Just In... Meeting News
Key news updates from recent oncology and hematology meetings.
Sunday, January 25, 2015
By Robert H. Carlson
San Antonio--Here's a switch: In Japan, where obesity is rare, it is lower body mass index (BMI) that correlates with worse prognosis in patients with early-stage breast cancer. In Western countries, of course, higher BMI and obesity are associated with worse prognosis.
The researchers, from the Exploratory Oncology Research and Clinical Trial Center of National Cancer Center Hospital East in Kashiwa, Chiba, reported their findings in a poster presentation at the San Antonio Breast Cancer Symposium, speculating that there may be an optimal BMI in patients with early breast cancer.
The retrospective analysis used data from the prospective Phase III N-SAS BC02 and BC03 adjuvant chemotherapy trials with 1,756 patients with early breast cancer. The principal investigator was Yoichi Naito, MD, of the Division of Experimental Therapeutics.
The researchers hypothesized that because low BMI is common in Japan and obesity is rare, a Japanese cohort would be suitable to assess the impact of low BMI on survival in breast cancer. Analysis from an earlier Phase IIl trial, JFMC 34-0601, suggested that low BMI was associated with decreased overall response to neoadjuvant endocrine therapy with exemestane (Takada et al: The Breast 2012;1:40-45).
In the study presented here, the patients’ median age was 56, 71.2 percent were ER-positive, 9.7 percent had HER2 overexpressed, and lymph node metastases were seen in 76 percent.
The mean BMI value of all 1,756 patients was 23.3; about 33 percent of patients had a BMI of less than 22, 4.8 percent had a value lower than 18.5, and only 4.6 percent had a BMI over 30.
Univariate analysis showed that a BMI under 27 was significantly associated with worse prognosis compared with over 27, with a hazard ratio of 0.55. Multivariate analysis showed a hazard ratio of 0.61.
Making a non-so-subtle point, the poster presentation included a 2003 chart of 16 countries in the Organization for Economic Co-Operation and Development (OECD) showing the percentage of population with BMI scores greater than 30 –i.e.., being technically obese. The weighted average was 14.1 percent. Japan and South Korea were had the lowest, at 3.2 percent. The U.S. topped the list, with 30.6 percent of the population at a BMI greater than 30.
Improving on TNM Predictive Ability
Another poster study at the meeting attempted to improve on the venerable TNM (tumor-node-metastasis) staging system; that classification has served oncologists well for decades, but the thought was that the impact of new prognostic factors would undoubtedly improve the system's predictive ability.
Researchers at Walter Reed National Military Medical Center developed a staging system that incorporated several new risk factors into the TNM system, using the Ensemble Algorithm of Clustering of Cancer Data (EACCD). Six different prognostic factors were sequentially integrated into the TNM system to show their combined impact on 10-year survival rates for breast cancer patients: tumor grade, estrogen receptor (ER) and progesterone receptor (PR) status, age at diagnosis, racial/ethnic group, and histological tumor type.
The researchers applied the algorithm to a SEER database of approximately 132,339 cases of female breast cancer diagnosed between 1991 and 2000. When survival rates were generated for every combination of prognostic factors, it was shown that the rates for some tumors with the same TNM stage varied greatly.
For example, a woman traditionally classified as having stage IIA disease by TNM alone could have a 10-year survival rate anywhere from 75 to 96 percent with all the possible combinations of TNM plus the six new factors.
Looked at another way, women with a 10-year survival rate of 90 percent could be classified as having TNM stage IA to IIIC, depending on the other variables.
First author Jigarkumar Patel, MD, a general surgery resident in the Department of Surgery at Walter Reed and a captain in the US. Navy, offered another example: “According to traditional TNM staging, a woman with T1, N2, grade 1, ER-positive, PR-positive disease who is under 50 years of age would be stage IIIA, but based on our algorithm, she would have a 10-year survival rate of 90 percent, which really should qualify her for stage I.”
