Just In... Meeting News
Key news updates from recent oncology and hematology meetings.
Tuesday, December 16, 2014
By Robert H. Carlson
New York-- It's a paradox that obesity is a risk factor for ER-positive post-menopausal breast cancer, even though estrogen production from the ovaries declines precipitously with menopause. One explanation may be that inflammation in adipose tissue in the breast increases aromatase expression--a possible connection that was described in a presentation here at the Chemotherapy Foundation Symposium by Clifford A. Hudis, MD, Chief of the Breast Cancer Medicine Service and Attending Physician at Memorial Sloan Kettering Cancer Center and Immediate Past President of the American Society of Clinical Oncology.
“Obesity in breast cancer may be one of the most important long-term issues we need to confront,” Hudis said. “The public health implications of obesity, from esophageal hypertension to coronary disease, diabetes to arthritis, are well known, but the association between obesity and cancer is not well appreciated by the general public.”
This will not only cause an increase in morbidity and mortality, he said, but will do so in a very specific way “that we need to plan for, and in fact we may have the opportunity to interrupt.”
And strategies that disrupt the obesity-inflammation-axis may be useful for reducing the risk of breast cancer or its progression, he said.
Role of White Adipose Tissue Inflammation
Medical students learn the notion that adipocytes make estrogen and leave it at that, Hudis said, but the question is why. That question led him and colleagues to explore the role of white adipose tissue inflammation, he explained.
“We began to develop the notion that at least part of the problem in postmenopausal breast cancer is increased estrogen synthesis related to an increase in pro-inflammatory mediators,” he said. “This is the underlying hypothesis we have been pursuing: that postmenopausal breast cancer may be an indirect consequence of chronic, low-grade inflammation.”
Specifically, that obesity induced inflammation is associated with pro-inflammatory mediators including prostaglandin E2, TNF-α, and IL-1 which cooperatively activate CYP19, the aromatase gene.
“This toxic stew of inflammation leads to increased aromatase activity leading to increased local production of estradiol from the conversion of androgen precursors via aromatization,” he said.
In a mouse model of diet, the white adipose tissue inflammation was increased in both the mammary gland and visceral fat, Hudis said. And around the lesions were elevated levels of the pro-inflammatory mediators, seen in the stromal-vascular fraction.
Hudis said the crown-like structure had already been identified by researchers in diabetes (Olefsky JM, Glass CK: Annual Review of Physiology 2010:72; 219-246), and now he and his colleagues are pursuing that connection in women with breast cancer.
In a series of 30 women undergoing routine surgery at Memorial Sloan Kettering for breast reduction or contralateral risk reduction, the researchers found an association between crown-like structures in breast
white adipose tissue and increased BMI (Morris PG, Hudis CA, et al: Cancer Prev Res 2011;4:1021-1029).
“This was consistent with what the animal model had predicted,” Hudis said, adding that an ongoing series with similar women continues to show the association between obesity and the crown-like structures.
There are additional risk factors for inflammation that explain why some lean patients have elevated pro-inflammatory mediators and crown-like structures in the breast. On the other hand, some obese and
overweight patients do not have inflamed adipose tissue. The inflammation is a systemic phenomenon, Hudis said, and the white adipose tissue of the breast can be a sentinel for generalized inflammation. Moreover, the presence of crown-like cells may be a biomarker of increased breast cancer risk or poor prognosis.
Hudis said this research suggests that interventions to address the obesity-inflammation-aromatase axis should
potentially focus across all domains, including diet, weight control, and anti-inflammatory agents (Howe, Subbaramaiah, Hudis, Dannenberg: Clin Cancer Res 2013;19:6074-6083). Other potential interventions are being tested to serve as treatment and prevention, he said.
Hudis concluded by noting that 2014 is the 50th anniversary of the government report linking tobacco use with lung cancer, and that obesity is now predicted to replace tobacco as the leading modifiable risk factor for cancer in the U.S.--“We have an important obligation to tackle this, and not see obesity undo the advances of the past 50 years.”
