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BY DEBU TRIPATHY | AUGUST 21, 2012
Cancer does not affect everyone equally. They type and extent of cancer matters, of course, but so does the nature of the individual.
One of the biggest differentiators is age, especially those who are in the adolescent and young adult age, which is arbitrarily defined as between ages 16-39. This so-called "AYA" range is an area where we need more information and research. While mortality has improved for all cancers on the average, patients in the AYA age range, as a whole, has not benefitted over the years. This could be due to a number of factors - less insurance coverage, patient naturally focusing on other aspects of their life and maybe affecting compliance, misdiagnosis or delay in diagnosis, and the lack of consensus or knowledge on the best treatment approach since cancer is not common at this age and some of the cancers are of rarer types.
Our center has embarked on an AYA program and we are aiming to address patient care, research and education through coordinating care, making resources available (such as fertility planning and social network-based support), supporting research through tissue banking and specialized clinical trials, and by exposing trainees in various medical fields to AYA oncology. (You can read more here.)
The shortage of funding in this area, and the fact about 10 to 12 percent of patients are in this range, force us to be creative and efficient with our efforts, but we believe that this mission is critical to a significant part of our cancer population.
Patients who are facing cancer at a time of personal and professional growth have to balance between these important priorities and run the risk of isolation and threats to relationships and careers in addition to fighting cancer. AYA cancers affect us all and we welcome the trend in building AYA oncology centers of excellence and raising awareness for this special effort.
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BY DEBU TRIPATHY | JUNE 29, 2012
It was a complicated decision – so complicated that a couple of the major news outlets reported incorrectly that the sweeping health care reform law enacted by Congress in 2010 have been struck down by the Supreme Court.
In fact, most of this law, with the exception of the Federal government's ability to withhold states' Medicaid funding, was upheld. Despite calls by some for this law to be dismantled, it is unlikely that the more popular measures of significant impact to cancer patients will go away. These include the outlawing of limitations of insurance coverage for pre-existing medical conditions or exceeding lifetime caps. It also means that 30-plus million individuals will join the ranks of the insured – entitled to health care screening and prevention, earlier cancer diagnosis and treatment and appropriate cancer follow-up. Reams of data show worse cancer outcomes among the uninsured. The consequences on care costs and improved productivity are also projected to be positive by most experts.
So this is a big deal (in Joe Biden's words – BFD) not only for cancer patients, but also for the whole country that shares the burden of cancer both in human and financial terms. While the law will certainly be amended by Congress and Executive actions over time, a new era in health care will emerge as the new law of the land is enacted.
Cancer patients and their advocates must stay on guard to understand and participate in this process and new initiatives that affect cancer care and research. Regardless of one's opinion in the whole matter, we must exercise our inherent rights bestowed by our government system – a time-tested model that still works in today's partisan environment.
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BY DEBU TRIPATHY | JUNE 14, 2012
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.
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BY DEBU TRIPATHY | JUNE 5, 2012
Even in the age of biologically targeted drugs, chemotherapy still remains what is known as the "backbone" of therapy in many situations. Chemotherapy is commonly used with biological agents both in early-stage breast cancer to lower the chance of recurrence and improve the cure rate. For metastatic breast cancer, it delays progression even though usually not curative. We are still refining our knowledge as to which drugs and schedules work the best – two important studies were presented today at the annual meeting of the American Society of Clinical Oncology (ASCO).
For metastatic breast cancer, some of the newer drugs including Abraxane (albumin-bound paclitaxel) and Ixempra (ixabepilone) have been approved on the basis of being better than older drugs like Taxol (paclitaxel) or better when added to Xeloda (capecitabine) in patients who have already received other chemotherapies. However, as initial therapy, it is not clear which option is best.
The CALGB 40502 study compared Taxol, Abraxane and Ixempra – all given in a weekly schedule, which is felt to be the best for each drug. Avastin (bevacizumab) was given with 98 percent of patients even through the FDA withdrew approval of this agent early during the course of the trial. The results showed that Taxol was better than Ixempra and similar to Abraxane in terms of time to disease progression and also associated with fewer side effects such as neuropathy. However, it is not clear that the optimal dose of Abraxane and schedule of Ixempra was used.
Another study (NSABP B-38) looked at adjuvant chemotherapy for early-stage breast cancer comparing two standard regimens of TAC and AC-T to an experimental regimen:
1. TAC (Taxotere [docetaxel], Adriamycin [doxorubicin] plus Cytoxan [cyclophosphamide] for 6 cycles)
2. AC-T (Adriamycin and Cytoxan for 4 cycles followed by Taxol for 4 cycles every 2 weeks, also known as dose-dense schedule)
3. AC-T with Gemzar (gemcitabine) added during the Taxol phase of therapy (experimental)
No difference was seen between these arms in the relapse rate of about 15 percent at 5 years and death rate of 10 percent. There were more side effects with the addition of Gemzar to AC-T. TAC was associated with more diarrhea and infection while AC-T resulted in more neuropathy and anemia.
