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whose tumors expressed high levels of PD-L1, especially when tumor-infiltrating immune cells expressed the ligand (Nature 2014;515:563–7; doi:10.1038/ nature14011). “Preexisting immunity is necessary for tumor response,” Herbst said. But PD-1 pathway blockade can work even when tumors do not express PD-L1, he said (http://meetinglibrary.asco.org/ content/115865-132).

Combination Treatments Researchers are excited about combining anti–CTLA-4 and anti–PD-1/PD-L1 immunotherapies. Many trials are under way, with a few completed. In an update of a phase I  study presented at the June 2014 American Society of Clinical Oncology meeting, researchers discussed the concurrent combination of ipilimumab and nivolumab in 53 melanoma patients (http://meetinglibrary.asco.org/ content/126008–144). One- and 2-year survival rates were 82% and 75%, respectively, about double compared with either drug alone. Clinical activity was similar to that in earlier reports, except that complete responses rose to 17%. The combination showed similar effects in patients regardless of BRAF mutation status. At 9  months, 42% demonstrated an 80% or greater tumor reduction, and the median duration of response was not reached. However, 53% of patients had grade 3/4 side effects, including liver abnormalities, which were mostly manageable and similar to what researchers see with ipilimumab alone. “While this is a small trial, that is very impressive 2-year survival data,” primary investigator Sznol said. Whether sequential or concurrent drug administration is better is an open question that will be answered with randomized trials, including the phase III CheckMate-067 study under way. In addition to combining PD-1 inhibitors with chemotherapies, scientists are

exploring combinations of PD-1 inhibitors with cancer vaccines, radiation therapy, antiangiogenic drugs, and tyrosine kinase inhibitors, Topalian said. In November, three drug companies agreed to evaluate MEDI4736, an anti–PD-L1 drug, with ibrutinib, an oral Bruton tyrosine kinase inhibitor that targets malignant B cells, in follicular lymphoma and diffuse large B-cell lymphoma. Jennifer A.  Wargo, M.D., assistant professor of surgical oncology at the University of Texas M.  D. Anderson Cancer Center in Houston, is investigating the use of checkpoint inhibitors with BRAF inhibitors in melanoma. Her rationale is that BRAF inhibitors increase expression of melanoma antigens and lower expression of immunosuppressive cytokines. These drugs also have a rapid but short-term effect on the tumor microenvironment, increasing dense CD8 cytotoxic T-cell infiltration of tumors for about 14 days. She set out to determine whether PD-1 checkpoint inhibitors might extend this effect. In human melanoma samples and mouse models of melanoma, Wargo explored the combination’s effects. In mice, it improved survival and delayed tumor growth more than either drug alone, and in both mice and humans it increased intratumoral CD8 cell density, as well as these cells’ production of the antitumor cytokines interferon γ and tumor necrosis factor α (Cancer Immunol. Res. 2014;2:643– 54; doi:10.1158/2326–6066.CIR-13–0215). “We found that the immune response to BRAF inhibition was early and transient but that T-cell infiltrate and an improved CD8:T-regulatory cell ratio could be sustained by adding an immune checkpoint blocker,” Wargo said. Researchers are hopeful that the discovery of additional ­ drug synergies will further increase survival. © Oxford University Press 2015. DOI:10.1093/jnci/djv141 First published online May 9, 2015

Understanding Random Cancers By Susan Jenks An analysis showing a striking statistical correlation between how often stem cells divide and cancer means that chance sometimes plays a powerful role in cancer’s development.

But that finding does not diminish the need for primary prevention, the study’s investigators said. Widely misinterpreted, the study (Science 2015;347:78– 81; doi:10.1126/science.1260825) found

that random mutations in genes during normal cell division account for twothirds of variation in cancer risk—not for two-thirds of all cancers. Individual cancer risk, the researchers said, probably

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“In our 2012 study in five types of cancer treated with an anti–PD-1 antibody, we saw a significant but imperfect correlation with PD-L1 expression and activity in a subgroup of patients,” Topalian said (N. Engl. J.  Med. 2012;366:2443–54; doi:10.1056/NEJMoa1200690). The same was true in a study she conducted in 2014 (Clin. Cancer Res. 2014;20:5064–74; doi:10.1158/1078-0432.CCR-13–3271). “While tumor PD-L1 expression reflects an immune-active microenvironment, there are still patients who are PD-L1 negative but do respond,” she said. Not wanting to shut out such patients who may still benefit from these drugs, Topalian said, “biomarkers are not ready for prime time yet.” For melanoma, Ribas sought to understand why only 30% of patients with melanoma responded to pembrolizumab. so he looked for biomarkers to help explain this. In a trial of 46 patients with advanced disease who took this drug and underwent biopsies before and after treatment, he found that the determining factor of response was whether patients had preexisting CD8 cytotoxic T cells at the invasive margin of their tumors (Nature 2014;515:568–571doi:10.1038/ nature13954). “These preexisting cells led to a greater CD8 response in treatment,” Ribas said. The presence of those cells indicates preexisting immunity, which is necessary for tumor response, he said. Ribas also noted that as an indirect marker of the adaptive immune response, PD-L1 is not a static biomarker, and its expression may thus fluctuate— one reason that it is not always a reliable biomarker. The presence of preexisting CD8 cells at the tumor site may be a better marker in melanoma, he said. In the same issue of Nature, Roy S.  Herbst, M.D., Ph.D., Ensign professor of medicine and professor of pharmacology at the Yale Cancer Center in New Haven showed that across tumor types, responses occurred in patients

not, because both carry relatively low predictability.