Monday, December 15, 2014
BY SARAH DIGIULIO
The latest findings from both the STORM and HeiLivCa trials were conclusive that the multikinase inhibitor sorafenib—the current standard of care for treatment of patients with inoperable advanced liver cancer—does not increase recurrence-free survival in hepatocellular carcinoma (HCC) in the adjuvant setting, according to reports presented at the International Liver Cancer Association (ILCA) 2014 Annual Conference.
“Negative outcomes like these need to be presented,” ILCA President Peter R. Galle, MD, PhD, Professor of Medicine and Director of the First Department of Internal Medicine at University of Mainz, noted in an email after the meeting. “Both studies were well-performed, sufficiently large, and clearly negative—thus, sorafenib for adjuvant therapy and as a bridge for those on the transplant list won’t play a role.”
The latest data from the STORM trial, presented during the plenary session at the ILCA meeting as well as at the 2014 American Society of Clinical Oncology Annual Meeting, showed that sorafenib does not improve recurrence-free survival for patients with hepatocellular carcinoma in the adjuvant setting (ASCO Abstract 4006).
“Sorafenib is the sole drug approved for management of advanced HCC cases,” study author Josep M. Llovet, MD, said in an email. Llovet is Professor of Research at Institució Catalana de Recerca i Estudis Avançats of the Barcelona Clinic Liver Cancer Group of the Liver Unit at IDIBAPS-Hospital Clínic, University of Barcelona, and Professor of Medicine and Director of the Liver Cancer Program at ICAHN School of Medicine at Mount Sinai. “We estimated that it would be a potentially effective treatment in cases of dissemination after resection.”
The trial included 1,114 patients who had surgical resection or local ablation with curative intent and had an intermediate or high recurrence risk—with Child-Pugh scores of five to seven, ECOG PS 0, and no residual disease (confirmed by CT or MRI testing). The patients were randomized to receive oral sorafenib (400 mg, twice daily) or placebo.
The data showed no differences in recurrence-free survival, time to recurrence, or overall survival for the two groups. Patients receiving sorafenib had a shorter median treatment duration (12.5 vs. 22.2 months) and lower mean daily dose (578 mg vs. 778 mg). And discontinuation rates with sorafenib were higher due to treatment-emergent adverse events—24 percent of patients taking sorafenib compared with seven percent of the patients receiving the placebo.
The most common grade 3-4 adverse events for patients receiving sorafenib were hand-foot skin reactions (28%), hypertension (7%), and diarrhea (6%).
“The fact that the final results are negative represents a halt in the development of agents in this setting,” Llovet said—noting that it will now likely be several years before a new agent is approved for the indication. “This is an unmet need.”
Also presented during the meeting’s plenary session were the latest data from the HeiLivCa trial. That data showed no statistically significant difference in time to progression of disease for patients treated with transarterial chemoembolization (TACE) plus sorafenib compared with patients treated with TACE plus placebo after neo-adjuvant treatment before liver transplant; and the safety profile of the patients receiving sorafenib was slightly inferior to that of the placebo group.
“Time to progression was similar after neoadjuvant treatment with TACE and sorafenib before liver transplant compared with treatment with TACE and placebo,” the study’s lead author, Katrin Hoffmann, MD, Attending Surgeon in the Department of General and Transplantation Surgery at Ruprecht-Karls-University in Heidelberg, Germany, said via email. “And tumor response, progression-free survival, and time to liver transplantation were comparable. This trial gives no evidence on the indication of sorafenib for HCC before liver transplantation.”
The trial included 50 patients with hepatocellular carcinoma from four centers in Germany, who were awaiting liver transplantation. The patients were randomly assigned to receive TACE plus either sorafenib (2 x 200 mg) twice a day or placebo (given continuously). TACE was scheduled every four to six weeks and continued until complete de-vascularization or until transplant.