These studies together tell us that in advanced breast cancer, good old-fashioned (and much cheaper) Taxol works just as well as the other drugs. For early-stage cancer, the common regimens of dose-dense AC-T or TAC are about equivalent but with different side effect profiles. While not earth-shattering new data, this is very practical information that helps guide us more definitely in chemotherapy treatment options.
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BY DEBU TRIPATHY | JUNE 2, 2012
We are still not curing advanced cancers with immunologic therapy, but an important step forward was announced today at the annual meeting of the American Society of Clinical Oncology (ASCO). Both at ASCO and simultaneously published online in the New England Journal of Medicine were the results of several trials of an antibody to PL-1, a receptor on immune T cells that normally dampens the immune system.
Our immune system deploys antibodies and cell-killing activity against foreign invaders, but has to rev back down after the infection and also has to develop a tolerance to "self" antigens on normal tissue. This dampening system is often hijacked by tumor cells to avoid immune destruction. There is already a drug approved that blocks the dampening effect and allows the immune system to better unleash its effects on tumor cells.
Yervoy (ipilumumab) blocks an immune-dampening receptor call CTLA-4 and has been shown to improve survival in patients with melanoma. Another such receptor called PD-1 (for "programmed death"), can be targeted with an anti-PD1 antibody. Two large early phase trials with this drug (known as BMS-936558) presented today reported activity in patients, with about 18 percent of patients with lung cancer having a response in addition to 30 percent of patients with kidney cancer and melanoma--the two cancer types that can respond to immunotherapy even though only about 5 to 10 percent are long-term remissions with the non-specific immune stimulator, interleukin 2.
The potential addition of lung cancer to immune-responsive cancer is clearly important--there is excitement already about vaccines that are in late-phase testing for lung cancer, as well. However, this new antibody, similar to Yervoy, appears to cause reciprocal immune injury to normal tissue, with these trials reporting inflammation of the colon, lung and endocrine glands.
Unleashing the immune system in other cancers will require further study and more understanding about the immune regulatory controls. Extending this to other cancers, testing it earlier to prevent metastases in the first place, and refining the immune response to spare normal tissue will all be important priorities for the future.
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BY DEBU TRIPATHY | APRIL 9, 2012
In an unusual move, several professional societies jointly released a set of principles entitled "Choosing Wisely" (see choosingwisely.org) – five tests and treatments for each of several specialties that physicians and patients should question. Things that eventually cause more harm than good and also tend to drive up healthcare costs. The ones that are listed for cancer are available at: choosingwisely.org/wp-content/uploads/2012/04/5things_12_factsheet_Amer_Soc_Clin_Onc.pdf.
While these recommendations will need to be tailored to individual situations, they have the common theme that these tests that are done for "reassurance" or early detection of recurrence or metastasis of cancer when the chances of having a positive test are low, even lower than the chances of "false-positive" results that commonly lead to further testing or even harmful procedures. Also, there are two recommendations to avoid medical treatments (white blood count boosting drugs and chemotherapy for advanced cancers) in situations where there is no proven benefit. However, there is certainly going to be vocal opposition and there are already some who are criticizing this as some type of healthcare rationing. In particular, the recommendation to withhold chemotherapy in patients who have almost no chance of being helped by such treatment will be hard for many to accept.
This illustrates one of the key dilemmas of medical care and one of the reasons that our healthcare costs are the highest in the world whereas our health outcomes are clearly not the best. In the U.S., doctors and patients are quick to request tests and procedures that on the average may yield a very small chance of benefit and a greater chance of unnecessary treatment. But if you happen to be one of the rare patients that is helped by one of these tests, your viewpoint may be different. At the moment, the public (and most lawmakers who are elected by the public) have no appetite for advocating any restrictions on what a doctor and patient feel is the best course of care. But as patients are burdened with more costs of insurance and co-pays, they are starting to "self-ration" care.
In the last couple of years, more patients are opting to defer test and even cancer treatments mostly because of cost. Despite the controversy this movement will stir, it is clear that patients and physicians need to have information available to prioritize what test and treatments can be omitted without any (or minimal) change in outcome. But will our society be willing to accept these statistics and forgo the long shot?
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BY DEBU TRIPATHY | MARCH 2, 2012
There has been much news lately about new cancer drugs designed to be given in combination with older drugs – two for breast cancer that probably will be approved by the summer.
