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Chemotalk NewsletterChemotalk Newsletter, Vol. 93 January 1, 2016 Welcome to 2016, Everyone! YOUNGER NON-SMALL-CELL LUNG CANCER PATIENTS MORE LIKELY TO HARBOR TARGETABLE GENOMIC ALTERATIONS By Dave Levitan Patients diagnosed with nonsmall-cell lung cancer (NSCLC) at a younger age are far more likely to harbor a targetable genomic alteration than older patients, according to a new study. Poor survival in these younger patients suggests more aggressive disease. Unlike with other malignancies such as BREAST or COLON CANCER, ³NSCLC occurring in young patients is a poorly studied clinical entity,² wrote study authors led by Geoffrey R. Oxnard, MD, of the Dana-Farber Cancer Institute in Boston. ³The median age at diagnosis of NSCLC is 70 years and less than 5% of patients are younger than 50 years at diagnosis.² The study authors hypothesized that young age at diagnosis might define a population with targetable genomic alterations. They analyzed genetic data and outcomes for a cohort of 2,237 patients with NSCLC who were genotyped at Dana-Farber between 2002 and 2014. Of these, 81 patients (4%) were under the age of 40 at diagnosis; 252 patients (11%) were between 40 and 49, 597 (27%) were aged 50 to 59 years, 697 (31%) were between 60 and 69, and 610 (27%) were 70 years or older. Results of the study were published online ahead of print in JAMA Oncology. The study found that several genomic alterations were significantly associated with age at diagnosis. A total of 26% of the full cohort had EGFR mutations, but these were more common in the youngest patients (32%) and in the aged 40 to 49 years group (34%) than in older patients (P = .02). Similarly, ALK mutations were present in only 5% of the full cohort, but in 19% of the under 40 years old group and in 13% of the 40 to 49 years group, compared with 5%, 3%, and 1% of the older three groups (P < .001). KRAS mutations, meanwhile, were more common among the older patients; they occurred in only 9% of the youngest and 13% of the second youngest group, compared with 26%, 34%, and 27% of the older groups (P < .001). There were trends toward more ERBB2 (P = .15) and ROS1 (P = .10) mutations in younger patients, but no such trend was seen for BRAF V600E mutations (P = .43). Overall, patients diagnosed at age 50 or younger had a 59% increased chance of harboring at least one targetable alteration. Patients in the youngest group and the oldest group had the lowest median overall survival (P < .001). A univariate analysis showed there is a significant relationship between the presence of targetable genotypes and survival (P < .001). Patients who had a targetable genomic alteration who received targeted therapy did have improved survival, while those with such an alteration who did not receive targeted therapy did not. In an accompanying editor¹s note, Howard West, MD, wrote that the conclusions to this study are limited by referral bias, meaning younger patients and those with identified mutations likely gravitated toward a high-profile Cancer Center such as Dana-Farber. Still, he wrote that ³this work provides an invaluable early step toward identifying the youngest patients with lung cancer as a subgroup that deserves more study and special consideration as a distinct clinical demographic most likely to benefit from a more extensive search for targetable driver mutations.² * * * DETAILING FINANCIAL LINKS OF DOCTORS AND DRUG MAKERS Pharmaceutical and device makers paid doctors roughly $380 million in speaking and consulting fees, with some doctors reaping over half a million dollars each, during a five-month period in 2013, according to an analysis of federal data. Other doctors made millions of dollars in royalties from products they helped developed. The data sheds new light on the on murky financial ties between physicians and the health care industry. From August to December 2013, drug and device companies made 4.4 million payments to more than half a million health car professionals and teaching hospitals -- adding up to about$3.5 billion. The lucrative arrangements are just some of the findings of the online database, which provides one of the most detailed looks at the payments health care professionals receive from drug and medical device companies. The website also allows consumers to find information about their own doctors to determine whether they might have conflicts of interest. The site, required by the recent health care law, is part of a broader push for transparency. Proponents say such disclosures are an important tool to help limit drug and device makers' influence on doctors. But the website is being questioned by the industry, which says that technical problems and data inaccuracies limit its value. For example, about 40% of the records do not tie back to a specific professional or teaching hospital, accounting for 645 of the overall payments. Under the new requirements, all manufacturers of drugs, medical devices and medical supplies that have at least one product covered by Medicare or Medicaid must report payments or gifts they make to doctors and teaching hospitals. This can be as seemingly trivial as a bag of bagels -- all payments above $10 are included -- or as lofty as a research grant. It also includes