The median time of treatment was 124.5 days for patients in the sorafenib group and 171 days for those in the placebo group. Five patients in the sorafenib group underwent liver transplant as did 12 patients in the placebo group.
The data showed that 14 patients in the study developed tumor progression--seven had received treatment with sorafenib and seven had received the placebo, with time to progression similar for both groups. The results of tumor response, progression-free survival, and time to liver transplant were also similar in both treatment groups.
The incidence of adverse events were similar for both groups, occurring in 23 of the 26 patients in the placebo group (92%) compared with 23 of 24 in the sorafenib group (96%). Four patients in the placebo group (16%) and 12 in the sorafenib group (50%) had severe treatment-related adverse events. And eight patients (6 in the sorafenib group, 2 in the placebo group) had dose reductions or temporarily discontinued treatment due to treatment-related adverse events; and seven patients (6 receiving sorafenib, 1 receiving placebo) discontinued the study because of treatment-related adverse events.
The most frequent, treatment-related adverse events, Hoffmann noted, were thrombocytopenia, diarrhea, and hand-foot-skin reactions.
Sorafenib Not the HCC ‘Wonder Drug’
Asked for his perspective for this article, Robert J. Mayer, MD, Faculty Vice President for Academic Affairs at Dana Farber Cancer Institute, Faculty Associate Dean for Admissions and Stephen B. Kay Family Professor of Medicine at Harvard Medical School, said that the findings from these studies do not close the door for sorafenib—“but I would say it is not the wonder drug that is going to reverse all the horrors and difficulties of hepatocellular cancer, and we need to continue looking for better and more effective therapies.”
Sorafenib is the standard of care for treating patients with advanced hepatocellular cancer—“and it remains the standard of care because it remains as good a treatment as we have,” Mayer, an OT Editorial Board member, explained in a telephone interview. “But it’s disappointing that sorafenib did not add benefit when combined with TACE, and it’s even more disappointing that it didn’t have adjuvant effect.”
When initial data came out on the efficacy of sorafenib in HCC (OT 8/10/07 issue), the mechanism behind that effectiveness was not clear, Mayer continued. That study—the SHARP trial—was a large, randomized controlled trial, which showed that patients with advanced hepatocellular cancer who had never received prior therapy did live longer after being treated with sorafenib—“but interestingly enough, their tumors didn’t shrink.”
It could be hypothesized that sorafenib was blocking blood nodules, which stopped tumor growth and led to prolonged survival in patients—“but it was not completely clear what was happening,” he said. “Now, the results of these two abstracts raise some questions about the long-term biological significance of the molecule [sorafenib], and also raise some questions as to what exactly the function of sorafenib is—and the extent of that function—in the SHARP study, where it may have had far less of an anti-tumor effect than was initially thought.”
The Future of Sorafenib
Despite the unknowns, Mayer said these latest findings still do not change the role of sorafenib for patients with advanced disease. “Sorafenib has been approved for this purpose appropriately by the Food and Drug Administration. Sorafenib is still the standard of care [for patients with advanced HCC], but it is not an optimal standard of care.
“The findings will likely diminish the enthusiasm of people devoting a great deal more time to investigating different ways to give sorafenib. And it probably will open the door to future studies with non-sorafenib containing treatment plans,” he said.
Sunday, December 14, 2014
BY PEGGY EASTMAN
WASHINGTON—Several factors are converging to quicken the pace of bringing effective new therapies to cancer patients earlier. That was the word from speakers here at the 2014 Conference on Clinical Cancer Research, co-hosted by Friends of Cancer Research (FOCR) and the Engelberg Center for Health Care Reform at the Brookings Institution, with support from the American Society of Clinical Oncology and Susan G. Komen.
Specifically, the invited speakers--many of whom had contributed to one of the three issue briefs distributed at the conference--cited a Congressional initiative on finding cures for life-threatening diseases; the use of single-arm trials and innovative trial designs for cancer therapy approval; efforts to develop registries to capture patient outcomes from off-label use of approved therapies; the success of the Food and Drug Administration’s Breakthrough Therapy designation; and the identification of a potential approach to speed the approval of supplemental indications for approved cancer drugs.
