverse spectrum of diseases that may be treated with somatostatin analogs, cytotoxic agents, and
molecularly targeted therapies. Radiolabeled somatostatin analogs and combinations with mammalian target of rapamycin
(mTOR) inhibitors also show potential. Large cell neuroendocrine tumors share numerous clinical, pathologic, and molecular
features with small cell lung cancer; however, whether they should be treated similarly or according to a NSCLC paradigm remains
a matter of debate.
Recent therapeutic advances in lung cancer have been almost
exclusively limited to adenocarcinoma histology.
Molecular profıling efforts to identify genomic alterations,
driver oncogenes, and druggable targets have focused on adenocarcinoma.
Until recently, antiangiogenic treatments
were limited to nonsquamous NSCLC because of concerns of
heightened toxicity (life-threatening hemoptysis) in squamous
cases. Additionally, use of the well-tolerated, convenient,
and effective cytotoxic agent pemetrexed is also
restricted to nonsquamous cases because of inferior outcomes
in squamous cases.
Lung cancer encompasses numerous diverse histologic
types (Sidebar 1). After decades of inactivity, recent years
have seen advances in our understanding and treatment of
lung cancer types beyond adenocarcinoma. Genomic alterations
that may provide therapeutic targets have been identifıed
in squamous cell carcinoma, and newer antiangiogenic
agents appear to be tolerated in this histologic subtype. Gene
sequencing efforts in small cell lung cancer have identifıed
one of the highest mutational burdens of any malignancy,
and prophylactic cranial irradiation in extensive stage disease
has been shown to improve neurologic outcomes and overall
survival. Although advances for less common lung tumors,
such as large cell carcinoma and bronchial carcinoids, have
been hampered by their low frequency and a lack of consensus
on disease categorization, recent data suggest that certain
molecularly targeted agents, liver-directed therapies, and radiolabeled
somatostatin analogs may improve outcomes.
This review provides an overview of the current approach
and future directions for these diverse malignancies.
SQUAMOUS CELL CARCINOMA
Recently, genotyping efforts—ranging from the comprehensive,
such as The Cancer Genome Atlas’ squamous lung cancer
study, to the individual, such as the characterization of
FGFR1 amplifıcation and DDR2 mutations—have brought
to light a number of putative therapeutic targets that appear
to occur in toto in more than half of all patients’ tumors.
What follows is a summary of recent diagnostic and therapeutic
developments aimed at improving the outcomes of patients
with this disease.
Squamous tumors account for 20% to 30% of all NSCLC
cases. 1 The prototypical squamous cancer is characterized by
From The University of Texas Southwestern Medical Center, Dallas, TX; Memorial Sloan Kettering Cancer Center, New York, NY; Case Western Reserve University, Cleveland, OH.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: David E. Gerber, MD, Division of Hematology-Oncology, Harold C. Simmons Cancer Center, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd.,
Mail Code 8852, Dallas, TX 75390; email: david.gerber@utsouthwestern.edu.
© 2015 by American Society of Clinical Oncology.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK 147