Patel called this “deconstructing” TNM--“These added prognostic factors truly affect what these outcomes are, which we already know to be true. The algorithm shows it into a way we can all understand.”
He added that integrating combinations of prognostic factors revealed frequent crossover pf stage groups at 10 years, a violation of a stating system that could impact the interpretation of clinical trials.
Chemotherapy, but Not Hormone Therapy, Associated with Weight Gain
Contrary to what some oncologists tell their breast cancer patients, and what some women expect, hormone therapy does not in itself cause weight gain, according to a study by researchers at Johns Hopkins Bloomberg School of Public Health.
But the study did show that weight gain occurred at a faster rate in breast cancer survivors than in women who are at high risk of breast cancer due to family history, and was particularly rapid in cancer patients who were treated with chemotherapy and used statins.
“But not in women treated with surgery and/or hormonal therapy alone,” said first author Amy Gross, MHS, a doctoral candidate in the Department of Epidemiology.
The 303 breast cancer survivors and 307 cancer-free women in the study were matched for age and menopausal status, and median baseline BMI did not differ significantly between the two groups.
Survivors treated with chemotherapy gained on average 5.58 more pounds than cancer-free women, whereas those treated with surgery and/or hormone therapy alone did not gain significantly more, Gross said.
Compared with cancer-free women, survivors diagnosed within the past five years were twice as likely to gain at least 11 pounds during follow-up.
Gross noted that oncologists she spoke with at the poster session were surprised that hormone therapy alone was not associated with significant weight gain. “Some oncologists tell their patients to expect to gain weight when starting tamoxifen or an aromatase inhibitor, but they should tell their patients not to expect to gain weight just because they are on hormonal therapy.”
PR+ a Plus for Prognosis
A study from Belgium showed that normal-weight postmenopausal patients have a reduced risk of developing distant metastases and of breast-cancer related death if the tumor is PR-positive versus PR-negative.
For overweight or obese patients with PR-positive tumors there was only a non-statistically significant trend toward lower risk, and then only for the first five years following diagnosis, said first author Kathleen Van Asten, a doctoral student at Katholieke Universiteit (KU), Leuven. The findings were based on data for 3,227 women over age 50 diagnosed with primary, operable breast cancer at the university's hospitals between 2000 and 2012. Median follow-up was 6.5 years.
The hazard ratio for breast cancer-specific survival was 0.22 for all women in the study with a BMI less than 25; 0.95 for women with BMI greater than 25; and 0.53 for BMI over 30. For luminal B-like disease, the hazard ratios were 0.14, 1.02, and 0.61, respectively.
“This is not what we expected, and we are investigating further,” Van Asten said.
“These added prognostic factors truly affect what these outcomes are, which we already know to be true. The algorithm shows it into a way we can all understand.”
Sunday, January 25, 2015
By Ed Susman
SAN FRANCISCO – Patients with metastatic pancreatic cancer appear to have similar outcomes but less adverse events if they are given a reduced regimen of standard gemcitabine and nab-paclitaxel, according to data reported here at the Gastrointestinal Cancers Symposium (Abstract 366).
The meeting is co-sponsored by the American Gastrointestinal Association Institute, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
“A less intense regimen of gemcitabine plus nab-paclitaxel maintains efficacy while significantly improving the toxicology profile and cost among patients with metastatic pancreatic cancer,” said Kavya Krishna, MD, a fellow in hematology/oncology at Ohio State University Comprehensive Cancer Center--Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.
“Instead of three weeks of treatment and one week off, we are treating patients every other week,” she said in an interview at her poster study. “We are reducing the amount of gemcitabine and nab-paclitaxel by one-third.”
In the Phase III clinical trial by Daniel von Hoff, MD, et al published in October in the New England Journal of Medicine (369:1691-1703) showing increased survival for combined gemcitabine and nab-paclitaxel, progression-free and overall survival times were 5.5 and 8.7 months, respectively. Survival times in the new study were 4.8 months for median survival and 11.1 months for overall.
