Chemotalk Newsletter, Vol. 86: June 1, 2015
NEW PROMISE IN NEW CLASS OF DRUGS FOR CANCER
By Andrew Pollack
A new drug that unleashes the body's immune system to attack tumors can prolong the lives of people with the most common form of LUNG CANCER, doctors reported, the latest example of the significant results being achieved by this new class of medicines.
In a separate study, researchers said they had found that a particular genetic signature in the tumor can help predict which patients could benefit from the immune-boosting drugs.
The finding could potentially extend use of these drugs to some patients with COLORECTAL CANCER, PROSTATE CANCER and other tumors that have seemed almost impervious to the new drugs. Most of the substantial results so far with these expensive drugs have been in treating MELANOMA and lung cancer.
"If you have the signature, you should treat with these checkpoint inhibitors," Dr. Luis A. Diaz Jr., an associate professor of oncology at Johns Hopkins University and the senior author of the study on the genetic market, said in an interview, referring to the new drugs.
Both studies were discussed at the annual meeting of the American Society of Clinical Oncology, in Chicago. The study on the genetic signature was also published online by the New England Journal of Medicine.
The checkpoint inhibitors work by releasing molecular brakes, or checkpoints, that prevent the body's immune system from attacking tumors. The products on the market so far are Keytruda, which is made by Merck, and Opdivo and Yervoy from Bristol-Myers Squibb. They have been the center of attention at the oncology conference the last two years and this year should be no different.
All three drugs are approved to treat melanoma, a deadly skin cancer. Opdivo was also approved in March to treat the so-called squamous-cell form of NON-SMALL CELL LUNG CANCER, which accounts for about one-quarter of the cases of lung cancer.
The new study discussed at the oncology conference shows that Opdivo also prolongs survival for patients with NONSQAMOUS CELL LUNG CANCER, which accounts for most of the rest of the cases.
Patients who received Opdivo lived a median of 12.2 months compared with 9.4 months for those treated with the CHEMOTHERAPY drug docetaxel. Moreover, Opdivo, also known as nivolumab, had far fewer serious side effects.
Patients whose tumors produced a protein called PD-L1, which looks to be another predictor of success for certain checkpoint inhibitors, fared even better. Among just those patients, median survival was 17.2 months in the group receiving Opdivo and nine months for those getting docetaxel.
"In a randomized trial I don't think people have ever been able to see this kind of difference," said Dr. Pasi A. Janne, a lung cancer specialist at the Dana-Farber Cancer Institute in Boston, who was not involved in the study.
The trial, paid for by Bristol-Myers, involved 582 patients with advanced cancer who had already had treatment with platinum-containing chemotherapy like carboplatin. This summer, Bristol intends to apply to have Opdivo approved to trust non-squamous lung cancer.
In other studies discussed at the conference, Opdivo significantly shrank tumors in 19% of patients with advanced LIVER CANCER and Keytruda in 25% of patients with HEAD AND NECK CANCER. There is now only one drug approved for liver cancer, Nexavar from Bayer and Amgen.
Other studies have shown the checkpoint inhibitors can help some patients with KIDNEY, BLADDER, STOMACH and other forms of caner. But there have been few signs of effectiveness with colorectal, prostate or PANCREATIC CANCERS.
Why do the drugs work so well for some cancers and barely at all for others?
One thought is that lung cancer and melanoma are often caused by things that damage DNA - tobacco smoke and ultraviolet radiation. They thus "have tons of mutations, hundreds of mutations per tumor," said Dr. Diaz more than most other tumors. That might make it easier for the immune system to recognize the cancer cells as something to be destroyed.
But some cancers have even more mutations -- those with a genetic defect known as mismatch repair deficiency. This deficiency prevents the repair of changes in DNA that can arise as cells divide, allowing mutations to accumulate.
The deficiency is found in Lynch syndrome, an inherited condition that puts people at a high risk of developing cancer, particularly colorectal. Lynch syndrome accounts for about 5% of colorectal cancers. The mismatch repair deficiency is also found in about 105 of colorectal cancers that are not inherited, and probably in a few percent of many other cancers, including prostate and pancreatic, Dr. Diaz said.
To test their hypothesis, the researchers tried Keytruda, also known as pembrolizumab, in a small study on patients with advanced cancer who were no longer being helped by other treatments.
Four of the 10 colorectal cancer patients with the deficiency experienced a significant shrinkage of their tumors, according to the paper in the New England Journal of Medicine. That was seen in none of the 18 colorectal cancers without the deficiency. Tumors also shrank in five of seven, or 71%, of the patients with cancers other than colorectal that had the mismatch repair deficiency.
Colorectal cancer patients with the deficiency also lived longer than those without the deficiency, though by how much is not yet known because many are still living.
