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ASCO Studies Enable Nuvera Biosciences to Advance Breast Cancer Dx Development

Nuvera Biosciences is in the process of developing two diagnostic tests to help determine the appropriate treatment for breast cancer patients, while two studies presented at the American Society of Clinical Oncology’s annual meeting earlier this month helped to further validate the company’s approach.
According to Nuvera President Nandan Padukone, the company is developing NuvoSelect eRx, a 200-gene index for breast cancer patients who experienced a good outcome from endocrine therapy, and NuvoSelect cRx, a 207-gene predictor of taxane-based chemotherapy response.
While the company has yet to say when it expects to begin marketing the tests, Padukone told Pharmacogenomics Reporter this week that Nuvera intends to introduce the NuvoSelect tests initially for research use.
He said that researchers at partner MD Anderson Cancer Center will use these assays later this year under an IRB-approved clinical protocol to assign treatments to patients. “We also expect that other cancer centers who have expressed similar interest may do so within their respective institutions early next year,” he added.
At the ASCO meeting in Chicago, results from studies presented by Pusztai et al. and Hatzis et al. used Nuvera’s assays, and according to the company, further advance the clinical development of the products.
The first study, lead by Lajos Pusztai, associate professor of medicine at MD Anderson Cancer Center, applied several different predictors, including Agendia’s MammaPrint along with Affymetrix’s U133A GeneChips, to predict disease prognosis. Researchers also used Ipsogen's Genomic Grade index, as well as Nuvera’s 200-gene endocrine sensitivity index and its 207-gene clinical phenotype-specific chemotherapy response predictor. They used these tools in the same clinical samples from two cohorts with a total of 427 breast cancer cases.
“The premise of the study is that it is important to have therapy-based diagnostics over and above prognostic tests that just direct patients whether they ought to have therapy or not,” Padukone said.
The second study, led by Nuvera’s vice president of technology Christos Hatzis, described the development of molecular phenotype-specific predictors of pathologic response to preoperative T/FAC chemotherapy in ER-/HER2-negative and ER-positive/HER2-negative breast cancer tumors.
Nuvera has not explicitly said it plans to clear its tests through the US Food and Drug Administration. Padukone noted that Nuvera is “mindful of regulatory requirements and [is] developing strategies to be in conformance with likely expectations. 
“We intend to work within the regulatory environment to find the best and most timely path to market,” Padukone said. “We do have very significant interest from cancer centers to study prospective use of the tests under a clinical research setting.”
Pusztai et al.
Using multiple gene-expression assays, researchers led by Pusztai concluded that they could simultaneously predict the risk of recurrence and sensitivity to endocrine-based drugs and chemotherapies from a single specimen. As a result, they said, the findings could “allow more personalized treatment decisions in the future.”
In the study, the researchers found that patients predicted to be at low risk for recurrence were mainly sensitive to endocrine therapy, but about 12 percent of them may also be sensitive to chemotherapy. Meanwhile, between 40 percent and 50 percent of high-risk patients were predicted to be insensitive to existing therapies.
Gene-expression profiling results generated with Affymetrix U133A GeneChips were available for 198 stage I-II, lymph node-negative patients who received no systemic adjuvant therapy and for 229 stage I-III, HER-2 normal breast cancer patients who received preoperative paclitaxel/FAC chemotherapy.
Researchers applied the Genomic Grade prognostic index and used Nuvera’s 200-gene endocrine sensitivity index and a 207-gene clinical phenotype-specific chemotherapy-response predictor for each case. Agendia’s MammaPrint prognostic prediction results were available on the 198 cases.

“So, in the cohort of 198 patients, the only way you would know whether someone would benefit from administration of endocrine or chemotherapy is by having the assay scores from NuvoSelect tests, not from MammaPrint alone.”