“We are suggesting that our regimen is equivalent to the standard treatment. Patients seem to have a sustained response and we have patients on this therapy tolerate it well going to several cycles. We treat until there is disease progression or unacceptable toxicity,” Krishna said.
“The combination of gemcitabine and nab-paclitaxel in first-line treatment of metastatic pancreatic cancer has a modest survival advantage over gemcitabine alone, but adds significant toxicities and increased cost. Based on data suggesting that biweekly administration of gemcitabine-based combinations preserves efficacy and improves the toxicity profile, our institution adopted a modified regimen of gemcitabine plus nab-paclitaxel. We adapted the every-other-week regimen of giving gemcitabine from our clinical experience with patients who would skip a week and seemed to do as well as patients treated every three weeks before taking off one week. And there are clinical trials that indicate that-every-other-week nab-paclitaxel is effective in treating diseases such as lung cancer.”
The regimen was better tolerated and resulted in less hematological toxicity (known to be a particular problem with gemcitabine)—“In the metastatic setting we have been using the every-other-week gemcitabine even before we adopted this regimen,” Krishna said.
“The most commonly used regimen is to treat with gemcitabine is on Days 1, 8, and 15 of a 28-day cycle. The gemcitabine plus nab-paclitaxel regimen uses the same treatment schedule. Now we administer gemcitabine plus nab-paclitaxel on Day 1 and Day 15. We have dose-delay and dose-reduction data but we didn’t record discontinuation data because it is a smaller patient population and most of the patients went off therapy because the disease progressed.”
Regarding the apparent increase in median overall survival pf 11.1 months, she said: “Another factor in this patient population was that they didn’t get beat up by the chemotherapy. They still had a pretty reasonable performance status so once they progressed they were able to go on to second-line and third-line therapies. That’s why the overall survival is so much better than progression-free survival.”
Not Ready to Use Routinely
Asked for his perspective, Tony Philip, MD, an attending physician in hematology/oncology at North Shore-Long Island Jewish Cancer Institute and Assistant Professor of Medicine at Hofstra North Shore-LIJ School of Medicine, said: “This study gives me another option if I had a patient who was older or frail and wanted to give a less-intensive chemotherapy regimen. However, I don’t think we have enough information now to use it routinely with people who are in good performance status.
“This is a single-institution study, and it is not compared with anything. I think we need to take these results with a grain of salt. There needs to be a prospective randomized trial comparing every-other-week treatment with three weeks on, one week off therapy.”
The researchers pointed out that a switch to an every-other-week regimen also results in substantial cost savings--an estimated $5,500 per patient per month of treatment. “That figure does not include the cost for growth factors used in treating neutropenia,” Krishna said. “Neulasta [pegfilgrastim] is pretty expensive too. In the clinical trial the rate of growth factor use was 26 percent, but in our experience with the every-other-week regimen, just eight percent of patients required growth factors.
“The combination of gemcitabine and nab-paclitaxel in pancreatic cancer is one of the most recent advances in pancreatic cancer treatment and has been shown to improve survival when compared with gemcitabine alone. But this improved survival comes with increased toxic side effects that can affect quality of life. We sought an alternative regimen that would prolong treatment effectiveness and reduce side effects.”
She and her colleagues identified 69 patients with pancreatic cancer who received the modified regimen of gemcitabine and nab-paclitaxel. Forty nine had previously untreated metastatic pancreatic cancer and the remaining 20 had either progressed on other chemotherapy treatments or had locally advanced or borderline resectable disease. The patients’ median age was 65.
Overall, less than two percent of patients had severe neurological toxicities compared with 17 percent in the previous Phase III study using the three-week-on, one-week-off schedule; 10 percent of patients had severe low white blood cell counts compared with 38 percent of patients in the Phase III study.
