By Turna Ray
Fresh on the heels of launching Oncotype DX for colorectal cancer recurrence in stage II patients last week, Genomic Health is already working on expanding the indication of the test into later stages of the disease as well as into renal cancer, ductal carcinoma in situ, and prostate cancer.
Oncotype DX for colorectal cancer analyzes the expression of 12 genes to yield a recurrence score that indicates the likelihood of stage II disease recurrence following surgery. Genomic Health developed the test with collaborators at the National Surgical Adjuvant Breast and Bowel Project, the Cleveland Clinic, and the QUASAR study group.
In order to develop the RT-PCR based test, researchers looked at more than 700 genes in more than 1,800 colon cancer patients. The final set of 12 genes used to yield the recurrence score for the test was independently validated in 1,436 stage II colon cancer patients in the QUASAR trial.
In the trial, the test met its primary endpoint in determining the likelihood of post-operative disease recurrence in patients with stage II colon cancer, but the study did not meet its secondary endpoint when using the test to predict which patients are likely to benefit with post-operative 5-fluorouracil/leucovorin treatment [see PGx Reporter 04-15-2009].
Despite not being able to offer a separate treatment score for predicting chemotherapy benefit with the initial launch of the test, Genomic Health is not giving up on the predictive indication. Depending on the results of additional studies, the company hopes to be able to offer a separate predictive treatment score for Oncotype DX colorectal cancer by 2013.
"Just as we did with Oncotype DX breast cancer — we started out and reported recurrence risk alone and then did additional tests over time that enhanced the value of the test — we're doing the exact same thing in colon cancer and doing additional studies to look at chemotherapy benefit … particularly with oxaliplatin," Steven Shak, Genomic Health's chief medical officer, told Pharmacogenomics Reporter this week.
In addition to the predictive claim, the company presented data at a major oncology conference last week that suggests the test might be clinically useful in detecting recurrence in stage III colorectal cancer patients.
Separately, the company is also planning to report results from a collaborative study with Pfizer focusing on identifying prognostic markers for renal cancer sometime this year, Shak said.
CRC Test Launch and Adoption
Following the release of data from the QUASAR trial last year, analysis by Thomas Weisel Partners showed that investors were disappointed that Genomic Health's colorectal cancer test was not predictive for chemotherapy benefit. However, a survey of oncologists and pathologists, also conducted around the same time by Thomas Wiesel, suggested healthcare providers were interested in using the test in their practices without the predictive claim [see PGx Reporter 07-15-2009].
Shak doesn't believe that not having the predictive claim for the colon cancer test will negatively affect adoption. In fact, he suggested that even without a separate treatment score to predict response to chemotherapy, doctors can use the prognostic recurrence score alongside standard clinical measures to discern which patients should receive chemotherapy.
"When you actually look at the recurrence risk, it's actually the recurrence risk that doctors use to provide an estimate of the magnitude of the benefit of chemotherapy," Shak said. "When we did the QUASAR study, we looked at the relative risk reduction as a function of the recurrence score. As the recurrence score increases, we estimate that the actual magnitude of the chemotherapy benefit is going to be greater in those patients.
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"This is an important component of understanding how to use the recurrence score, [which] gives you information on the likelihood of recurrence, but also since the relative risk reduction depends on the baseline risk, it also provides insight into the magnitude of chemotherapy benefit," Shak explained.
In developing the colon cancer test, Genomic Health compared the assay with measures doctors are currently using in standard practice. As a result, the company recommends doctors use the colorectal cancer recurrence score in conjunction with two other markers, T-stage and mismatch repair status.
"I think in talking about our tests our focus and success has really been based on understanding the needs of physicians and the needs of patients, and making sure that we did the right studies and developed the evidence and delivered a service that would really be used in clinical practice," he said.
In order to report the recurrence score, the test analyzes the expression of 12 genes: three stromal genes (FAP, INHBA, BGN); three cell cycle genes (Ki-67, C-MYC, MYBL2); GADD45B; and five reference genes (ATP5E, GPX1, PGK1, UBB, VDAC2).
According to Shak, the company will follow its previous strategy of driving physician and payor adoption of the test through published studies and inclusion in oncology treatment guidelines.