21st Century Cures Initiative
Keynote speaker Rep. Fred Upton (R-Mich.), Chairman of the U.S. House of Representatives Energy and Commerce Committee and a strong supporter of biomedical research, gave an update on the multi-year 21st Century Cures Initiative, a bipartisan plan to speed the pace of cures for cancer and other life-threatening diseases. In introducing Upton, FOCR Chair and Founder Ellen V. Sigal, PhD, predicted of the cures initiative: “It’s going to change the way we do business.”
In his talk, Upton, whose mother is a cancer survivor and whose wife has lupus, said that of 7,000 diseases, there are cures for just 500. He said legislators need to make sure there is not a gap between “the science of cures and the way we regulate those therapies.”
He added, “We have spent the last year listening to people, and we’re getting close to introducing legislation.” He said he and his co-sponsor Diana DeGette (D-Colo.) plan to release a draft discussion document on the cures initiative for comment during the second or third week of January 2015.
He added that his goal is to move a bill on accelerating the pace of cures into committee in March 2015, have it on the House floor before Memorial Day and pass it in 2016. As envisioned, the bill would: stress patient-centeredness; modernize clinical trials; facilitate data sharing through digital applications; encourage and support young scientists; and provide incentives to develop new drugs and devices for unmet needs.
‘Strong Commitment to Bipartisanship’
Upton stressed his strong commitment to bipartisanship: “Our goal is absolutely to keep this a bipartisan effort,” he said. “I came here to make a difference, and I’m going to partner with someone on the other side of the aisle on every bill.”
Efforts to streamline the cancer clinical trials process are already underway. Although randomized trials are the gold standard, “single-arm trials are commonly the basis for accelerated approval today,” said Deborah Armstrong, MD, Professor of Oncology, Gynecology and Obstetrics at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.
Armstrong noted that a non-randomized single-arm trial can be done using fewer resources, typically has an endpoint of overall response rate rather than overall survival, and allows for a much quicker accrual of subjects--which can be important for a refractory population).
“What patients want from a clinical trial is to know that they will live longer,” she said. On the negative side, subjects in a single-arm trial may not be comparable with historical controls.
Paradigm for Successful Use of Single-Arm Trial
The paradigm for successful use of a single-arm trial is crizotinib for ALK-positive non-small cell lung cancer (NSCLC), said another speaker, Mace Rothenberg, MD, Senior Vice President for Clinical Development and Medical Affairs and Chief Medical Officer at Pfizer, Inc., who noted that this drug showed “an unprecedented response rate” in development, a factor that points a drug to a single-arm trial.
There is often a high attrition rate in traditional Phase III trials, which can lead to a failed trial, noted Gideon Blumenthal, MD, Clinical Team Leader in the FDA’s Office of Hematology/Oncology Products. The new clinical trial paradigm that is emerging is smaller patient numbers with low-frequency subsets, he said. In these trials, responses can differ both qualitatively and quantitatively.
“Patients don’t want to go in control groups,” said Josh Sommer, Executive Director of the Chordoma Foundation and a chordoma survivor. He noted that rare cancers account for about 25 percent of all cancers, so “we’re now facing some of the practical considerations in trying to design clinical trials” for chordoma and other rare tumors. Sommer told OT he is one of the lucky ones who had successful surgery. But, he noted, chordoma “has a dreadful impact” on many patients, giving them a very poor quality of life, so there is clearly a need for accelerated development of therapies for this rare cancer.
“Are we holding oncologists to a trial standard that is impractical for 25 percent of cancers?” asked Sommer.
Pazdur: How Quickly Can We Get Approved Drugs Out to Patients?
Also speaking, Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products in the Center for Drug Evaluation and Research, said that while historically the agency came to favor overall survival as a clinical trial endpoint, “we now have drugs that have unprecedented response rates and durable responses.
