|
||
BY DEBU TRIPATHY | NOVEMBER 30, 2011
This year's Annual San Antonio Breast Cancer Symposium has several presentations that could have immediate impacts on breast cancer care. Many of the details of results of clinical trials and other studies will not be fully disclosed until the time of the actual presentations, but the titles that have been posted offer some hints.
Several studies examining the effects of bisphosphonates on preventing recurrences of breast cancer will be presented for the first time or updated from previous presentations. So far, studies have yielded mixed results and these drugs are currently not recommended as adjuvant therapy - it is not clear yet if new information will tilt us toward new recommendations.
Also, the first large scale trial to be reported testing Tykerb (lapatinib) as adjuvant therapy for early stage HER2+ breast cancer will be revealed. While this may not change standards in the U.S., where Herceptin (trastuzumab) is the treatment of choice, there is also interest in combining the two drugs even though the combination study results are still pending.
Combining two hormonal therapies in metastatic breast cancer has not received much attention, so we are eager to see the results of a trial combining Arimidex (anastrozole) and Faslodex (fulvestrant) compared with Arimidex alone. In a similar vein, drugs that affect growth signaling have been shown to augment the effects of hormonal therapy, and updated results of the BOLERO II trial, showing improvements with the addition of the mTOR inhibitor Afinitor (everolimus) to exemestane for metastatic breast cancer will be presented. This strategy could very well be in practice soon as submission for FDA approval is planned. On the heels of the FDA's withdrawal of Avastin (bevacizumab) for metastatic breast cancer, two studies – one in combination with Herceptin in metastatic and one for patients on neoadjuvant (pre-operative) chemotherapy who are not responding will be presented, reminding us that the final chapter on this drug is still ahead.
On the diagnostic front, new information on molecular profiling to assess the risk of local recurrence of ductal carcinoma in situ (DCIS) may be helpful in planning surgery and radiation for this type of pre-invasive cancer that is being picked up more frequently with screening mammograms – a disease that rarely spreads and kills, but can recur in the breast and sometimes as a more dangerous invasive cancer. New information on markers that could help predict benefit from Herceptin and other biological drugs will also be presented.
Many advances in basic biology can be anticipated – the ones that are generating much interest (though still some way from clinical application) are further understanding of breast cancer stem cells and how they can be targeted therapeutically, new insights from full genome sequencing of breast cancers, and more details of growth factor receptor signaling pathways and how they vary among cancer cases, providing clues to vulnerabilities of cancer cells that can be exploited.
Overall, the agenda is very robust and we plan to continue our updates as soon as the news breaks.
Note: For full SABCS coverage, go to curetoday.com/sabcs2011.
RELATED POSTS
COMMENTS (0) |
PRINT |
SUBSCRIBE
BY DEBU TRIPATHY | AUGUST 28, 2011
With all the news of cancer drug shortages and the FDA's controversial decision to withdraw approval of Avastin (bevacizumab) for breast cancer, we are also getting some positive developments.
Just recently (on Aug. 26), the FDA granted accelerated approval to Xalkori (crizotinib), the newest member of an emerging generation of "niche" drugs. These are drugs that work in very defined subsets of patients, based on certain biological characteristics.
In the case of Xalkori, this is confined to the approximately 3 to 9 percent of patients with non-small cell lung cancer (NSCLC) who carry a chromosomal translocation that results in overexpression of the ALK protein (anaplastic lymphoma kinase). In fact, the approval of this drug is accompanied by the approval of a gene-based test to detect this translocation in tumor tissue. This approval comes on the heels of the approval of Zelboraf (vemurafenib) just eight days earlier for advanced melanoma, and again, only for the subset who harbor a mutation in the BRAF gene, and also approved with a diagnostic kit called the cobas 4800 BRAF V600 Mutation Test. In this case, the mutation is more common, seen in about half of all melanomas.
The big question is whether these two approvals herald the new age of personalized drugs. The now old story of Herceptin that many regard as one of the first targeted therapies, was spread out over 17 years from discovery of the gene to drug approval (or 11 years if you go from the discovery of HER2 amplification in breast cancer).
The new generation of drugs is being developed in a just a few years based on our exponentially growing body of data on mutations carried in cancers and new clinical trial designs that rapidly test drugs and verify biomarkers that predict response. Moreover, they seem to be quite effective with a higher percentage of patients responding, but not to the point that permanent cures are expected.
One can only hope that we are truly in the new era – and there are several indicators that this is the case. The Cancer Genome Atlas (TCGA) program is one of several worldwide that is collaboratively sequencing tumor genomes. Drug companies are investing more effort into biomarker analyses and integrating them earlier in the clinical trial process. Healthcare reform is demanding that drugs have a larger impact and that they not be used indiscriminately. Finally, the public's expectations are rising – they want more information about their cancers and access to clinical trials.
While it is possible that the initial wave of "low-hanging fruit" of "druggable" gene targets will soon be exhausted, it is more likely that we will have more targets and drugs than we can test. The bottleneck will really be in the patient clinical trials and how quickly and widely they can be deployed and fully enrolled. There will still be negative trials and other disappointments, but perhaps we are entering a new era where the bar of success is being raised.