meals, travel expenses and speakers' fees. Group-purchasing organizations, which serve as middlemen between health care providers and manufacturers, also must disclose doctors' ownership and investment interests in their companies. The data is likely to raise questions about doctors' financial interests. Several studies and reports, including one by The New York Times, have shown that doctors with relationships to industry are more likely to prescribe expensive and potentially inappropriate drugs. "When you look at why do drug companies and device companies make gifts and offer consulting payments and honoraria to physicians, the main goal is to influence prescribing practices," said Dr. Michael Carome, the director of Public Citizen's Health Research Group. "The interest of those companies is to improve their financial bottom line, and not necessarily represent the best interest of patients." While some relationships may leave doctors open to scrutiny, other ties are important for innovation. Drug and device makers say they regularly consult with doctors to help them decide where the need is the greatest, and doctors conduct clinical trials that help get products approved. Research, for example, accounted for nearly $1.5 billion of payments during the reporting period. Companies spent an additional $302 million on royalties and licenses money that is paid to doctors and teaching hospitals for their role in developing companies' products. Royalties created lucrative relationships for doctors, particularly in fields that are highly dependent on medical devices. Dr. Steven S. Burkhart, a San Antonio orthopedic surgeon who has written a textbook for surgeons called "A Cowboy's Companion" received more than $7 million in royalties travel expenses and speaking engagements, mostly from Arthrex, which makes supplies for orthopedic surgeries, during the reporting period. He didn't not return a call for comment. Other orthopedic surgeons were also among the highest-paid doctors. Dr. Chitranja Ranawat, a Manhattan orthopedic surgeon, received nearly $4 million on payments from DePuy Synthes, the orthopedic unit of Johnson & Johnson. Sometimes a large royalty payment contributed to the bulk of a company's reported spending. Genentech the United States division of the Swiss pharmaceutical company Roche, reported $210.2 million in payments during the last five months of 2013, according to a company spokeswoman. Company officials said a large chunk of that total -- $122.5 million -- were royalty payments that went to the City of Hope, a California cancer hospital, for sales of several products, including the drugs Herceptin, Rituxan and Avastin. "We have very close relationships with physicians who use our devices in the field, and those physicians bring back valuable ideas and help us develop new improvements", said Christopher L. White, general counsel of AdvaMed, an industry trade group for device makers. The website comes with significant caveats in part because it is rather clunky. To look up an individual doctor, visitors to the home page had to click to another page, open a database and then scroll through an unwieldy series of data fields to view basic payment information. The data is also incomplete. Besides the unidentified payments, companies were permitted to delay the release of information about research payments for products that haven't been approved, or for new uses of existing products. The Centers for Medicare and Medicaid Services, which is overseeing the release, said about 190,000 research payments during the August-to-December 2013 period were not made public for this reason. when the website went live, one large payment to a doctor, a Boston neurologist, turned out to be an error. The data showed that Dr. Reisa Sperling, an Alzheimer's researcher at Harvard Medical School, received a payment from the drug company Boehringer Ingelheim totaling more than $150,000 for travel expenses in September of 2013. Bur Dr. Sperling said she only did a one-day consulting assignment for the company in Boston and was paid no more than $5000. A spokeswoman for Boehringer Ingelheim confirmed that the amount was incorrect and said the company had previously notified the federal government of the error. She said the data released did not include the corrected information that the company provided. Dr. Robert M. Wah, president of the American Medical Association, said his members had reported a variety of problems with the website; they were granted advance access to the data to verify its accuracy. Some had trouble logging on. Others found the information to be wrong. Only about 26,000 health care professionals registered to check their information beforehand, out of about 546,000 in the database officials said. The disclosure rules apply not just to medial doctors but also to dentists, chiropractors, podiatrists and optometrists who are legally authorized to practice. Dr. Raed Dweik, a Cleveland Clinic lung specialist, said he was surprised to se that they drug maker Boehringer Ingelheim had reported that he had received a lunch worth about %40 during a presentation at the clinic. Dr. Dweik, who is chairman of the clinic's conflict of interest committee, said he had spoken at the event but deliberately skipped the lunch. He said he