According to Padukone, this study is significant because it shows that “even if patients are [identified as] low risk by a prognostic test, such as MammaPrint, a pretty high fraction, greater than 40 percent, are sensitive to therapy.”
In the study, for the 198 cases in which prognostic data were available, 32 percent were determined to be low-risk patients. Among this subset, 8 patients, or 12 percent, were predicted to be highly chemotherapy sensitive, and 20 patients, or 31 percent, were predicted to be highly endocrine sensitive.
“Having this information creates more options for the patient and physician and might be important to have,” Padukone said.
Among the high-risk patients, 69 patients, or 51 percent, were predicted to be highly sensitive to chemotherapy, while 8 patients, or 6 percent, were highly sensitive to endocrine therapy; 57 patients, or 42 percent, showed low sensitivity to both modalities.
“So, in the cohort of 198 patients, the only way you would know whether someone would benefit from administration of endocrine or chemotherapy is by having the assay scores from NuvoSelect tests, not from MammaPrint alone,” Padukone said.
Although a recent report released by an HHS advisory committee suggests that physicians may be using Agendia’s prognostic test off-label to guide breast cancer treatment, Agendia has said that it is not aware of such use [see PGx Reporter 06-04-2008].
MammaPrint “was developed with patients who did not receive any therapy so that the distinction of high and low risk can point to whether a patient should be considered for therapy at all,” Padukone explained. “Based on their clinical design and the label, it has not been tested on patients who have received some form of therapy, and therefore, inherently [it] is unable to distinguish whether a patient would be likely to respond to endocrine therapy or chemotherapy even if identified as high risk.”
In the neoadjuvant data, 82 patients, or 36 percent, for whom prognostic data was not available, were determined by the Genomic Grade index to be at low risk for cancer recurrence. Ten of these patients, or 12 percent, were predicted to achieve excellent pathologic response. Sixty-one, or 41 percent, of the high-risk patients were predicted to have “excellent pathological response,” and 54 percent of the poor prognosis group was predicted to be insensitive to both endocrine therapy and chemotherapy.
“These findings are exciting as they suggest that different predictive tests that evaluate the risk of recurrence and therapeutic response can be used conjunctively on a single tumor sample to help physicians gain a clearer picture of a patient’s treatment needs,” Pusztai said in a statement released by Agendia. “The information gained from multiple predictive tests can be used to help physicians make more personalized decisions related to patient management.”
This study involved researchers from Nuvera, MD Anderson Cancer Center, a collaborator from Agendia, and contributors from the TransBIG study, also known as the “Translating molecular knowledge into early breast cancer management building on the Breast International Group network for improved treatment tailoring.”
Hatzis et al.
In Hatzis et al. researchers described the development of a phenotype-specific chemotherapy-response predictor in ER-/HER2-negative and ER-positive/HER2-negative breast cancer tumors, using a classification system called “residual cancer burden,” as well as Nuvera’s 207-gene predictor of taxane-based chemotherapy response.
In this study, the ER-/HER-negative predictor included 116 probes and had 78 percent sensitivity, 77 percent specificity, and 78 percent positive (PPV) and negative (NPV) predictive values and an area under the ROC curve (AUC) of 0.85. The ER-positive/HER-negative predictor included 89 probes and had 64 percent sensitivity, 84 percent specificity, 44 percent PPV, and 92 percent NPV, and an AUC of 0.84.
With the use of the predictors, ER-/HER2-negative patients with a positive signature were found to be seven times more likely to achieve “excellent response” with T/FAC chemotherapy, while ER-positive/HER-negative cases were five times more likely.
“Prediction of excellent pathologic response (pCR/RCB- I) was significantly correlated with better distant relapse-free survival for the entire study population (p<0.001),” the study authors said in the abstract. “When cross-tested on the other clinical phenotypes, the predictive values dropped dramatically.”
In this study, the researchers counted pathologic complete response or minimal residual cancer burden as signs that patients were having desirable treatment response since these markers are associated with long-term survival.
Residual cancer burden, or RCB, is a response metric developed by Nuvera and MD Anderson that helps physicians better quantify and predict patients’ response to chemotherapy. RCB’s “value is in the ability to clearly distinguish which patients have an ‘excellent’ or a ‘very good response,’ a ‘partial response,’ or a ‘clear resistance’ or a ‘non-response,’” Padukone said. “No other metric allows this.”
Data linking measurement of the RCB as a predictor of survival following neoadjuvant chemotherapy was published in the Journal of Clinical Oncology by Symmans et al. last year. 
On Nuvera’s website, researchers from other institutions can access a calculator, in which they can plug in their patients’ tumor parameters and see what class of RCB the patients may fall in. 
“It is critical to use more definitive tools to assess tumor response so that diagnostic tests identify not only those who benefit from treatment, but also those whose tumor is intrinsically resistant” said co-author Fraser Symmans, a professor at MD Anderson’s Pathology Department, in a statement released by Nuvera.
According to Nuvera, the company is planning a prospective clinical trial at MD Anderson Cancer Center using its genomic assays to select treatment options for newly diagnosed patients. Nuvera is a start-up venture launched by MD Anderson Cancer Center.

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