“We can’t say anything about specific cancers from our study. But in no way, by any stretch of the imagination, are we saying that people should avoid [reducing] risky behaviors.” Follow-Up Musings Vogelstein and Tomasetti released 10 pages of follow-up “musings” to address some statistical and technical issues that arose among their scientific colleagues (published online Jan. 21). One issue concerned using the term bad luck to describe random genetic mistakes at the cellular level. The researchers chose the term to distinguish random errors beyond our control from those directly linked to environmental carcinogens, which in principle are preventable. And although inherited mutations might be considered bad luck as well, they said, these mutations differ from a mechanistic standpoint and might be preventable in the future with nascent technologies. Otis Brawley, M.D., chief medical officer of the American Cancer Society (ACS), said he does not dispute that some cancers result from bad luck, even when individuals do everything right to prevent them. In his own practice, he’s treating several 50-year-old women who followed preventive advice to the letter yet now deal with metastatic disease. Nevertheless, Brawley described the study as “the glass half-empty” because it focuses on cancer’s randomness rather than the many lifestyle factors we can control. ACS estimates that individuals can prevent 50%–60% of all cancers by changing or eliminating harmful risk behaviors. Research has tied tobacco use to one-third of all cancers, whereas another third has been linked to obesity, high caloric intake, and lack of physical activity, with some overlap. “This is a great paper for molecular biology,” Brawley said. “It shows the more a cell divides, the more apt it is to be

corrupted and headed down the pathway to cancer.” But ACS’s greatest concern, given public misunderstanding, he said, is that “people are going to say, ‘there’s nothing I can do to prevent cancer,’ and secondly, why invest money to promote public health?” Barnett S. Kramer, M.D., director of the National Cancer Institute’s division of cancer prevention, voiced similar concerns. And, though he described the study as carrying an interesting twist with its mathematical Bert Vogelstein, M.D. model to measure this variable cancer risk, he said, issues exist on several levels. One issue: The investigators took data that others had already published to estimate total stem cell mutations. Another, he said, is equating bad luck with random mutations during DNA replication. These stochastic processes, as they are called, occur in all biological processes and even physical ones, carrying precise definition. “An atom of uranium decaying is not a matter of bad luck,” Kramer said. In comparison, the term bad luck implies “it’s your fate, over which there’s no control,” he said, even though most cancers are highly preventable. Just avoiding the sun’s UV rays can make a huge dent in skin cancer incidence, Kramer said, whereas not smoking can prevent some 85%– 90% of lung cancers. Also, even when a cancer technically might be beyond one’s control, such as inheriting a genetic susceptibility to colon cancer, Kramer said, strategies to try to modulate cancer risk exist. Vigilant screening is one tactic; the eventual removal of the colon is another. And in men, nonsteroidal anti-inflammatory drugs can reduce the number of polyps to reduce risk, as well, he said. “We’re always looking for strategies to lower the risk over and above what the mutations are,” Kramer said.

Staying on Message At the community level, “everyone’s asking about the study,” doctors and patients alike, according to Ravi Shankar, M.D., president and medical director of the Cancer Care Centers of Brevard in Melbourne, Fla.

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results from the cumulative effect of “bad luck, bad genes, and bad environment.” Random DNA mutations occur over a person’s lifetime during normal cell division at rates that have nothing to do with heredity or environment, said Bert Vogelstein, M.D. He cowrote the study with Cristian Tomasetti, Ph.D., both of Johns Hopkins University School of Medicine in Baltimore. “We can’t say anything about specific cancers from our study,” said Vogelstein, the Clayton Professor of Oncology and codirector of Hopkins’s Ludwig Center. “But in no way, by any stretch of the imagination, are we saying that people should avoid [reducing] risky behaviors.” One perspective also lost amid the outpouring of media attention, he said, was the study’s comforting message to those cancer has stigmatized, especially parents of afflicted children who somehow feel to blame. “We’ve received numerous messages to this effect,” he said, “Not knowing what causes a child’s cancer gives parents a lot of guilt.” In their analysis, Vogelstein and Tomasetti, assistant professor in the division of biostatistics and bioinformatics, took published data on the number of stem cell mutations that occur in 31 tissues and plotted them against lifetime cancer incidence rates. They found a surprisingly robust, but by no means perfect, statistical correlation across tumor types and classes. For example, the theory did not explain certain epidemiologic observations, such as why glioblastomas occur more commonly than small intestinal cancers, despite many more stem cell divisions occurring in the small intestine. Other statistical correlations, however, matched up nicely, confirming what scientists have long known: Some tissues are far more cancer prone than others. But the researchers left out of their mathematical model two of the most common cancers: breast and prostate. Vogelstein said no published data on stem cell divisions in these cancers yet exist because of a lack of technologic capability. Many data generated for the article describing their results became available only in the last few years, he said. Whether including breast and prostate cancers in the mix might have affected the study’s findings poses an interesting epidemiologic question that several investigators have asked, according to Vogelstein. He said he suspects that including those cancers would

