PROGRESS IN CANCER GENOMIC RESEARCH

It would not be an overstatement to declare that 2010 was the year when personalized cancer care, based on defined molecular characteristics within an individual patient’s tumor, began to have genuine clinical relevance across multiple tumor types.

Three studies focused on the management of non-small cell lung cancer (NSCLC). In the first, investigators demonstrated considerable biological and clinical activity of a novel antineoplastic agent directed against a specific rearrangement in anaplastic lymphoma kinase, or ALK, which is found in approximately 2% to 7% of all patients with NSCLC.[1] Of the 82 patients with metastatic disease studied, the majority of whom had received prior treatment, an objective response rate of 57% was observed. Of perhaps even greater importance, the 6-month progression-free survival in this difficult setting was 72%. In addition, the side effect profile for the agent in this study was very acceptable.

Next, an important role for a targeted therapeutic approach in the primary treatment of metastatic disease was revealed in a phase 3 trial that documented the superiority of gefitinib (a tyrosine kinase inhibitor of the epidermal growth factor receptor [EGFR]) over cytotoxic chemotherapy (carboplatin plus paclitaxel) in individuals with a documented mutation in EGFR.[2] The study demonstrated an improved objective response rate (74% vs 31%) and median progression-free survival rate (10.8 months vs 5.4 months) in this patient population. In addition, gefitinib was reasonably well tolerated, with a different toxicity profile (rash and abnormal liver function tests) from that of standard chemotherapy.

Finally, in an analysis of 52 patients with adenocarcinoma of the lung who had never smoked and were of East Asian descent, investigators were able to identify 1 of 4 specific molecular abnormalities in 90% of the population.[3] These data suggest that it might someday be possible to identify very specific molecular defects in the majority of patients with NSCLC that can point the way to personalized targeted therapeutic regimens in these individuals.

In breast and ovarian cancers, investigators confirmed the utility of bilateral salphingo-oophorectomy as a strategy to reduce the risk for both breast and ovarian cancer in women with known BRCA1 and BRCA2 mutations.[4] Overall, in patients who underwent surgery, the risk for breast cancer was reduced by 50%, and the risk for ovarian and fallopian tube cancers was reduced by approximately 80%. The presence of BRCA1 and BRCA2 mutations was also shown to be associated with a substantially increased risk for breast cancer in the contralateral breast in women with a history of breast cancer, emphasizing the benefits associated with prophylactic mastectomy in this clinical setting.[5]

In malignant melanoma, a landmark study revealed the impressive activity of an inhibitor of activated BRAF in patients with metastatic melanoma, an abnormality present in approximately 50% of patients with this cancer.[6] In an initial exploration of clinical utility, 11 of 16 patients known to have a V600E BRAF mutation showed an objective response, and an additional 26 of 32 patients who were given the agent in an extension phase of the initial trial experienced substantial activity. Of considerable additional interest, the median time to disease progression for patients who participated in this trial was more than 7 months.

Finally, a highly provocative study explored the potential clinical utility of obtaining genetic analysis of individual tumors and to develop specific treatments based on that analysis.[7] Results showed that it was possible to define abnormalities that could be approached with particular antineoplastic agents. In addition, for a large percentage of the study population, there was evidence that the time to subsequent disease progression was substantially prolonged with this method compared with the prior treatment regimen used in the individual patient.

In light of the progress made in 2010, it is reasonable to anticipate that in coming years, we will see additional novel cancer treatment strategies based on unique molecular characteristics within individual tumors that significantly change clinical practice and -- most important -- that improve outcomes for patients with malignant disease.