“Now it’s not should we approve the drug, but how quickly can we get it out to patients. I ask myself, if I were a patient, would I go on this trial?... Are we asking a meaningful question that really needs to be answered?”
Pazdur said it is true that “we are losing something by not having a randomized trial,” since in a single-arm trial there is no comparative efficacy to a standard therapy if one exists, but he said that use of a single-arm trial does expedite the drug-approval process.
“This is not a static process,” Pazdur emphasized. “It isn’t just all or nothing.”
He said a single-arm trial, which he called “a collection of case histories of patients who were treated in the same way,” may be appropriate at a particular time, and a randomized trial may then be done at a later date. “We’re going to have smaller numbers of patients to base a decision on--that’s a fact,” he emphasized. “Our world is changing, and so is the world of drug development.”
In addition to new trial designs, current efforts to capture evidence on off-label cancer drug therapy will lead to better patient care, said Mark McClellan, MD, PhD, Senior Fellow and Director of the Healthcare Innovation and Value Initiative at the Brookings Institution, former administrator of the Centers for Medicare & Medicaid Services (CMS) and former FDA commissioner.
“If these efforts succeed, physicians will be able to make more informed decisions based on real-world evidence from patients,” he added.
ASCO’s TAPUR Study
As previously reported in OT (11/25/14 issue), ASCO plans to launch a first-ever study to describe and record the performance (both safety and efficacy) of commercially available, targeted anticancer drugs used off-label for patients with advanced cancer that has a potentially actionable genomic variant. The Targeted Agent and Profiling Utilization Registry (TAPUR) study will focus on overall response rate per RECIST criteria as an endpoint, said Richard L. Schilsky, MD, ASCO Chief Medical Officer.
He said he hopes data from TAPUR will benefit patients, physicians, pharmaceutical companies, payers, and regulators. An initial pilot test of TAPUR is expected in the second or third quarter of 2015, and Schilsky told OT that he hoped that in the future, accepted drug compendia would expand to include data from TAPUR. Then, he said, insurers would most likely cover the off-label treatments.
Molecular Evidence Development Consortium
A second effort to develop an off-label drug registry is underway by Medicare Administrative Contractor (MAC) Palmetto GBA under its Molecular Diagnostic Services (MolDX) program, said Dane Dixon, MD, Director of Clinical Science for MolDX at Palmetto GBA.
The proposed effort, called the Molecular Evidence Development Consortium (MED-C) is an independent non-profit organization that aims to help newly diagnosed Medicare cancer patients in defined clinical areas gain access to approved drugs used off-label. “The goal is to get the patient tested molecularly and treated molecularly,” said Dixon. The testing would pinpoint off-label mutations for which treatments exist in other disease states--an example might be BRAF mutations targeted by existing treatments in melanoma.
“We hope to unlock pathways of molecular mutations,” she said, noting that an early pilot test of MED-C is planned for the third quarter of 2015.
Janet Woodcock on the FDA’s Breakthrough Therapy Designation
Janet Woodcock, MD, Director of the FDA’s Center for Drug Evaluation and Research, the meeting’s keynote speaker, said the FDA’s Breakthrough Therapy approval process, which arose as a concept at a 2011 FOCR conference and was signed into law in 2012 (OT 12/25/12 issue), has been highly successful in speeding effective new drugs to patients. “We’ve had many more requests for the breakthrough designation than we thought would be possible--something is changing in drug development,” she said.
“The biggest factor seems to be the magnitude of treatment effects” for a serious or life-threatening disease. As of October 2014, 68 Breakthrough Therapy designations were granted, and FDA has approved 14 of these, including nine in 2014. “There has been no letup in applications, so expect a robust program going forward--that’s good news for patients.
“There’s pretty much concurrence on what a Breakthrough [drug] is and what it isn’t,” Woodcock said, noting that therapies with a genetic component in their indication have been more likely to be granted Breakthrough status, and there are slightly more targeted therapies among the Breakthrough therapies that FDA approves.