Gives Immune System Time to Recover
The study’s senior author, Tanios Bekaii-Saab, MD, Section Chief of Gastrointestinal Oncology at the James and Associate Professor of Medicine, explained that shifting to a regimen of every other week gives the immune system time to recover between chemotherapy sessions and results in less overall toxicity. It is also more convenient for patients since it means fewer visits to the infusion center to receive chemotherapy.
“Pancreatic cancer is an especially difficult diagnosis, so weighing the survival benefit of available treatments against how treatment side effects will impact a patient’s remaining life is a critically important part of the treatment planning process,” Krishna said.
Friday, January 23, 2015
BY ED SUSMAN
SAN FRANCISCO – Neoadjuvant chemotherapy plus radiation appears to allow a high percentage of pancreatic cancer patients deemed borderline resectable to safely undergo surgery – which leads to significantly extended overall survival -- researchers reported here at the Gastrointestinal Cancers Symposium (Abstract 360).
Even a few patients who are diagnosed with locally advanced pancreatic cancer – usually not considered eligible for surgical resection – can undergo successful resection, said Eric Mellon, MD, PhD, a resident in radiation oncology at H. Lee Moffitt Cancer Center and Research Institute.
“In our experience, whether a patient has borderline resectable pancreatic cancer or locally advanced pancreatic cancer status entering the treatment protocol, it is unimportant compared with whether patients undergo complete resection,” he said in an interview at his poster presentation. “Patients who undergo resection after treatment have the best prognosis.”
Among patients who were resectable after chemotherapy and stereotactic body radiation, about 50 percent were alive at 36 months compared with only about five percent who did not undergo surgery, he reported.
“About 10 to 20 years ago, all of the patients in this series would not have had surgery – they would have been doomed to die. The only way to cure someone with pancreas cancer is to get them to surgery. Our goal here is to treat these patients who are borderline resectable or even some of those who are locally advanced and get them to surgery.
“Some of those patients with locally advanced pancreatic cancer who were never going to get surgery before can be resected, probably because of treatment with FOLFIRINOX [fluorouracil, leucovorin, irinotecan, and oxaliplatin],” Mellon continued, adding that none of the patients with locally advanced pancreatic cancer who received gemcitabine-based chemotherapy responded sufficiently to undergo resection.
Goal: To Shrink the Tumor Enough to Get It Off the Superior Mesenteric Artery
In addition to the chemotherapy regimen, stereotactic body radiation is also used to further shrink the tumor, he explained. “The goal is to shrink the tumor enough to get it off the vessel – the superior mesenteric artery. If you have to clip the blood vessel and take out part of the artery to remove the tumor, it is considered unresectable.”
He said that attempts to perform surgery that would take out the tumor and then re-attach the artery segments generally have not been successful.
Mellon said that in the few cases in which locally advanced tumors have been reduced enough to permit surgery, the outcomes are encouraging: Of the 49 patients initially diagnosed with locally advanced pancreatic cancer, five of the patients or 10 percent had complete resection of their tumor. The small number of patients kept the results from achieving statistical significance, he noted.
“After six months of follow-up, none of those patients have died. None of them have even had cancer recurrence.” Two other patients went to surgery but could not be resected. The remaining 86 percent of these locally advanced pancreatic adenocarcinoma patients did not undergo surgery.
The Real Issue…
“The point we are trying to make here is that it is not important whether you come in with borderline resectable or locally advanced disease, the real issue is whether you got to surgery,” Mellon said. “If you get to surgery, you do so much better.”
Of the borderline resectable patients, about 50 percent got to surgery, and while the median survival is three years for the group who underwent the neoadjuvant chemoradiation, historically, the survival is better than that seen with upfront surgery, he said.
Study of the Two Schedules
Mellon said he is currently working on a study that compares the two schedules—i.e., upfront surgery versus surgery following neoadjuvant therapy.