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Shankar, who previously worked as a radiation oncologist at H.  Lee Moffitt Cancer Center in Tampa, described the study as interesting, but just part of the cancer picture that continues to emerge. The research process, Shankar said, resembles the Indian tale of six blind men asked to describe an elephant. While one

grabs the tail and says the elephant looks like a snake with its hat on, another grabs the middle and says it feels like a rough blanket, and so forth. Similarly, piecemeal progress occurs in understanding cancer, he said, which is why he’s not surprised that environmental and genetic risk explains only a certain amount of

cancer—or that some cancer is beyond our control. Still, the public-health message should not change, he said. “We need to do whatever we can do to reduce our personal risk.” © Oxford University Press 2015. DOI:10.1093/jnci/djv144 First published online May 9, 2015

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Colorectal Cancer: To Stack or Sequence Therapy? By Anna Azvolinsky the more intense regimen statistically significantly improved OS by 4  months (from 25.8 months in the control arm to 29.8 months; p = 0.030). “Two other recent studies, the FIRE-3 and Cancer and Leukemia Group B (CALBG) 80405 phase III trials, also reached a median OS of 30 months—and using a more gentle approach without a triplet chemotherapy combination,” Grothey said.

similar in either the bevacizumab or the cetuximab arm (J. Clin. Oncol. 32:5s, 2014 [suppl.; abstr. LBA3, http://meetinglibrary.asco.org/content/126013–144]). About 73% of patients received FOLFOX rather than FOLFIRI as the chemotherapy backbone. “Because we can achieve a 30-month median OS with a less intensive therapy, the [TRIBE results] are not very exciting,” Grothey said.

“My approach is to use

Sequencing or Stacking?

more intense treatment

“The TRIBE study indicates that the FOLFOXFIRI regimen improves the response rate and OS compared to FOLFIRI, but at the expense of greater side effects,” said Neal Meropol, M.D. Meropol is chief of the division of hematology and oncology at University Axel Grothey, M.D. Hospitals Case Medical Center and associate director of clinical research at the Case Comprehensive Cancer at Case Western University in Cleveland. He also was not involved in the trial. “The regimen is clearly more toxic than the chemotherapy regimens currently used in the U.S.” More patients had grade 3 or 4 neutropenia (50% compared with 20.5%), peripheral neuropathy (5.2% compared with 0%), stomatitis (8.8% compared with 4.3%), and diarrhea (18.8% compared with 10.6%), in the FOLFOFIRI group than in the control group. In the United States, FOLFOX is the most commonly used chemotherapy regimen for CRC.

when needed and back off when the tumor is controlled. We recognize that cancer is a chronic disease that requires chronic therapy.” The FIRE-3 first-line metastatic CRC trial showed that FOLFIRI plus cetuximab (Erbitux), an antibody against the epidermal growth factor receptor, yields a survival advantage of 3.7 months over treatment with FOLFIRI plus bevacizumab for patients with wild-type KRAS tumors (Lancet Oncol. 2014;15:1065–75). The PFS and response rates were similar in both therapy arms. The CALGB 80405 study also compared outcomes of FOLFIRI and cetuximab with those of FOLFIRI plus bevacizumab in previously untreated metastatic CRC. Patients in each treatment arm could also have been treated with leucovorin, fluorouracil, and oxaliplatin (FOLFOX). Median OS and PFS were

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Patients with previously untreated metastatic colorectal cancer (CRC) who received a triplet combination chemotherapy plus bevacizumab (Avastin) had a 25% lower risk of progression than those treated with a dual combination chemotherapy plus bevacizumab (N. Engl. J. Med. 2014;371:1609–18 and J. Clin. Oncol. 2015;33 (suppl. 3; abstr. 657, http://meetinglibrary.asco.org/content/139397-158). Researchers presented these findings of the Triplet plus Bevacizumab (TRIBE) study at the 2015 Gastrointestinal Cancers Symposium in January. The median progression-free survival (PFS) was 12.1  months in the leucovorin, fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab arm, compared with 9.7  months in the fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab control arm (p  =  0.003). The rate of response, 65%, was also higher in the triplet therapy arm than the control arm’s 53% (p  =  0.006). But this doesn’t mean that this regimen should now be the new standard of care, said Axel Grothey, M.D., oncologist at the Mayo Clinic in Rochester, Minn., who was not involved in the study. “The median overall survival was similar in both treatment arms, “Alan Venook, M.D., professor of medicine at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, who was also not part of the study, agreed. “This is not a sea change and not for all advanced CRC patients. It’s an effective regimen, but I’m not sure it is better than other options.” In the initial analysis reported in the New England Journal of Medicine, the difference in overall survival (OS) was not statistically significant (p  =  0.054). But after a median follow-up of 48.1 months,

Understanding random cancers.

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