She said the FDA is now working on a way to make Breakthrough Therapy denials more standardized; most denials have cited trial design and trial data issues.
Streamlining Adding New Indications
Finally, conference participants also discussed how to streamline the process of adding a new indication to the labeling of an approved cancer therapy. Currently, a supplemental new drug application (sNDA) or supplemental biologics license application (sBLA) parallels the content of an original NDA/BLA application, consuming a great deal of time in additional reviews and analyses that may not always add value to the regulatory determination of safety and efficacy.
As set forth in one of the three conference issue briefs, there may be instances in which the manufacturer and the FDA already have significant information about a drug, and thus more targeted data collection and less comprehensive supplemental-indication submissions may suffice. These “summary reviews” that leverage existing knowledge, when appropriate, could free up FDA’s time and resources for reviews of investigational new drugs.
Conference speakers including Pazdur, who contributed to all three issue briefs, proposed that supplemental indications eligible for this streamlined “summary review” might include an approved drug with a large safety data base; no new concerning safety signal; an established, objective primary endpoint (overall survival or very large progression-free survival); a robust effect; internal consistency; and a clear risk/benefit profile.
Eligibility for summary review would be determined by the FDA Office of Hematology and Oncology Products at a pre-sNDA meeting, a pilot phase would ensue, a validation sample would be submitted for quality control, and--if all is found to be in order--a potential shortened review of the supplemental drug indication, a summary review, could be granted. As the issue paper states: “The time and resources currently spent collecting, preparing for submission, and reviewing data that do not contribute to the quality of the submission or the regulatory review and decision, could be better spent on projects with tangible benefit for patients.”
Friday, December 12, 2014
BY ED SUSMAN
SAN ANTONIO – The molecular subtype of hard-to-treat triple-negative breast cancer does not appear to make it any easier for doctors to determine which of these women would be best treated with specific anticancer drugs, researchers said here at the San Antonio Breast Cancer Symposium.
When the team, led by William Sikov, MD, Clinical Associate Professor of Medicine at Brown University, looked at pathological complete response in triple-negative breast cancer, they were unable to determine if basal-like designated tumors responded better to chemotherapy than non-basal-like breast cancers, he reported, speaking at a news conference.
“Pathological complete response breast rates do not differ between basal-like—54 percent--and the relatively small number of non-basal-like cancers—52 percent. The addition of either carboplatin or bevacizumab was associated with significantly higher pathological complete responses and pathological complete response breast/axilla rates in patients with basal-like cancers.”
However, in the molecular analysis of patients’ tumors in the CALBG 40603 study, he was able to find an interaction only between a subtype and treatment with bevacizumab: Bevacizumab appeared to increase the pathological complete responses in basal-like tumors, but appeared to worsen outcomes among those patients identified with non-basal-like tumors.
Of the 360 breast tissue examined in the study, Sikov said that about 86 percent of the patients were identified as having basal-like characteristics; less than 14 percent of patients in the study had breast cancers of the non-basal molecular type.
‘Definitely Have Work to Do’
In commenting on the work, Steven Isakoff, MD, PhD, Instructor at Harvard Medical School/Massachusetts General Hospital Cancer Center, said in an interview: “We definitely have work to do here in trying to further identify which drugs are best to use in these patients.”
Added Joanne Mortimer, MD, Co-director of the City of Hope Breast Cancer Program: “We all struggle to know when cisplatin and bevacizumab are useful. Biologically it makes a lot of sense that these are active drugs, but the data has been difficult to direct us in what subtype of patients “
Sikov’s findings, she said, could be “hypothesis generating, but I’m not sure it is practice changing.”
Isakoff explained that the researchers, in this analysis, broke up the patient cohorts by basal-like and non-basal-like using the PAM 50 gene subtypes. “Going back about a dozen years, we realized that breast cancer can be categorized not just by immunohistochemistry but by molecular subtypes. In any kind of analysis of triple-negative now you don’t just break it up by estrogen receptor and HER2 receptor but by molecular subtype.”