DNA sequencing revealed that tumors with the deficiency had an average of 1,782 mutations, compared with only 73 for the tumors without the defect.
One of the patients in the study, Stefanie Joho, has Lunch syndrome. Her mother had COLON CANCER at age 44, then UTERINE CANCER six years later. Ms. Joho was even unluckier, diagnosed with colorectal cancer shortly after graduating from New York University.
Two surgeries and two different types of chemotherapy failed to stop the disease. Out of options and in terrible pain despite taking high doses of a narcotic, Ms. Joho said she quit her job in New York and returned to her parents' home outside Philadelphia, where she was mostly bedridden.
But after she began receiving Keytruda in August, her tumor started shrinking. Her pain ebbed so much that she threw away her narcotics, then had to be treated briefly at the hospital for withdrawal symptoms "I haven't felt this well in four years," said Ms Joho, who is now 25.
Genetic tests for mismatch repair deficiency are commercially available. But insurers might not pay for the drugs -- Keytruda and Opdivo cost $150,000 a year -- based on such a small study. The study was paid for by Swim Across America and other charities, and the National Institutes of Health. Some of the authors have a patent pending on technology used in the study.
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RESEARCHERS DISCOVER BREAST CANCER SUSCEPTIBILITY GENE
By Lauren Evoy Davis
Specific hereditary gene mutations that cause BREAST CANCER have become well-known to the medical and patient community, and recently researchers in Canada have discovered a new gene: RECQL.
RECQL (RecQ helicase-like) is a breast cancer susceptibility gene, according to new research published in Nature Genetics. This finding underscores that more gene mutations have yet to be found, signaling an important moment in personalized treatment.
Mohammad Akbari, MD, PhD, and colleagues of the University of Toronto and the Women's College Research Institute at Women's College Hospital have linked mutations in a gene called RECQL with the onset of breast cancer among French-Canadian women, and those from Poland. The good news is that the gene mutation is rare, but unfortunately, half of those who carry the gene mutation will likely develop breast cancer during their lifetime.
The researchers used two populations and applied whole-exome sequencing of 195 patients (approximately 20,000 genes) whose family had a history of breast cancer, but lacked the commonly known BRCA1 or BRCA2 gene mutations. They identified rare, recurrent RECQL mutations in each population of women. According to Akbari and colleagues, RECQL is responsible for stalled DNA replication forks to prevent double-stranded DNA (dsDNA) breaks.
To validate their findings, the researchers sequenced the entire 14 coding exons of RECQL in 475 Polish and 475 French-Canadian patients with breast cancer who tested positive for other well-known gene mutations. Although the discovery cohort didn't have the RECQL mutations, the researchers did observe two other truncating mutations in this cohort ‹ specifically c.1667_1667+3delAGTA in two Polish patients and c.634C>T (p.Arg215*) in two French-Canadian patients.
Knowing what genetic mutations patients carry can greatly improve precision medicine and offer greater success in treating patients to achieve longer survival periods. Further research will demonstrate how common this genetic mutation is in other populations, and how research scientists can target and search for this mutation to provide the best treatment option for patients.
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And more on breast cancer:
RESEARCH WORTH WATCHING: ANOTHER LOOK AT DENSE BREASTS
It has recently been estimated that 43% of women between 40 and 74 have dense breasts on mammogram. That actually calculates out to 27.6 million women! By now we all know the limitations of mammography screening particularly when women have dense breasts. Not only does the increase in fibrous tissue around the ducts and lobules make it harder to distinguish a cancer, but also there are data suggesting that dense tissue itself may stimulate cancer growth.
For example, studies that looked at whether tamoxifen decreased the risk of BREAST CANCER in high-risk women suggested that the women whose breasts became less dense on the drug, which blocks estrogen, also had the most benefit in decreasing risk.
Twenty-two states have passed laws requiring that you be notified if your mammogram is dense. Meanwhile websites such as DenseBreast-info.org have been developed to help women understand what dense breast tissue is and what options they might have for other forms of imaging, such as ultrasound or MRI.
It is against this background that Karla Kerlikowske¹s group at the University of California, San Francisco has come out with a new effort to better determine whether and to what extent breast density increases breast cancer risk. Their new study, published on May 19, 2015, in the Annals of Internal Medicine , reviewed 831,426 mammograms from 365,426 women and calculated the interval cancer rate. (Interval cancers are invasive cancers that are found within 12 months after a normal mammogram.) They then factored in breast cancer risk using the risk calculator, which calculates risk based on five factors: age, race/ethnicity, family history of breast cancer, and breast density.
The study confirmed that women with dense breasts had a higher risk of breast cancer; however, they were able to show that the magnitude of risk also depended on the other risk factors assessed with the risk calculator. The chance of a cancer showing up after a ³normal² mammogram (an interval cancer) was highest in women with extremely dense breasts who also had a five-year risk on the risk calculator of 2.5% or greater. For these women, learning about additional imaging with ultrasound or MRI was beneficial. But for the vast majority of women who had a low five-year risk‹including those with dense breast tissue‹the risk of an interval cancer was low.
