Chase Doyle

Interim analysis of a clinical trial of multiplex gene testing for inherited cancer risk suggests that fears of unnecessary surgery or adverse psychological effects associated with testing may be unwarranted, according to data presented during the 2016 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of over 30,000 oncology professionals in Chicago.

Researchers reported that patients undergoing genetic testing for pathogenic mutations did not demonstrate increased rates of prophylactic surgeries, intrusive thoughts or regrets. Patients who were positive for genetic mutations were also more likely to advise relatives to get tested, suggesting that they understood the implications of test results.

“After multiplex testing of diverse patients, few reported preventive surgery at three months,” said Allison Kurian, an associate professor of Medicine and of Health Research and Policy at Stanford University School of Medicine, and director of the Stanford Women’s Cancer Genetics Clinic. “In addition, patients testing positive for a variant of uncertain significance (VUS) had no more distress, regret or uncertainty than negative patients.”

As Kurian explained, the use of multiplex gene panels, which can simultaneously test between 15 and 40 genes, is on the rise, leading to a significant increase in the pathogenic detection rate of mutations in selected patients. However, this heightened sensitivity comes with the added cost of complexity.

“Sequencing more genes increases the likelihood of finding VUS, which can be frustrating for both patients and clinicians,” said Kurian. “The key question here is, does multi-gene panel testing cause distress or inappropriate intervention?”

Researchers in three cancer genetics clinics, LA County, University of South California and Stanford University, conducted a prospective cohort study of a multi-gene panel, sequencing the following genes: APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11 and TP53.

Patients were eligible for the study if they had no prior genetic testing, were 18 years or older and had at least a 2.5 percent probability of carrying one of the mutations on the panel.

Participants were surveyed at entry, and then three, six and 12 months after receiving their results. These surveys included a validated instrument, the Multidimensional Impact of Cancer Risk Assessment (MICRA) scale, to measure distress.

Kurian and her colleagues aim to enroll 2,000 patients, but planned for an interim analysis after 1,000.

Of the 1,000 participants, mostly females, 11.6 percent tested positive for a pathogenic mutation, 51.9 percent were negative and 36.5 percent had a VUS in any of the genes. Kurian noted the study was made up of a diverse population including non-Hispanic whites, non-Hispanic blacks, Hispanics and Asians.

Analysis of post-testing surgical procedures showed that the rate of bilateral mastectomy at median follow up of three months was low. In general, these were treatment mastectomies, said Kurian, with only one in the VUS category being reported for cancer prevention.

Researchers also observed low rates of prophylactic hysterectomy and oophorectomy, with the majority of both types of operations being for cancer treatment.

Patients were then asked to report their experience in relation to genetic testing, grouped by the categories of positive, VUS and negative. According to survey results, adverse psychological effects were minimal.

“At least at this early stage, we don’t see much evidence of harm in terms of high prophylactic surgery rates or intrusive thoughts or regret,” said Kurian. “Most patients never or rarely had thoughts of cancer affecting daily activities, never regretted testing and wanted to know all results, even those that doctors do not fully understand.” Results of the validated MICRA questionnaire were divided into three components: distress, uncertainty and positive experiences.

“As could be expected, patients who tested positive had slightly higher distress scores compared to the negative and VUS groups. However, uncertainty was not so different, and there were only slightly lower positive experiences of testing among patients who test positive for a mutation,” said Kurian.

In addition, scores of VUS patients did not differ significantly from those of negative patients for any MICRA components.

“It appears that the VUS patients were really behaving more like the negative patients and not like the positive patients in this setting,” Kurian reported.

Finally, researchers asked patients whether they notified their relatives about their results and whether those relatives went on to have a genetic evaluation or testing.

Interim analysis showed that patients who had a positive pathogenic mutation encouraged relatives to have genetic testing significantly more than VUS or negative patients.