RELATED POSTSCOMMENTS (1) |
PRINT |
SUBSCRIBE
BY DEBU TRIPATHY | FEBRUARY 28, 2011
There have been few drugs that have received more hype and coverage than PARP inhibitors. These work in a very elegant way – by inhibiting one of the mechanisms of DNA repair and appearing to exert the greatest effect on cancer cells that already have defects in another mechanism of DNA repair. (CURE's "A New Hope," about PARP inhibitors, was published in Fall 2010.)
The BRCA gene encodes a double-strand DNA repair protein and when mutated, causes familial breast and ovarian cancers that appear to respond particularly well to PARP inhibitors. "Triple-negative" (estrogen, progesterone and HER2 receptor-negative) breast cancers encompass those associated with DNA-repair deficiency. In advanced cancers of this type, the addition of the PARP inhibitor iniparib (also known as BSI-201) to chemotherapy yielded significant improvements in time to progression and overall survival. These results were even more dramatic than had been seen with Herceptin over 10 years ago, and had the rather sedate oncology community in a buzz.
Then why did the larger confirmatory phase 3 trial, which was supposed to lead to rapid FDA approval of this drug, not meet its endpoint? This rather shocking news was announced in a press release on Jan. 27 by sanofi-aventis, the company that now owns BiPar, the small start-up that discovered and initially developed this drug and moved it into a phase 3 trial with lightning speed.
There are many possible reasons for this. We really don't know exactly why clinical trials of the same design do not give us consistent results, but it does happen quite often. It might be just the play of chance, as from a statistical standpoint, any experiment can only give you a certain level of probability that the result reflects reality. We accept a 95% probability as sufficient proof – but what happens if another trial falls just short of that mark – is it really a conflicting result? We are also realizing that the behavior of cancer and response to specific treatments can vary among the different subtypes that we are just starting to discern with sophisticated molecular tools. An imbalance of these subtypes among the treatment arms might go undetected, but could alter the findings.
Whatever the reasons, the road ahead for PARP inhibitors is unclear. For iniparib, the timing of the FDA approval, the population that should be treated and the need for further studies will be decided shortly. For olaparib, AstraZeneca recently announced that ovarian cancer and not breast cancer will be the future focus of study. There is also evidence that the several PARP inhibitors in clinical development are not the same and may have different targets, mechanisms of action and side effects.
Most scientists and clinicians agree that these drugs are a big step forward. In fact, it is important to recognize that the iniparib phase 3 trial did in fact show a big improvement in patients receiving second- and third-line therapy, and this needs to clearly be pursued. It is just very hard to know exactly how this will all unfold.
RELATED POSTSCOMMENTS (8) |
PRINT |
SUBSCRIBE
BY DEBU TRIPATHY | OCTOBER 28, 2010
As both a clinician and scientist, I always look at new biological findings with a mixture of enthusiasm and skepticism. In the New England Journal of Medicine, a very provocative finding was published (the Journal prides itself on being the first to report something that just might be a game changer).
A new property of a well-known protein called the follicle stimulating hormone receptor (FSHR) was described – namely, its presence in the blood vessels of many different types of tumors in humans – breast, prostate, colon, and host of other cancers. Normally, FSHR is expressed in specific cells within the ovaries and testes, in keeping with its known roles in sex hormone production and menstrual cycle control. This was a very carefully done study, with multiple antibodies against FSHR and very careful analysis over the areas of many tumors and adjacent normal tissue. Staining for FSHR was seen in tumor-associated blood vessels within all of the tumor tissues in 1,336 cases, and in some cases of "precancerous" tissue. Its expression in blood vessels fell off progressively in moving away from the tumor into normal tissue.
Might this new finding represent a target for treatment against many types of cancer? Well, we have been down this road before – a tumor-specific antigen that is hailed as a way to develop the perfect magic bullet, only to lead to disappointment once tested in patients. Still, anti-angiogenic therapy - the targeting of tumor blood vessels that are necessary for tumor growth and spread, has been a successful strategy, with the drug Avastin showing improvements survival in colon and brain cancer, but not fully curative in advanced cancers.
In the case of breast cancer it delays progression without improving survival. Avastin does not only target tumor blood vessels, since the growth factor it targets is also involved in non-tumor blood vessel formation and other cellular functions – hence it has side effects.
In the case of FSHR, the investigators showed that they can deliver particles bound to antibody to tumor blood vessels using animal tumor models. This might therefore represent a promising therapeutic avenue, although there may be toxicity to the ovaries and testes that would need to be addressed. It remains unknown why FSHR is expressed on tumor blood vessels – but there is good reason why it made the "scientific front page."
RELATED POSTSCOMMENTS (0) |
PRINT |
SUBSCRIBE
BY DEBU TRIPATHY | AUGUST 10, 2010
The story surrounding the FDA's process for the final approval of Avastin (bevacizumab) for advanced breast cancer raises many questions about the standards on drug approval in this changing era of targeted therapy and personalized medicine.