Another piece of good news that came out of the study is that the overall rate of false positives (mammogram shows something but on additional imaging or biopsy it turns out to be benign) is low, except for the women who are at extremely low risk and have dense breasts. These women had a higher rate of false positives. This confirms that mammographically determined breast density is only one factor in breast cancer risk, and that other factors need to be taken into consideration when women and their doctors are discussing additional screening.
Figuring out who can most benefit from additional screening and who will not is an important distinction in what has become a continuing debate. The more a woman knows about her breast cancer risk, the better she will be able to make decisions about her health, including breast cancer screening.*
* This study explains why almost every woman I met during my treatment who was diagnosed with late-stage breast cancer, had dense breasts, like my own.
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Finally, this story concerns the term "cure", a word I believe should be used rarely, maybe even never, when it comes to cancer:
CANCER'S SEMANTICS ISSUE
By Mikkaela Sekeres, M.D.
I had to admit I was more than a little excited to see my next patient. This was a big day, for both of us.
Five years earlier, when he was 68, he had come to the emergency room, feeling terrible. His white blood cell count was higher than his age, and he was profoundly anemic -- really, to a degree that was almost incompatible with life. He was transferred to our hospital, where we performed a bone marrow biopsy that clinched the diagnosis of ACUTE LEUKEMIA.
:you sat on my bed," he said to me, "and you gave it to me straight. You laid out my options." He stared up toward the fluorescent lights in the clinic room, thinking back to this seminal moment. His wife sat next to him, focusing on his face, her smile frozen as she probably thought about that same moment from her own perspective.
For people approaching their eighth decade the decision of whether or not to take CHEMOTHERAPY for leukemia is anything but straightforward. The treatment can be brutal confining a person to his or her hospital room for a month, and it can accelerate a death that might have taken months if the leukemia were left to its own devices. People go through with it to try to win the golden ticket -- the chance to be cured of leukemia. In someone my patient's age, that occurs only 5% of the time.
Two handfuls of people of the hundreds I have treated over the past decade.
Our definition of "cure" is a functional one. I can't look a patient in the eye and tell him right after a round of chemotherapy that I was able to remove all of the cancer, as a surgeon might after an operation to excise a tumor. "Cure," for us, means a person has lived five years without the leukemia coming back.
For my patient, that meant this day.
"I think you made a good decision to take the drugs", I said, and he and his wife laughed at the understatement.
In the past, with other patients who had achieved this five-year goal, I would count bounding into their exam rooms exclaiming :We can say it now! We can use the C-word. You're cured!" And we would all celebrate noisily. Oncologists, like baseball players, tend to be superstitious. Until this time point has been reached, we tend to avoid tempting the fates by using words like "cure," preferring instead convoluted phrases like "long-term disease-free survival." But after this five-year mark, I would tell my patients that, as much as I enjoyed their company, they no longer had to fight the traffic to see me anymore.
But then, a couple of these patients showed up on my clinic schedule again, eight or 10 months later, having gone to their primary care doctors complaining of fatigue, or of just not feeling "right." Routine blood work again showed abnormalities, and they returned to my office, confused and devastated.
Sometimes I realized that we hadn't really cured the leukemia so much as reset the clock to a time just before the leukemia diagnosis, when they had an underlying bone marrow disorder that turned into leukemia and that this was responsible for the recurrent abnormal blood counts. Sometimes they really did have leukemia again, and I wondered if we had caused this second bout with the chemotherapy we had used to treat the original treatment.
I would be equally devastated. As a result, I have become more reserved in the joy I used to have for my patients. Rather than rejoicing, I caution them that there is still a chance the leukemia may return. Is it fair of me, though, to continue to burden them with this threat of relapse, to hold the sword of Damocles over their heads, when we all know how special it is to reach this five-year mark?
My patient, his wife and I basked in the silence for a few seconds quietly enjoying his good health, his normal blood counts, what he had been through, and how far he had come.
"Ordinarily, we would say you're cured now," I told him, "because the chance that the leukemia will come back is so low. But..."
He interrupted me. "Dock, I'd feel more comfortable if we kept seeing you," he said, almost intuiting my hesitation, my muted enthusiasm, and what I was about to say. "Just to be on the safe side."
I nodded, relieved. "I'd like that, too," I said.
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A final personal note: This July marks my 10th year with no evidence of the disease that was diagnosed stage 4. I know I'm not cured. Cancer is a sneak and a snake. It can come seemingly out of nowhere, even in a different form, even after decades of good health. For anyone in my position, I suggest that the best defense is vigilance. Don't obsess, but don't forget.
And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com.