believed the company simply divided the number of event participants by the cost of the meal and did not check who had attended the lunch. "I'm very sensitive about this," Dr. Dweik said, adding that other drug companies had also previously marked him down for lunches he did not eat. "I make it clear ahead of time that I'm not doing it." Dr. Dweik said he disputed the payment with the federal government, and it does not appear in the database. His personal experience, he said, led him to warn other physicians at the Cleveland Clinic to scrutinize their records. "I think the concept itself is really good," he said. However, "the problem with this website is one has no context," he added. "You don't know if this relationship is legitimate or not, and the bigger problem is the inaccuracies." * * * T-CELLS THAT RECOGNIZE HER2 RECEPTOR MAY PREVENT HER2+ BREAST CANCER RECURRENCE Recurrence of HER2-positive BREAST CANCER after treatment may be due to a specific and possibly cancer-induced weakness in the patient's immune system -- a weakness that in principle could be corrected with a HER2-targeted vaccine -- according to a new study from the Perelman School of Medicine at the University of Pennsylvania. Results of the study show that T cells from patients whose breast cancer had recently recurred showed far weaker response to the HER2 receptor protein, compared to T cells from patients whose breast cancer had not recurred over a long period following treatment. The study, published in JAMA Oncology, suggests that patients with HER2-positive breast cancer -- which accounts for roughly 20 percent of the 260,000 invasive breast cancers diagnosed in the US each year -- might someday undergo immune status monitoring with blood tests before, during and after treatment, to allow physicians to gauge the risk of recurrence, and possibly to reduce that risk with therapies that boost anti-HER2 immunity. "We know that it's not a fixed immune defect, because we have several clinical trials open where we're vaccinating people and can restore anti-HER2 responsivity," said the study's senior author Brian J. Czerniecki, MD, PhD, the Rhodes-Harrington Professor in Surgical Oncology at Penn and the co-director of the Rena Rowan Breast Center at Penn's Abramson Cancer Center. An Immune Marker for Recurrence Risk Czerniecki and colleagues have been investigating the role of the immune system in breast cancer, and the potential of cancer vaccines, for most of the past two decades. Their most recent research has focused on the T-helper type 1, or Th1, immune response in cancer, in which 'helper' T cells mobilize killer cells to attack cancer-related targets. In the new study, the Penn team, including first author Jashodeep Datta, MD, a general surgery resident and a member of the Czerniecki laboratory, isolated immune cells from 95 women with invasive HER2-positive breast cancer, and analyzed the cells' ability to mount a Th1 response against the HER2 growth factor receptor protein. HER2-positive breast cancer cells overexpress the HER2 receptor to help drive their rapid proliferation. The team found that, by a standard measure, the cells from women with recently recurrent cancer that had not yet been re-treated had only about a tenth of the anti-HER2 responsivity compared to that seen in women whose HER2+ breast cancer had not recurred for at least two years following treatment. Looking at anti-HER2 responsivity across all the patients, the researchers found that patients with the least amount of responsivity had experienced only 47 disease-free months after treatment, on average, compared to 113 disease-free months for the patients in with the most responsivity. The low anti-HER2 responsivity seen in the women with recurrent cancer was not part of a broader immune suppression. "We detected no other immune deficit -- just the deficit in the anti-HER2 response," Czerniecki said. The findings complement those from two other studies published earlier this year by Czerniecki and his colleagues. In one, the scientists found that the Th1 responsivity against HER2 tends to vary strikingly from high responsivity in cancer-free and early-stage HER2-positive breast cancer patients, to low responsivity in advanced HER2-positive breast cancer patients. In the other study, patients whose tumors shrank during standard pre-surgery drug treatment had much stronger anti-HER2 responsivity, compared to patients whose tumors responded less completely to that drug treatment. How patients lose their anti-HER2 responsivity during the formation and growth of a HER2-positive tumor isn't yet clear. "The thinking is that the patient's anti-HER2 T cells somehow become exhausted and die or otherwise stop responding," Czerniecki said. "We're trying to determine the mechanism, but we already know that we can 'fill the tank' with vaccines to restore that specific responsivity to HER2." In addition to conducting ongoing mechanistic studies and vaccine trials, Czerniecki says his team hopes to confirm the association between anti-HER2 responsivity and cancer recurrence risk in larger clinical trials that would track patients' immune status over time. * * * And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com. Elaine Jesmer
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