A Brief Look: Cancer Genomic Medicine at the 2013 Annual Meeting of the American Society of Clinical Oncology®

Maurie Markman, MD


August 21, 2013

Increasingly, the management of cancer is focusing on the use of more precise treatments based on the identification of specific molecular abnormalities. A few highly provocative abstracts presented at the 2013 Annual Meeting of the American Society of Clinical Oncology® demonstrate how this shift toward more molecular-targeted therapies is changing the paradigm of cancer medicine. Although these abstracts may not have been the most unique or important molecular studies presented at the meeting, they clearly emphasize the scope and complexity of this rapidly evolving arena.

From Melanoma to Lung Cancer...

Activating mutations in BRAF have been shown to be an important driver of progression in approximately 50% of patients with malignant melanoma,[1] but such mutations are uncommon (< 2% incidence) in non-small cell lung cancer (NSCLC). To evaluate the biological and clinical activity of BRAF inhibition in this clinical setting, investigators treated 17 patients with BRAF-positive NSCLC with dabrafenib, an antineoplastic agent that has activity in BRAF mutation-positive melanoma.[2] Among the 13 patients previously treated with chemotherapy who were evaluable for response at the time of the report, 7 had achieved a partial response and 1 patient had stable disease as the best response. The response in 1 patient lasted for 49 weeks, and the majority of patients were on active therapy at the time of the report.

And From Lung Cancer to Colorectal Cancer

ROS1 and ALK rearrangements have been found in 2%-5% of NSCLC adenocarcinomas and have been shown to be highly responsive to specific tyrosine kinase inhibitors.[3,4] Investigators evaluated the tumors from 236 patients with metastatic colorectal cancer and found that 3 tumors (1% of the entire group) demonstrated either an ALK rearrangement or a ROS1 mutation.[5] Future studies will be required to determine whether these molecular abnormalities are as clinically responsive to the specific targeted antineoplastics as observed in lung cancer.

Redefining the Target for PARP Inhibitors...

A previously reported phase 2 trial demonstrated the utility of the PARP inhibitor olaparib in delaying the time to disease progression when used as maintenance therapy in patients with high-grade serous ovarian cancer who had achieved a second response to platinum-based chemotherapy.[6] Following on earlier data showing that PARP inhibitors might be particularly useful in the 5%-10% of patients with ovarian cancer who harbor BRCA mutations,[7] the study investigators reported a reanalysis of this trial among the 218 of 265 patients enrolled in whom it was possible to obtain tissue for analysis of BRCA mutation status.[8] In this group, treatment with olaparib nearly tripled the median time to disease progression to 11.2 months vs 4.1 months for placebo-treated patients.

And Revisiting the Definition of CUP

With modern technology, the majority of patients presenting with a cancer of unknown primary (CUP) can have the site of origin of their malignancy ultimately defined.[9] However, in a small but not insignificant number of patients with poorly differentiated CUP, currently available diagnostic efforts are unsuccessful. This may pose a serious dilemma for clinicians, because this diagnostic information may be vitally important in defining prognosis and -- most important -- in optimizing therapy.

Of 751 patients with CUP seen at 1 institution from 2000 to 2012, investigators examined their experience with molecular tumor profiling in 30 patients in whom a definitive site of origin was unable to be defined by other measures.[10] Molecular tumor profiling was successful in 25 (83%) of these patients in suggesting the site of origin, including settings where specific beneficial therapies are currently available, such as germ cell tumors, melanoma, and lymphoma.