Sorting out the low-risk cancers


Debu Tripathy blog image

There is so much attention on the aggressiveness and dangers of cancer – and rightly so, as it is a major cause of death in our society. However, there is a flip side to this story – a diverse group of low-risk cancers, or "precancers" that could in some cases even be better left undiagnosed, as the treatment may actually cause more harm than good. These types of malignancies include diagnoses like "in situ" or "non-invasive" cancers that are commonly seen in the breast, prostate and cervix, or "borderline ovarian tumors."

In many cases, they do not have the potential to invade other tissue or to spread, so they don't carry the same risks of illness and death. Some have even advocated that we rename these diseases without using the words "carcinoma" or "cancer," which bring out fear and anxiety and also motivate patients, as well as clinicians, to carry out more aggressive treatments.

However, these low-risk cancers can sometimes co-exist with more dangerous invasive (or infiltrating) cancers, and as they are typically treated with surgical removal, there can still be recurrences over the course of time, which can be either in situ or invasive. They rarely can result in death. However, these bad outcomes are unusual enough that when one looks at large population statistics for many of the in situ types of cancer, survival rates are indistinguishable from the normal population.

So, what are medical experts and even some patient advocates now saying?

The messages are mixed as there is controversy that balances the small risks of these cancers against side effects of diagnosis and treatment. For one, there are calls for modifying our cancer screening procedures – this is particularly true for breast and prostate cancer, where "overtreatment" of harmless cancers carry significant short- and long-term side effects. We also need to develop better imaging and tissue-based tests to identify the rare aggressive cancer hiding among a sea of low-risk cases. Finally, we need to make sure that physicians and the public are up to date on the latest recommendations and developments in this area, as it will continue to evolve.


AACR update: Breast cancer studies offer more potential treatment options


Debu Tripathy blog image

Two studies announced at this year's annual meeting of the American Association for Clinical Research are targeting unique molecular features that drive breast cancer. One study is testing the drug palbociclib, which targets an abnormality in the cancer cell cycle. The drug is being tested in hormone-positive breast cancer in combination with the aromatase inhibitor, Femara (letrozone). The combination significantly delays the time it takes for the cancer to continue growing. At the current time, it's not showing a survival advantage, but a phase 3 trial in progress may be the deciding factor for the drug's approval.

Another study is looking at a drug called neratinib, specifically in HER2-positive breast cancers. It's part of the I-SPY2 study, which is testing multiple new therapies before surgery, as neoadjuvant therapy. The results show that neratinib can result in complete disappearance of the tumor. This may represent a new drug for patients with HER2-positive breast cancer, including patients who have progressed on other HER2-targeted therapies.

Debu Tripathy is an oncologist and editor-in-chief of CURE. He is the co-leader of the Women's Cancer Program at Norris Comprehensive Cancer Center and Professor of Medicine at the Keck School of Medicine at the University of Southern California.


Personalized medicine and what it means


Personalized cancer medicine has become a major buzzword as of late, but what does it really mean?

Everyone defines it differently, so the bird's eye view of this term would be as encompassing as possible. On one level, it means that every patient is an individual and that their course through the diagnosis and treatment of cancer should reflect their values and preferences within the boundaries of medical evidence that is works. The way information is communicated, the way different choices are presented, and even how treatment choices are balanced against side effects (sometimes permanent), all need to be customized.

A mother of two young children and a professional violinist might make very different treatment decisions about using a chemotherapy agent that causes neuropathy even if the benefit (improvement in cure rate) is identical. Similarly, the medical care team needs to formulate tailored strategies to keep patients satisfied with treatment, compliant with medications and educated about when to call with side effects. Using a one-size-fits-all approach will probably lead to much lower performance in all these departments.

A very different definition of personalized medicine is the high tech world of genomics and proteomics that exposes unique vulnerabilities in an individual's cancer. Just in the last year, massive amounts of genomic information from the tumors of many patients has been made available through publications and databases-–analyzing this fire hose of data is starting to reveal that cancers do in fact harbor many genetic "drivers," and the next step will be to squelch these with targeted drugs. Also, deciphering inherited variations the drug metabolizing enzymes will help us predict who is more susceptible to drug side effects--further customizing treatments.

The best model of personalized medicine is one that integrates all these definitions to create an environment that revolves around the patient. This includes a rationally composed and individualized treatment plan using the best science along with supportive approaches that add up to a holistic plan that is reflective of the individual. Let's hope that health care reform will encourage and incentivize personalized medicine for cancer.


Do you understand the goal of your cancer treatment?


The New England Journal of Medicine tends to publish larger and higher impact studies that will affect standards of care, but they also will print eye-opening studies that tell us something unexpected and give us pause for thought.