Genomic Health has reported that approximately 225 million lives are covered for its Oncotype DX breast cancer test when used in node-negative breast cancer patients, representing 92 percent of all insured lives and 98 percent of lives insured by private payors. The company also reported recently that in 2009, it delivered approximately 49,030 Oncotype DX tests for breast cancer.
The pharmacogenomics firm's existing payor and physician relationships will likely help start discussions regarding the colorectal cancer test.
Genomic Health currently has 80 sales people and expects to add another 10 this quarter. The company's entire sales force would sell both the Oncotype Dx for breast cancer and the assay for colon cancer.
CRC Test Expansion
Though the company has just launched Oncotype DX for colorectal cancer, it is already thinking of ways to expand the indication of the test.
At the American Society of Clinical Oncology's Gastrointestinal Cancers Symposium last week in Orlando, Fla., Genomic Health presented studies that suggested the colorectal cancer test's recurrence score may be combined with nodal assessment and the test may be able to determine disease recurrence in stage III colorectal cancer patients.
The first study analyzed data from the QUASAR trial to assess the prognostic value of nodal assessment in combination with the recurrence score and other variables. In this study, researchers reported that both recurrence score and number of nodes examined were independent predictors of recurrence risk. "Additionally, the study results proved consistent with the National Comprehensive Cancer Network's recommendation of 12 or more nodes examined as a target for nodal assessment," Genomic Health said in a statement.
The second study compared pathologic markers and gene expression by disease stage in the four clinical trials conducted in the development of the Oncotype DX colon cancer test. Researchers compared pathologic markers and the expression of 375 genes between 634 stage II and 844 stage III patients.
"Results demonstrated that the vast majority of the 375 genes and the recurrence score showed no significant interaction with stage, and there were similar patterns of gene expression by stage," Genomic Health stated. "However, there were differences identified between stage II and stage III colon cancer for some tumor characteristics and a small number of the individual genes."
Among the differences between the two stages noted by researchers were, for instance, stage II patients tended to be mismatch repair deficient and have mucinous histology. "Additionally, interaction of grade and stage was significant, and interactions of stage with T-stage, mismatch repair, and mucinous histology were borderline, indicating prognostic value in stage II, but not stage III disease," the researchers found.
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Despite these differences, the results of this second study suggests "there is a striking similarity between the two stages for the vast majority of the 375 genes studied and for the 12-gene Oncotype DX colon cancer recurrence score," said Michael O'Connell, associate chairman of the National Surgical Adjuvant Breast and Bowel Project, in a statement. "As physicians begin to incorporate Oncotype DX into clinical practice for stage II colon cancer patients, it is worth conducting additional studies to evaluate this test for treatment planning in stage III disease, based on the similarities observed in this study."
Additional Product Launches
Beyond colorectal cancer and breast cancer, Genomic Health has plans to expand its Oncotype DX franchise into renal cancer, DCIS, and prostate cancer.
Genomic Health and Pfizer inked a collaboration in 2008 to develop a genomic test based on the Oncotype DX technology to gauge the risk of post-operative kidney cancer recurrence. Shak said that a study involving 900 patients and looking at more than 700 candidate genes to uncover prognostic markers for renal cancer recurrence is currently underway. The results of this study will be released this year and the test is slated for launch in the first half of 2013.
"The long-term goal of this would be to assist in the selection of early-stage patients for treatment with targeted therapies, like their targeted therapy for renal cancer," Shak said.
Pfizer markets the drug Sutent, a kinase inhibitor indicated for advanced renal-cell carcinoma. The company has not released any details on whether a predictive test for renal cancer would accompany Sutent or another drug in its pipeline.
"We will define the next steps [of this collaboration], based on the results of the study," Shak said.
Genomic Health is also conducting studies for a test for ductal carcinoma in situ, which is slated for launch in 2011; and developing a prostate cancer test with a projected launch in 2014. Company officials have previously indicated that the company may in the future release a second-generation breast cancer test that includes new genetic markers.
"We are doing studies to explore whether the addition of new genes would further enhance the value of the Oncotype DX breast cancer test," Shak said. "It's early and we don't have any specific plans as to launch."