The researchers were trying to isolate the triple-negative subtypes and were asking if there was a treatment difference based on the subtype, Isakoff said. “They went into this thinking that platinum would be more effective, but they determined that it didn’t matter if you were triple-negative basal or triple-negative non-basal.
“There was no difference in the pathologic complete response rate. His study shows that you can’t use identification of the basal-like group to help distinguish who should get platinum based therapies.”
Such Testing Not Gained a Lot of Traction’
Isakoff said that the testing for molecular subtypes has not gained a lot of traction in the oncology community: “This is not a test that most of us are doing. These results mean that the test to identify basal-like or non-basal-like triple negative tumors is one less test that we should have to push forward. There still may be other value to the test, but sorting out who should get platinum chemotherapy is not one of them.”
The one surprise from the study, he said, was “that the basal-like group got a lot more benefit from bevacizumab, but the non-basal-like patients may have actually been harmed by bevacizumab.
“This kind of data would lead to an adjuvant study with bevacizumab, but that study has already been done and it was negative. Bevacizumab is not a standard treatment in the United States anymore.”
The moderator of the news conference, AACR President Carlos Arteaga, MD, the Donna S. Hall Chair in Breast Cancer and Professor of Cancer Biology and Medicine at Vanderbilt-Ingram Cancer Center, rejected the idea that finding a role for bevacizumab by drilling down into the molecular level of triple-negative breast cancer would be fruitful: “We don’t use bevacizumab in breast cancer,” he said in an interview. “I don’t see any reason in these data for using bevacizumab at all.
“I asked Dr. Sikov specifically if he thinks this work is practice changing and he said he doesn’t think so. I think that maybe we need more work before we make the jump to use this information in practice. His study would indicate there is a role for carboplatin, but not for bevacizumab.”
Isakoff was somewhat more positive, saying, “This kind of study supports the idea that we may be able to find specific subgroups of patients where there could be a role for bevacizumab, but it is not likely to come directly from this study. We have a long way to go.
An important takeaway from the study, Isakoff said, is that using intrinsic subtypes is not predictive of adding platinum to a new anti-cancer regimen. “One interpretation of this is that platinum is an active drug but we can’t yet identify a population in which it provides more benefit than another.”
Mortimer added: “Clearly what we need to do is start planning therapies and clinical trials that revolve around true identification of basal cancers, since not all triple-negative cancers are basal cancers, and if this is a signal that these drugs are beneficial, we need to start subtyping these patients using the intrinsic subtype and actually study that group as a single population.”
Friday, December 12, 2014
BY ED SUSMAN
SAN ANTONIO – Premenopausal women diagnosed with low-risk early stage lung cancer will likely do well without chemotherapy or ovarian function suppression, but high-risk women will most likely require ovarian suppression regimens. That was the conclusion of a study reported here at the San Antonio Breast Cancer Symposium.
The big unanswered question, though, is how to treat patients who fall between those groups – i.e., those at intermediate risk.
As reported by Prudence Francis, MD, Associate Professor of Medicine at the University of Melbourne/Peter MacCallum Cancer Centre, in a plenary session, the Suppression of Ovarian Function Trial (SOFT) showed that women at low risk did well whether they were on tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression: “After 5.6 years of follow-up we saw that there was a small, but not a significant improvement in disease-free survival among the women who received ovarian suppression.”
The five-year disease-free survival rates in the no-chemotherapy and chemotherapy groups were 84.7 and 86.6 percent, respectively. “The overall premenopausal population did not benefit from the addition of ovarian function suppression — some women do very well with tamoxifen alone,” Francis said.
“However, there were important differences between the two distinct patient groups.” In younger women, those around age 40, there was a 22 percent reduction in the risk of recurrence among the women who were treated with tamoxifen and ovarian suppression when compared with women treated with tamoxifen alone.