A very important survey appeared in the Journal recently – it was part of a larger study that explored the attitudes and knowledge of patients with colorectal and lung cancer. This analysis of patients with advanced metastatic cancer who opted for chemotherapy showed that most patients had unrealistic expectations of cure – something that is rare in metastatic cancer. This is in contrast to earlier studies, many of which were done at larger and specialized cancer centers, which showed that most patients understood that cure was not likely.

What does this study say about patients being seen in clinical practice that reflects the average across the United States? At initial glance, it appears that patients are not adequately informed or do not fully understand their accurate prognosis. However, it is difficult to interpret results of questions asked or over the phone and to surrogates who answer in the patient's stead as was the case in this study. This study was not designed to delve into the complexities of patients' levels of hopes and understanding about their disease. Still, there are important lessons for us all in these results.

A higher expectation of cure was seen in patients who were non-white, or had colorectal cancer, and interestingly, who reported better communication with their physician. It means that physicians need to use better educational methods, but still retain their patients' trust and confidence. We live in a time where technology keeps pushing the envelope on outcomes in cancer, but where cure of many common cancers in the metastatic setting is still fleeting. The public needs to make fully informed decisions about their health care – whether it is for metastatic cancer or open heart surgery for coronary artery disease.

In this age of information at one's fingertip, this should be much more achievable, but on the other hand, the savviest of readers needs a guide in the informational jungle. CURE's special edition on metastatic cancer, which will be available in December, aims to educate with compassion, realism and hope – we believe that all of these are mutually compatible.


Super Herceptin?


So how does T-DM1, an investigational agent that attaches Herceptin to a toxic drug, stand up when tested against the current treatment for cancer already progressing on Herceptin?

Well, it's been quite a busy time at ASCO, a lot of advancements on many fronts. The first and foremost is a new HER2-targeted therapy called T-DM1. This is for patients with HER2-positive breast cancer.

We've known for many years that the antibody Herceptin can clearly improve outcome in early stage and can even improve survival in advanced stage. However, in advanced breast cancer, most patients eventually progress.

In addition to Herceptin, there has been one other FDA approval, a drug called Tykerb, or lapatinib. When combined with a chemotherapy called Xeloda, it can delay progression, but it hasn't shown to improve survival. So, we're still in need of better therapies for HER2-positive advanced breast cancer.

This new drug, T-DM1, uses the Herceptin antibody, but it's bound to a very toxic drug. This drug couldn't ordinarily be used alone because it has too many side effects, but when it's bound to the Herceptin antibody with a linker, it works like a Trojan horse. It gets internalized into the tumor cell and induces cell death.

This drug was earlier found to be effective in patients who had already progressed on Herceptin and Tykerb, but the FDA did not want to use this data alone to approve the drug. The FDA wanted to see a randomized trial, and then it wanted to see a survival advantage. So, it took another two years to get the trial done.

The researchers compared T-DM1 to Tykerb and Xeloda, and the results of this trial show a pretty dramatic benefit. There was about a third longer time to progression in patients receiving T-DM1 compared with Tykerb and Xeloda. There also seems to be a survival benefit, but it's too early to fully confirm it. However, the way the data is panning out, it almost will certainly show a survival advantage. Most of us think this will be sufficient to get the drug approved, but we'll have to see if that's the case. It will certainly change the treatment approaches in treatment of HER2-positive breast cancer.

There are also combinations with T-DM1 being tested. We've mostly heard about safety data, not effectiveness just yet. We know we can combine it with the chemotherapy Taxol, and it appears to be safe. There is a large randomized trial combining T-DM1 with another drug called pertuzumab. This is an antibody, when combined with Herceptin, appears to improve outcomes in first-line therapy, whereas T-DM1 was tested in second-line therapy.

Finally, as one might expect, there are trials designed to look at T-DM1 in early-stage breast cancer. We know the best we can do for patients is to prevent metastatic recurrence in the first place, so we're putting a lot of effort into treating early-stage breast cancer. No results yet, though; it will probably take a couple of years for that data to emerge.

When you look at the big picture, you have to recognize that HER2-positive breast cancer 20 years ago was considered the most aggressive type of breast cancer. Now it's one of the better types of breast cancer because we have effective therapies for it. But there is still a lot of room for improvement. We're still not curing advanced HER2-positive breast cancer.


What to look for at this year's SABCS breast cancer meeting


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


Drug approvals: Are we in a new age yet?


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.


Negative PARP inhibitor trial raises questions and dampens hope


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.


Is a new anti-angiogenic strategy on the horizon?


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."


ODAC's decision on Avastin in breast cancer raises many questions


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.


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