He said that prospective, randomized data are necessary to change treatment guidelines. Moffitt is a member of the National Comprehensive Cancer Network (NCCN), which writes guidelines for treatment of cancer that are accepted worldwide. Mellon said that current NCCN guidelines suggest that neoadjuvant treatment be given to patients with borderline resectable pancreatic adenocarcinoma before surgery is attempted in these patients, but there are no data about which regimen is preferred for neoadjuvant therapy--“This may be one option.”
He said that the use of stereotactic body radiation therapy is emerging for use in pancreatic cancer in hopes of increasing the radiation dose to the cancer without causing radiation toxicity to nearby organs such as the duodenum and stomach.
And even if the neoadjuvant therapy fails to reduce the tumor enough to permit safe surgery, there are still benefits: “Local disease control is good after stereotactic body radiation therapy even if the cancer is never amendable to surgery,” Mellon said. “In patients who were not surgically resected, our one-year local control was 78 percent. However, the patients still die of metastatic disease.”
In his study, he and his colleagues reviewed all cases of non-metastatic borderline resectable or locally advanced pancreatic cancer patients who were treated by stereotactic body radiation therapy from 2009 to 2013 at Moffitt. Median follow-up from the start of chemotherapy was 14 months, and patients underwent induction therapy with gemcitabine, docetaxel, and capecitabine (GTX), FOLFIRINOX, or other gemcitabine-based regimens.
One week after chemotherapy ended, the patients underwent stereotactic body radiation therapy. Patients were prescribed stereotactic body radiation therapy in five5 equal fractions. Dose-painting techniques were used to increase the dose to areas of tumor-vessel abutment – a median of 40 Gy. Gross disease received a minimum dose of 30 Gy.
A median of seven weeks after radiation therapy – up to three months after radiation -- patients were reassessed for resectability. Of the 110 borderline resectable pancreatic cancer patients, 51 percent underwent resection with a three percent positive margin rate.
A total of 21 percent of patients did not go on to surgery due to progression to unresectable status on imaging; seven percent were unresectable at surgery; metastases was found in 14 percent of patients at surgery, and seven percent of patients were deemed medically inoperable due to performance decline during neoadjuvant therapy,
Mild acute radiation-induced toxicities, including Grade 1 and Grade 2 fatigue, pain, nausea, and diarrhea, were common but no toxicity prevented surgical resection.
Possible Selection Bias
Asked for his perceptive for this article, Tony Philip, MD, an attending physician in hematology/oncology at North Shore-Long Island Jewish Cancer Institute, said: “We need a randomized clinical trial to determine if neoadjuvant chemotherapy is really changing outcomes in pancreatic disease for patients who have borderline resectable pancreatic cancer--It may be that the patients who are selected for neoadjuvant therapy are simply better candidates for surgery and so these outcomes look better because of that selection bias.”
In a related study also performed by researchers at Moffitt, Omar Rashid, MD, JD, a complex general oncology surgery fellow, suggested that by following a multidisciplinary treatment pathway, more than half of patients with borderline resectable pancreatic cancer can undergo potentially curable surgery (Abstract 374).
“We looked at the clinical pathway that is used to assess these patients,” Rashid noted at his poster presentation “Right now how borderline resectable pancreatic cancer is treated in different parts of the country depends upon where the patients are, in terms of how they are staged and to what regimen is used.
“Some things are unique to Moffitt. We use a CT-scan, PET-scan and also endoscopy with ultrasound to image the patient,” he said. “Then everyone comes together – different surgeons, gastroenterologists, and the tumor board – and they decide if the patients are indeed borderline resectable. If they are, then we give them GTX and stereotactic body radiation therapy, and then re-stage the patient. If there is a chance of resection, we then take patients to surgery.”
The study showed that from 2006 to 2013, borderline resectable pancreatic cancer was diagnosed in 121 patients presenting at Moffitt. Of that group, 101 were entered into the study of the multidisciplinary clinical pathway assessment.
Rashid reported that about 93 percent of these patients were able to complete adjuvant therapy. The panel of doctors then determined that 55 (54.5%) of the patients were suitable for and underwent surgery. Of those who went to surgery, 53 (96%) had a complete resection of the tumor – an RO resection; and two patients had an R1 resection.