“For women at sufficient risk of recurrence to warrant adjuvant chemotherapy and who retained pre-menopausal estradiol, the addition of ovarian function suppression to tamoxifen reduced recurrence,” she said.
“Basically, in the group of women who had prior chemotherapy and still retained ovarian function, the best outcomes came with use of exemestane and ovarian suppression compared with tamoxifen alone, with a 35 percent relative risk reduction of recurrence of breast cancer.”
While the addition of ovarian function suppression had benefits, Francis noted that it also increased the risk of menopausal symptoms, depression, hypertension, diabetes, and osteoporosis.
“Benefit from ovarian function suppression is most striking in women under the age of 35,” she said.
In the trial, 112 women under the age of 35 were assigned to tamoxifen only and about 68 percent of those women were free of breast cancer at five years; 121 women under age 35 were assigned to tamoxifen plus ovarian suppression and 79 percent of that group were free of breast cancer at five years; 117 women under the age of 35 were given exemestane plus ovarian suppression and 83 percent of them were free of breast cancer at five years.
Francis said that the women who received no chemotherapy – possibly because they were deemed to be at a lower risk of recurrence due to favorable tumor and other factors – did quite well. The 476 women in this group who received only tamoxifen for five years following surgery achieved a 95.8 percent disease-free survival rate.
Of the 473 women given tamoxifen and ovarian suppression, 95.1 percent achieved a five-year disease-free survival rate, and the 470 women who were treated with ovarian suppression and exemestane achieved a 97.1 percent disease-free survival rate at five years.
“These women had excellent outcomes,” Francis said. “We see no advantage for adding ovarian suppression in this group.”
Discussant: New Algorithm for Treatment
In commenting on the trial as a discussant, Hope Rugo, MD, Professor of Medicine at the University of California, San Francisco, cautioned interpretation of the results. “It’s still early,” she said. “We can’t possibly expect to see survival differences now. It is a short follow-up for overall survival in this population. And attention must clearly be made to management of toxicities such as hypertension and bone health.”
She said the study creates a new algorithm for treatment. The women who do not take chemotherapy and have smaller tumors, negative nodes, and low-grade tumors can be reasonably well-treated with tamoxifen for at least five years, she said. “We haven’t answered the duration question yet.
“For patients who have clearly high-risk disease, particularly for those patients who are less than 35, ovarian suppression appears to provide a marked and clinically significant reduction in breast cancer recurrence. Whether to treat with tamoxifen or exemestane due to differences in toxicity needs to be made on an individual basis. We still remain with the question of what to do with the intermediate-risk patients – those with low-grade, but larger tumors; low-grade tumors but with nodal involvement.”
Rugo asked: “Is there a group of patients where we could use endocrine therapy and ovarian suppression or endocrine therapy alone? My argument would be that in premenopausal women, endocrine therapy and ovarian suppression would be reasonable.”
In performing the SOFT trial, Francis and colleagues needed the strength of an international collaboration, she said--patients were recruited from 426 centers in 27 countries on all six inhabited continents. Women who were assigned to receive ovarian suppression were given the choice of being treated with triptorelin, bilateral oophorectomy, or irradiation.
In the trial 1,018 women were assigned to treatment with tamoxifen only; 1,015 women were treated with tamoxifen plus ovarian suppression; and 1,014 women were treated with exemestane and ovarian suppression.
The women were about 43 years of age, about 35 percent were lymph node positive (just nine percent of the women who were not receiving chemotherapy were lymph node positive); about 14 percent of the women not receiving chemotherapy had lesions smaller than 2 cm in size compared with 47 percent of the women assigned to chemotherapy.
The study, which was simultaneously published in the New England Journal of Medicine (DOI: 10.1056/NEJMoa1412379), was was co-sponsored by the Breast International Group; the North American Breast Cancer Group, and the International Breast Cancer Study group. Financial support and drugs used in the trial were supplied by Pfizer, Ipsen, and the U.S. National Cancer Institute.