One of these is the HER2 antibody pertuzumab, which is given in combination with another HER2 antibody, Herceptin (trastuzumab). The other is the mTOR inhibitor Afinitor (everolimus) given with hormonal therapy.
The concept of specific therapeutic combinations makes biological sense because there are many intersecting biological pathways that drive cancer. However, our knowledge of these pathways and the specific proteins involved in them is very primitive at the moment, so we don't have a reliable way of finding the spectacular combinations (or secret formulas) that are considered synergistic – that is, where 2 + 2 = 100 in terms of effect.
This term is also known in scientific circles as "synthetic lethal," the sort of perfect storm, biologically speaking, where a specific combination of drugs disables cancer cells so effectively that none survive (or just a few in a trillion) so that a patient is effectively cured – or at least can live with advanced cancer with a normal quality and length of life.
The latest drugs that will be approved by breast cancer are not quite in this league, but certainly a step in the right direction. To finish the job, we need a combination of innovations in the laboratory and more information from the genetic abnormalities in human cancers. Specifically, systematic DNA and RNA sequencing and in-depth protein analyses of large numbers of cases tumors. It is hard to know if that alone will get us there, but it has become the new holy grail of cancer drugs.
Most cancers will probably require "cocktails" of drugs, very much like what it took to successfully treat (but not cure) AIDS. But the cocktail will need to be customized – much like a Chinese herbal formula, but in this case based on the molecular features of the individual cancer.
However, there is still a twist. This is termed "intratumoral heterogeneity," or differences between cells of a tumor that can lead to evolution over time, or selection of the fittest cells able to withstand cancer therapy. This is another challenge, but also an opportunity to learn how to develop better treatments. I will discuss this more in my next blog, so stay tuned.
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BY DEBU TRIPATHY | DECEMBER 11, 2011
The final day of the San Antonio Breast Cancer Symposium began with an update from members of the working group of the Cancer Genome Atlas (TCGA) and International Genome Consortium (IGC) who are together embarking on a massive project to obtain broad scale gene sequencing, RNA profiles and functional protein information on breast tumors and to assemble a comprehensive database that can be immediately shared and "mined" to obtain important clues to the triggers of cancer and its vulnerabilities that can be exploited for therapy.
The efforts in the breast cancer component of this project will eventually involve over 1000 cases and a very large team of scientists, bioinformaticians and clinical consultants. The sheer amount of data generated (3 billion base pairs for each tumor genome just for starters) is mind-boggling. But special data analytical tools and high-powered computers are able to generate patterns – a glimpse of this was presented in a progress report on Sunday, revealing some new insights.
Most tumors contain several mutations, but only a few are commonly seen. The recurrent genetic abnormalities are presumed to be "drivers" – directly responsible for cancer behavior, while some are "passengers" – results of genetic instability and errors in DNA division and processing, but not affecting malignant potential. This is an important distinction, since drivers represent potential diagnostic markers and targets that are "druggable", and would only have been discovered through this extensive effort.
The numbers and types of mutation seen are distinct among the recognized classes of breast cancer based on hormonal and HER2 receptor status. Also, the consequences of these mutations on cell function appear to be similarly grouped. The expression of genes and their translation into protein, which are the actually workhorses of cellular structure and function, are not only affected by gene mutations but also by "epigenetic" alterations. These are not picked up by gene sequencing, but rather by detecting attachments to certain base pairs of DNA and the proteins that help organize DNA into a useful template that orchestrates when and where genes are expressed.
There is growing evidence that epigenetic changes may be the earliest events that set the stage for genetic mutations and modulation of the tissue microenvironment that help support cancer growth and spread. The field of epigenetic is rapidly growing and a few approved cancer drugs work through these mechanisms. At Sunday's session, a clearer map of epigenetic changes in the context of cancer subtypes began to emerge and this will undoubtedly provide a roadmap to better classification systems and treatment strategies.
What was special about this session is the power of collaboration and large numbers. The tiny pixels are starting to come together to provide a landscape – and we all hope this will be transformative.
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BY DEBU TRIPATHY | DECEMBER 10, 2011
Dr. Debu Tripathy discusses how a test, a variation of the Oncotype DX test, could help physicians decide on radiation therapy for their patients diagnosed with ductal carcinoma in situ (DCIS).
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BY DEBU TRIPATHY | DECEMBER 10, 2011
Dr. Debu Tripathy explains the HER2 pathway's involvement in breast cancer and how new investigational drugs, including pertuzumab and TDM1, as well as combinations of new and approved drugs are targeting this pathway.
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