“One of the reasons we did so well, maybe,” Rashid speculated, “was that we were so selective at the beginning. Another might be the chemotherapy regimen – 81 percent of patients had a partial response, and 14.5 percent had a complete pathological response.”
Patients who were not resectable after therapy achieved a median 14-month overall survival compared with 33 months for patients who were able to have surgery. “We are not curing these people with surgery, but we are moving the curve more in that direction,” Rashid said.
Call for Prospective Intergroup Study
He said that a prospective study needs to be performed to test the various regimens: “It shouldn’t be that the treatment you get depends on where you end up. It should be based on data. The only way we will get that is if the pancreatic cancer Intergroup comes together and says, ‘Look, we are going to do this.’”
The three-day, which is co-sponsored by the American Gastrointestinal Association Institute, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology, had approximately 3,400 attendees this year.
Friday, January 23, 2015
By Robert H. Carlson
New York--Neuroendocrine prostate cancer is a high-risk, lethal subset of disease, often referred to as representing only two percent of all diagnosed prostate cancer. In fact, though, it probably occurs far more often because the disease is not recognized as different from metastatic castration-resistant prostate cancer. That was the word from Himisha Beltran, MD, Assistant Professor of Medicine in the Division of Medical Oncology at Weill Cornell Medical College, speaking here at the Chemotherapy Foundation Symposium.
Men rarely undergo biopsy of their tumors once those tumors have spread to bone or soft tissue regions of the body, Beltran noted. So while only a few prostate cancers are diagnosed originally as neuroendocrine prostate cancer, many cases that develop after adenocarcinoma has evolved into neuroendocrine prostate cancer go undetected. She estimated that as many as one quarter of patients who are dying of prostate cancer are dying from treatment-related neuroendocrine prostate cancer.
The clinical features of the disease include frequent visceral and bulky soft-tissue metastases and limited duration of response to both hormonal therapy and cytotoxic chemotherapy.
“Some men who are initially responsive to potent androgen-deprivation therapy develop gradually progressive disease with bone and lymph node metastases and rising PSA,” she said. “But men in this much smaller neuroendocrine group with resistant/refractory disease have rapidly progressive disease with metastases to liver and other abdominal visceral organs, and low PSA. They may even become worse on potent androgen-deprivation therapy.”
This aggressive subtype of prostate cancer, with survival of approximately one year, most commonly evolves from preexisting prostate adenocarcinoma, she continued. And while it rarely arises de novo, the amount of neuroendocrine differentiation of prostate adenocarcinoma increases with disease progression and in response to androgen-deprivation therapy.
“Neuroendocrine prostate cancer does not express the androgen receptor and it's considered clinically hormone refractory. With the introduction of new highly potent androgen receptor-targeted agents into the clinic, such as abiraterone acetate, treatment-related neuroendocrine prostate cancer is becoming an even more important disease to recognize.”
Beltran and colleagues have written that treatment-related neuroendocrine prostate cancer should be suspected in patients with castration-resistant prostate cancer who experience rapid progression with a low serum PSA, especially in the setting of potent androgen deprivation therapies (JCO 2012;36:e386-e389).
Patients with treatment-related neuroendocrine prostate cancer will likely not respond well to hormonal agents and may respond to platinum-based chemotherapy,” they wrote. “In this new era of potent androgen receptor-targeted drugs, there is an evolving change in the clinical landscape of advanced prostate cancer, and we believe there is potential to drive tumors toward this more virulent form of prostate cancer.”
Beltran is principal investigator in an ongoing multi-institutional single-arm, open-label Phase II trial evaluating MLN8237 (alisertib) in patients with histologically confirmed or clinically suspected metastatic neuroendocrine prostate cancer (http://clinicaltrials.gov/ct2/show/NCT01799278), which is sponsored by Weill Cornell in collaboration with Millennium Pharmaceuticals, Inc.
