It is already December and we are ending this year with a newsletter that has some encouraging news for women with ovarian cancer. Last month, Avastin became the first drug to be approved in the United States for ovarian cancer treatment in 15 years! This approval is for treatment of patients whose cancers are resistant to platinum. For those who are responding to platinum or are in remission, there are likely to be new options coming soon based on the new results for drugs called PARP inhibitors.   As you will read in the articles by our volunteer writers, Drs. Cory Bentley and Evan Friend, there is also promising data that women will be able to use tumor blueprints (or signatures) to determine who will most benefit from these drugs.  As usual, we will keep you informed about further development of these and other biomarker tests in the coming year. 

 All of us here at Clearity wish you, your family and friends a joyous holiday season.

The search for a biomarker to predict response to the angiogenesis inhibitor, bevacizumab (aka Avastin), may be nearing a successful conclusion.  Researchers at Edinburgh Cancer Research Center in Scotland reported that they may have discovered such a predictor for ovarian cancer patients treated with Avastin. They presented their findings at the June ASCO meeting and showed that this predictor is not a single gene or protein, but a "signature" that combines information from 63 genes.  The information is derived from molecules in the cell called messenger RNAs (mRNA), which act as communicators between the DNA blueprint in the cell nucleus and the cellular protein-making factory by giving instructions for the type of proteins that are to be made.  The investigators used tumor samples collected during a previous Avastin clinical trial (ICON7) in newly diagnosed patients who had surgery followed by standard platinum-based chemotherapy with or without Avastin.   They measured mRNA for these 63 genes in the tumors and designated them as "pro-angiogenic" or "immune"-like.   Those patients with "immune-like" tumors lived longer than those with "pro-angiogenic" tumors, suggesting that this signature might also be a prognostic marker.  Importantly, those women with "immune-like" tumors did not benefit when they were given Avastin as first-line treatment and for maintenance.  These results must be confirmed in additional studies and still need to be evaluated for recurrent ovarian cancer patients who receive Avastin-usually in combination with other chemotherapies.  But, the current data suggest that there may soon be a molecular test that will help patients and their doctors make informed decisions regarding the use of Avastin based on their tumor molecular profile in addition to the clinical factors, including cardiovascular issues or intestinal involvement of the cancer. 

Preliminary results from a Phase 2 clinical trial ("ARIEL-2") testing the PARP inhibitor rucaparib in ovarian cancer patients with platinum-sensitive recurrent cancer were presented at the recent EORTC-NCI-AACR conference.  Much excitement has been generated from the interim analysis of this trial, since for the first time, a biomarker ("biological indicator") consisting of an actual "signature" event identified from an individual patient's tumor was found to correlate with favorable responses (to see the interim results, click here). Importantly, in addition to BRCA1/2 mutant patients, for whom PARP inhibitors have previously shown clinical effectiveness, the women without BRCA mutations whose cancer was positive for the identified genomic signature also derived significant benefit from rucaparib.

The signature event is described as "loss of heterozygosity (LOH)" within the genome.  This refers to the loss of an entire chromosomal region on one copy of the double-stranded DNA genome and is a sign of DNA damage that has occurred in the tumor.  As expected, high levels of this type of damage were found in the tumors of patients who have BRCA mutations.  Moreover, this genomic LOH signature seems to match the state of "BRCAness", which describes BRCA mutation-negative women whose tumors behave as though there was a BRCA mutation, and have responded to PARP inhibitors in previous trials.  Now, for the first time, we have preliminary favorable results from a clinical trial that yields not only a specific biomarker protein or gene, but in this case, a specific molecular DNA "signature" which will hopefully allow clinicians to identify those patients who would be expected to derive the maximum benefit from the addition of PARP inhibitors to chemotherapeutic regimens, both in the relapse and maintenance settings.

An "ARIEL-3" (maintenance setting, platinum-sensitive patients) Phase 3 clinical trial is currently underway and will evaluate the effects of the PARP inhibitor rucaparib in women whose cancers have been tested for the presence of BRCA mutations as well as for this genomic LOH signature.  Thus, that study will prospectively show whether this signature is a significant predictor of rucaparib benefit.  Stay tuned!