In early 2008, the FDA granted an "accelerated" approval on the basis of a trial that showed a significant delay in the time to progression, but no difference in survival time, when added to Taxol (paclitaxel) as first-line treatment. This meant that final approval would be dependent on subsequent trials showing similar degrees of benefit. When two additional trials were submitted for review, both showed significant improvements in time to progression, but again with no difference in survival. The advisory panel to the FDA voted on July 20 this year to NOT recommend full permanent approval.
Did the FDA and the advisory panel change the ground rules, now asking for a survival benefit when none of the trials were designed to enroll enough patients to do this? Or was it that the difference in progression time was not as large in the subsequent trials, even though statistically, one cannot compare these values across trials.
Either way, researchers and advocacy groups are both split on whether the FDA advisory panel made the right call and what the final FDA ruling should be, which is due by September 17. For other indications in advanced lung, colon, and refractory brain cancer, Avastin produces a survival advantage. However, does delay in progression in its own right represent a real benefit? The FDA has the charge of ensuring that new drugs have a favorable benefit/risk profile, but it does not specifically define what the rules are for measuring each of these. In some cancers, prolongation of progression is tightly linked to an improvement in survival, but this is not solidly the case in breast cancer. Also, progression delay might improve quality of life, but such evidence is hard to generate, and was not clearly shown in the two Avastin trials. The issue of the economic cost of small incremental benefits is also being raised, but the FDA is not supposed to take that into account--still, some wonder whether this factor somehow crept into the advisory board's decision.
The way the FDA thinks and decides on these issues still remains somewhat veiled. While FDA officials are very open about discussing their thoughts and regularly meet with companies ahead of time to review trial designs and strategies for approval, none of these discussions bind them to their ultimate decision. This leaves companies trying to figure out the quickest and surest path to approval, not necessarily representing the best scientific or societal plan, or even for that matter, the best thing for the company itself.
This sage may tell us that NOW is an opportune time for governmental agencies (both regulatory and Medicare/Medicaid), patient advocates, the pharmaceutical industry, and clinical researchers to all come to the table to discuss a framework, or "rules of the game," for moving forward in light of both health care reform and new discoveries in cancer biology personalized medicine.
RELATED POSTSCOMMENTS (0) |
PRINT |
SUBSCRIBE
BY DEBU TRIPATHY | APRIL 17, 2010
As more and more information comes in from large-scale trials, it is clear that estrogen replacement therapy in the usual form of an estrogen plus a progesterone drug (E+P), commonly called hormone replacement therapy or HRT, increases the risk of breast cancer.
When the results from the "definitive" randomized trial, the Women's Health Initiative (WHI) study, were announced in 2002 and showed about 25 percent more breast cancers with E+P compared with placebo, the use of HRT plummeted. A few years later, this became evident with fewer breast cancers diagnosed, reversing a longstanding trend of rising rates.
However, the estrogen receptor is expressed in many other tissues besides the breast, so further analyses of this trial looking at other cancers showed interesting effects--such as a higher death rate from lung cancer with E+P, but interestingly, a lower risk of colorectal cancer.
Just this month, a group at the University of North Carolina, using a less reliable case-control design, found the lower end of colon and rectal cancer risk has halved with any HRT use. However, on further follow-up of the WHI study, it turns out that the colorectal cancer cases on E+P were of higher stage, so that there were actually more deaths from colorectal cancer on replacement therapy. Finally, E+P also increased the risk of stroke and blood clots in the lung and appeared to raise the chance of heart attacks, especially in the first year of therapy. It did lower hip fracture rates, in keeping with its bone density-enhancing properties.
So clearly, E+P causes more cancers and does not, as initially thought, protect the heart. Even though there are still detractors who criticize the trial design--the age at which patients were started on therapy and the exact form of therapy--one wonders if there is at all a silver lining in this story.
Well, there might be--and that is therapy with estrogen alone. This therapy can only be given to women who have had their uterus removed. In women who do have a uterus, estrogen-only therapy can cause a build-up of the uterine lining and raises the uterine cancer risk. (Women with a uterus receive E+P because adding progesterone reduces that risk of uterine cancer).
The WHI study also randomized more than 10,000 women who had prior hysterectomy and gave them either estrogen alone or placebo. In this trial there were actually fewer cases of breast cancer, not quite statistically significant, though. There was no effect on colorectal or lung cancers. There were also slightly fewer stokes and heart attacks, but more clots to the lung; however none of these were statistically different.
So, it is possible that estrogen might be a useful drug in women without a uterus, but clotting problems are still a concern. We have seen the emergence of designer anti-estrogen drugs like raloxifene (approved for breast cancer reduction and osteoporosis), and more recently lasofoxifene, an investigational drug found to lower fracture, breast cancer, stroke, heart attacks, but increased clots.
Manipulating the hormonal milieu is a tricky proposition, but future generations of "estrogen modulators" might just strike the right balance for multiple health effects.
For more on HRT and the risk of breast cancer, read "The HRT Connection" from Fall 2007.
RELATED POSTSCOMMENTS (0) |
PRINT |
SUBSCRIBE