“We think that notification and testing of relatives at this early stage appears relatively appropriate,” said Kurian. “Patients who have a pathogenic mutation were more likely to tell their relatives to test, which is what we’d hope to see.”

That being said, with a median of only 3.3 months, follow-up time remains short at this stage of the study. “It will be interesting to see if rates of prophylactic surgery, distress or regret rise as the trial progresses,” said Kurian. “And what will happen if these VUS are reclassified?”

Researchers expect enrollment of 2,000 patients to be completed by the end of the year.

Articles

Multiplex gene testing may not bring about unnecessary surgery or adverse psychological effects, according to findings from a recent study. 

Minimal Harm Associated with Multiplex Gene Testing for Inherited Cancer Risk

An analysis of patients with advanced liver cancer and elevated alpha fetoprotein (AFP) who received second-line Cyramza (ramucirumab) showed a significant improvement in overall survival (OS), according to data from the randomized phase 3 REACH study presented at the 2015 Gastrointestinal Cancers Symposium.

Initiated in 2010, the double-blind study enrolled 565 patients across 27 countries. Patients with advanced liver cancer, also known as hepatocellular carcinoma (HCC), were randomized to receive best supportive care plus either the VEGFR-2 inhibitor Cyramza or placebo following first-line treatment with Nexavar (sorafenib).

“After first-line sorafenib, no treatment has demonstrated a survival benefit in the second-line setting,” said lead author Andrew Zhu, MD, director of Liver Cancer Research at Massachusetts General Hospital.

In June 2014, it was announced that REACH had missed its primary endpoint of a statistically significant improvement in OS.

In an analysis of the trial results, it was observed that Cyramza treatment led to a greater reduction in the risk of death in patients with progressively higher baseline AFP values. Thus, additional analyses were conducted to evaluate the relationship between baseline AFP and Cyramza treatment. AFP is a protein made by the liver and commonly used as a biomarker for liver cancer. About two-thirds of liver cancers produce high levels of the protein.

The analyses found that with Cyramza, the median OS for patients with a higher baseline AFP was 7.8 months compared with 4.2 months for the placebo group. In contrast, for patients with a lower baseline, OS was 10.1 months with the treatment compared with 11.8 months for those receiving placebo.

“The overall survival decreases in both arms as increasing AFP thresholds were applied because these patients represent worse prognosis. However, the difference between these arms was generally in the range of 3 to 3.5 months,” Zhu said.

When asked by a member of the audience at the symposium to explain the underlying biology of this phenomenon—why patients with higher AFP levels responded to Cyramza treatment&mdash;Zhu was uncertain, but stressed the importance of finding an answer.

“This is a critical question we are actively pursuing,” he said. “We think there may be an underlying link with increased (angiogenesis), but whether this is driven by VEGF or VEGFR-2, the literature is not clear. There is mounting evidence suggesting the high AFP group is really a unique subgroup of patients with a unique genetic signature,” he hypothesized, “but this is a critical question.”

Zhu noted that further investigation of the relationship between baseline AFP level and angiogenesis inhibition was ongoing to better understand Cyramza’s mechanism of action in HCC.

“The additional AFP threshold was posthoc analysis,” he concluded. “There are no clear data yet. Patients will probably benefit between the normal and upper-limit, too, but additional study is necessary.”  

Cyramza has approved indications as a single-agent and in combination with paclitaxel to treat patients with advanced gastric or gastroesophageal junction adenocarcinoma. It is also approved in combination with docetaxel for the treatment of patients with metastatic non-small cell lung cancer. It is also currently being examined in colorectal cancer. 

An analysis of patients with advanced hepatocellular carcinoma and elevated AFP who received second-line Cyramza showed improved survival, according to data from the phase 3 REACH study.


Chase Doyle

Minimal Harm Associated with Multiplex Gene Testing for Inherited Cancer Risk

Cyramza Improves Survival in Subgroup of Liver Cancer Patients

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