Anna Ferrari: ‘Evolving Beyond ADT’
Anna C. Ferrari, MD, Co-Director of the Genitourinary Cancer Program at NYU Langone Medical Center, who was co-moderator of the GU oncology session at the meeting, said that it is becoming apparent that as a prostate cancer tumor evolves to become castration resistant, it then evolves beyond the targeting of the androgen- receptor agents. This phenomenon of trans-differentiation drives alterations of pathways other than the androgen receptor, and a subgroup of those become neuroendocrine carcinomas.
“It is clear that these tumors have more of a proliferative pattern and a more aggressive pattern, and the metastases tend to grow in soft tissues.”
She said many clinicians are using cisplatin or carboplatin in combination with taxanes to treat patients with neuroendocrine prostate cancer.
It is rare that someone will present with the disease de novo, she noted. “This is a progression after multiple lines of androgen-axis targeted therapies, and the tumors have been castrate-resistant for a number of years.” A biopsy will typically show small-cell components of neuroendocrine cancer mixed with the adenocarcinoma--but not generally in the primary tumor, it's usually in the progression, in the metastatic sites.”
William Oh: ADT Encourages Neuroendocrine Differentiation as Pathway of Resistance.
The other co-moderator, William K. Oh, MD, Chief of the Division of Hematology and Medical Oncology and Professor of Medicine and Urology at Mount Sinai School of Medicine, said that the disease is becoming a “hot area in prostate cancer” and that he is definitely seeing more patients with it in the clinic.
“These are men with prostate cancer who are living longer, but when they relapse, they relapse in places like the liver and lung. How to treat these men is going to be the biggest challenge we have.”
Oh also said that the development of neuroendocrine prostate cancer is a function of treatment: “I think the androgen-pathway blockers that we’re using are actually encouraging neuroendocrine differentiation as a pathway of resistance. We need to develop new treatments that really target neuroendocrine differentiation.”
Thursday, January 22, 2015
BY ROBERT H. CARLSON
SAN ANTONIO--Direct-to-consumer testing for BRCA1 and BRCA2 mutations is on the horizon, and geneticists and oncologists should get involved if they want to have input in a genetic screening program. In her AACR Distinguished Lectureship in Breast Cancer Research given at the San Antonio Breast Cancer Symposium, Mary-Claire King, PhD, Professor of Medical Genetics and Genome Sciences at the University of Washington School of Medicine in Seattle, continued on with the theme she first made in an article in the Journal of the American Medical Association published in conjunction with her receipt of the Lasker-Koshland Special Achievement Award in Medical Science (JAMA 2014:312:1091-1092).
“The provision of these services directly to consumers, with FDA approval, without involving any of us, is imminent,” she said in her SABCS presentation. “I would like very much for us, as geneticists and physicians working with these patients, to be involved in formulating this testing and follow-up in a way that makes sense to us.” She has called for population-based screening of all women over age 30 to test for mutations in BRCA1 and BRCA2, which are strongly associated with a high risk of breast and ovarian cancers.
“Every woman identified with a BRCA1 or BRCA2 mutation after she has developed breast or ovarian cancer clearly represents a missed opportunity for prevention,” is King's mantra, and the reason she advocates moving beyond testing families at risk and instead testing all women.
Her work has focused on understanding the inherited factors that can increase the risk for developing breast and ovarian cancers, and the molecular mechanisms of BRCA1, BRCA2, and other genes associated with an increased risk of developing cancer.
“Those of you who have been doing medicine since you were wee tots appreciate that you undertook a profession that would save lives, and that you would see it happen,” King said as she began her speech, which she had titled “Genomic Analysis of Inherited Breast and Ovarian Cancer.”
“Someone like me who grew up doing evolutionary biology--and who loved evolutionary biology--never in a thousand years did I think I would be presenting a talk like this now. So, here's what an evolutionary biologist thinks we should do next about BRCA1 and BRCA2.”
