Personalized Medicine: A Promising Future in Oncology Practice

Andre Goy, MD, MS

Editor-in-Chief Contemporary Oncology Chief, Lymphoma Division, Chairman John Theurer Cancer Center at Hackensack University Medical Center

This issue of Contemporary Oncology includes a focus on 2 challenging situations: management of metastatic triple negative breast cancer (TNBC) and of advanced stage non—small–cell lung cancer (NSCLC).

Christiansen and colleagues report on actual first-line treatment patterns for the management of metastatic TNBC in community practice settings in the United States. TNBC is characterized by aggressive tumors with cells that lack estrogen receptors (ERs) and progesterone receptors (PRs), and do not overexpress HER2. The study looked at patients with stage IV metastatic TNBC in 2 databases (Georgia Cancer Specialists Database and International Oncology Network’s Treatment and Outcomes Database). Though the number of patients evaluated was relatively small, the patterns seen confirmed previous observations.That is, the analysis found that there was no general consensus in current treatment for stage IV TNBC. The basis of therapy remains the use of conventional cytotoxics from single agent chemotherapy (capecitabine, taxanes) or combinations regimens (cyclophosphamide, doxorubicin with and without bevacizumab), with corresponding significant differences in costs.

Although the metastatic potential in TNBC is similar to that of other breast cancer subtypes, these tumors are associated with a shorter median time to relapse, a greater chance of visceral- and organ-based metastatic disease, and overall worse outcomes and survival. Unfortunately, there are no reliable prognostic factors in TNBC, and molecular studies have shown this is a very heterogeneous disease.

Although TNBC is often referred to as surrogate for basal-like breast cancer, there is clearly a need for further subclassification. One of the main issues, as seen in these results, is the lack of clear guidelines in TNBC. Ongoing studies (more than 60 currently) looking at new combinations—including new targeted therapies focusing on EGFR, CHK-1, PARP-1, PI3K/mTOR inhibitor, and TKI (dasatinib), among others—may shed some light on the management of this disease. Recent work (Lehmann, BD et al. J Clin Invest. 2011;121:2750-2767.) identified 6 molecular subtypes of TNBC. Using representative TNBC cell lines of the 6 distinct subtypes, investigators showed that the various subtypes had different sensitivities to targeted therapies currently under laboratory and clinical investigation, providing a rationale for future studies.

Meanwhile, the treatment of NSCLC has seen a paradigm shift over the last decade, with the integration of novel therapies based on a better understanding of some of the driving mutations. In this issue, the article by Steven A. Sandler, MD, reviews these advances.

NSCLC, which accounts for approximately 85% of all lung cancers, is divided further into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma histologies. Lung cancer is the leading cause of cancer-related mortality in men and women, both in the United States and worldwide. In 2006, lung cancer resulted in 158,000 deaths in the United States alone—more than colorectal, breast, and prostate cancer combined.

Most lung carcinomas are diagnosed at an advanced stage, conferring a poor prognosis. Only a third of patients with NSCLC present at diagnosis with disease that is sufficiently localized to attempt curative surgical resection (stages IA and IB, IIA and IIB, and IIIA). Radiation is a reasonable option for lung cancer treatment for those who are not candidates for surgery. However, approximately half of patients who undergo an attempt at curative local therapy experience local or systemic relapse. As a result, about 80% of all patients with NSCLC receive chemotherapy at some point during the course of their disease. NSCLC is only moderately sensitive to chemotherapy, with single-agent response rates in the range of 15% or better. Newer agents (eg, gemcitabine, pemetrexed, docetaxel, vinorelbine) have shown promising single-agent activity, with response rates from 20% to 25% (although there has been no clear benefit demonstrated with triple agents combinations).

The most impressive changes seen in NSCLC relate to the benefit of targeted therapies. These changes have been so dramatic that screening for “driver mutations” in NSCLC is now part of routine management and National Comprehensive Cancer Network guidelines. One driver mutation—overexpression of epidermal growth factor receptor (EGFR), which is common in NSCLC—correlates with increased resistance to therapy, metastatic potential, and poorer outcome. Gefitinib and erlotinib, both EGFR tyrosine kinase inhibitors (TKIs), have shown dramatic benefit in NSCLC, particularly in subsets of patients carrying a mutation for EGFR. (In one study, patients with mutated EGFR had significantly longer PFS in the gefitinib group, for example, compared with carboplatin-paclitaxel). These favorable mutations for EGFR were more common in women, non-smokers, and patients of Asian origin. On the other hand, patients with EGFR expression and absence of KRAS mutations (similar to what has been seen in colon cancer) may be considered for the addition of cetuximab to first-line chemotherapy.

Another remarkable example of the benefit of targeted therapies is crizotinib (Xalkori), which was approved by the FDA in August 2011, for the treatment of locally advanced or metastatic NSCLC that is anaplastic lymphoma kinase, ALK-positive as detected by the Vysis ALK Break Apart FISH Probe test. Other directed therapies, such as the anti- VEGF monoclonal antibody (bevacizumab), have already been approved for clinical use, while a number of others are in clinical testing (eg, targeting MET, VEGFR, HER2, PIK3CA, and IGF-1). Finally, ongoing efforts to identify additional targetable driver mutations will help dissect further the heterogeneity of NSCLC to the benefit of our patients.

The paradigm shift in lung cancer offers great hope for future endeavors, including in TNBC, but also represent a true illustration of the ongoing shift toward personalized medicine across the board in oncology.