First, Eliminate VUS
Doing away with reporting variants of unknown significance (VUS) would be a start, King said in an interview after her talk.
“Testing for BRCA1 and BRCA2 should focus solely on unambiguous loss-of-function mutations with definitive effect on cancer risk. We have to get rid of the problem of VUS.”
She explained that early in the era of commercial testing the consequence of many mutations was unknown, so reports would list such mutations as “a variant of unknown significance.”
But this term has no prior history in medical genetics, King said, and today it only causes confusion in clinical management. “It has really run amok, to the point that literally every missense allele, every in-frame deletion-- things that should never be called even remotely significant--creep into reports wreaking havoc for patients and complete despair for their providers who are trying to give them accurate information.”
King called for an expert panel to define a reference list of unambiguously damaging mutations. “Whoever carries out the sequencing and bioinformatics should not be responsible for the clinical interpretation,” she said. “They should simply look at the list and see if the variant, the mutation, they have encountered, is or is not on the list.”
The concept of reaching a medical consensus is not new. Forming such a panel would not be hard, she said, and she would “take all comers” as experts for participation in this panel.
“We already have a number of groups that are assembling lists of genes that are actionable or not--not just for breast cancer but for many purposes,” she said.
A ‘Most Wanted’ List of Actionable Genes
King said a consensus list of actionable mutations for BRCA1and BRCA2 should have:
· All frameshift and nonsense mutations anywhere in BRCA1, and before the late polymorphic stop in BRCA2--“All of these mutations are damaging,” she said;
· Exonic or larger genomic deletions or duplications that lead to such stops;
· Splice junction mutations that lead to stops in message--“There is an entire branch of cancer genetics that looks at these mutations in these genes”;
· Missenses that have been shown experimentally to abrogate gene function, most obviously the RING finger mutations in BRCA1, and a very few missense mutations in other codons in the BRCT (BRCA1 C Terminus) domain of BRCA1, and toward the C-terminal region of BRCA2; and
· Mutations in splice enhancers that have been shown experimentally to lead to stop--“There are several of these in BRCA2 exon18, and a few elsewhere,” she said.
King further suggests that only mutations of unambiguously damaging consequence to patients should be reported; that the reference list be made public; and that it be decided in a transparent way, “after lots of argument.”
As additional experiments are carried out--for example, for enhancer mutations or for protein abrogation--they should be added to the list, she said.
“This will probably mean that a whole class of mutations, distant regulators about which we presently know very little will be discovered. We know almost nothing about these mutations,” she said, adding that this is an area her lab is particularly interested in.
“All this is by way of saying that no test is perfect when first proposed, no test in genetics picks up absolutely every damaging allele--we learn as we go along. The goal is to separate sequence and base calling from interpretation.”
The object of a workable reference list is to be able to give oncologists information they can pass on to their patients that is usable, King explained.
“None of this ambiguous stuff, [clinicians] have to be able to get a report back that they can discuss with their patients, and either say, to the vast majority of patients, 'You do not have a mutation to BRCA1 or BRCA2,' or 'you do have a mutation for which action needs to be taken, and let me refer you to the high-risk clinic at the local medical center.'
“We need to be able to separate all women to one group or the other, and that is feasible; it is doable.”
Technology in Place
The technical capability of identifying these mutations is one link already in place, and assuring technical quality “is the least of our problems,” King said. “Isn’t it amazing? A year ago I couldn’t have said that.”
She said the process has gotten very good and there is very good regulation of it. “Getting the base pairs right, avoiding undocumented pseudo-genes, doing the alignment properly, doing the calling properly — this is done well by both commercial and public-based laboratories, and there is constant rechecking to keep standards high,” she said.
What will change is the cost. “In our hands the marginal cost is $200 per sample, less than one-tenth of what is charged now based on having an old code system that is still largely used. But I have no doubt there are companies that will market these tests directly to consumers, and that will drive down costs.”