MaverickNY | Pharma Strategy Blog

Improved survival with ipilimumab in metastatic melanoma

By MaverickNY on August 19, 2010

The latest New England Journal of Medicine dropped in the mail yesterday afternoon, it has some interesting articles on how palliation plus chemotherapy offers improved survival over chemo alone and a small study on the positive impact of T'ai Chi on fibromyalgia. My attention, however, was drawn to the ipilimumab data in advanced metastatic melanoma.

We saw the first major presentation of this phase III trial recently at ASCO, and my pre-ASCO notes can be found here. At the BMS investor meeting held during the conference, the executives were clearly very excited about the prospects for the agent. It would seem that the FDA agrees with them, as it was announced yesterday that Priority review status has been granted in previously treated people with melanoma. The PDUFA action date is estimated as December 25th, 2010, so I think we can safely assume that it will likely happen a bit before that 🙂

Going back to the NEJM paper, what can we expect?

The complex study design looked at the impact of ipilimumab, which targets CTLA-4 antibodies resulting in anti-tumour effects, with and without gp100, a vaccine based on melanoma vaccine, versus ipilimumab alone in a phase III trial of 674 patients. In short, here's how the median overall survival results stack up:

Ipilimumab + gp100: 10.0 months
gp100 alone: 6.4 months
Ipilimumab alone: 10.1 months

There was no difference in survival between the two ipilimumab groups, suggesting that the gp100 vaccine isn't adding anything to the mix. I'm not really convinced, however, of the arguments for using gp100 as an unconventional control over dacarbazine (DTIC) in patients who had previously failed IL2 therapy. From this data, we have no idea how ipilimumab stacks up versus dacarbazine in the second-line setting, but given there is no standard of care in the refractory setting for patients who have failed dacarbazine, it presented a tricky issue in trial design. Still, the overall survival advantage in favour of ipilimumab alone speaks for itself.

It will be interesting to see what BMS do with this commercially, if the FDA approve it and they most likely will. Based on this data, it appears to make sense to market ipilimumab alone without the extra costs and potential toxicities associated with adding gp100.

Four months improvement in advanced refractory melanoma is a relatively big jump, and like many I'm excited to see that, despite the low responses rates seen in the ipilimumab groups (6-11%). The editorial by Hwu also noted that:

"… the true importance of this drug lies in the long-term benefit that was seen in a subgroup of patients. Follow-up from the earliest cohort of patients that received the anti–CTLA-4 drug shows that ongoing complete responses in some patients with metastatic melanoma can continue past 6 years."

The biggest downside of this trial though, was the side effect profile. Whereas we recently saw few fatal toxic side effects associated with the Provenge vaccine in castrate-resistant prostate cancer, immunotherapy with ipilimumab is an entirely different kettle of fish, as the NEJM article demonstrated:

Grade 3-4 immune related adverse events:

10-15% of ipilimumab treated patients
3% treated with gp100 alone

Deaths in study:

14 related to study drugs (2.1%)
7 associated with immune-related events

Now, we need to remember that people entering clinical trials at Academic centres are not the typical patients seen in the Community setting. They tend to be younger and have a much better performance status for a start, so it is likely that there will be some nervousness associated with management and complications in older, more frail patients. The authors noted that:

"Adverse events can be severe and long-lasting, or both, but most are reversible with appropriate treatment."

It reminds me somewhat of the situation with another immune-related therapy a few years ago with alemtuzumab (Campath), an monoclonal antibody that binds to CD52 in chronic lymphocytic leukemia (CLL), where the occasionally urgent side effect management and rare complications that can arise (CMV activations, severe infections etc) were so resoundly disliked by the Community, that most avoid using it where at all possible. Urgent medical attention of severe and, potentially fatal, complications is much easier to handle in a hospital than an office setting, especially on a Friday afternoon or over the weekend.

Ipilimumab looks to be an efficacious therapy that extends life, but at a cost. I can therefore see that it will mostly likely get used in Academic settings, where there is more comfort and familiarity in dealing with the potential complications, especially in advanced, relapsed disease. I could be wrong in that assessment, but that is what instinct tells me.

Most doctors will try something once, especially in the refractory or salvage setting, but the first sign of potentially fatal complications requiring urgent medical attention creates an environment that is fraught with stress and worry, busy Community practices may well decide it will be easier to refer appropriate patients in that situation.

In an accompanying editorial (see below for reference link), Patrick Hwu summed up the trial and new directions in metastatic melanoma admirably:

"Despite dramatic effects in a subgroup of patients receiving the anti–CTLA-4 drug, the majority of patients with metastatic melanoma do not respond to this agent, and further work is vital to improve these results.

Future efforts should include the rational combination of anti–CTLA-4 agents or alternative checkpoint inhibitors with targeted therapies or other immune agents. Instead of attempting to marginally increase the median survival, the primary goal of these new combination therapies should be to enhance the percentage of long-term survivors, thereby elevating the “tail” of the survival curve."

{Disclosure: Long on BMS}

Hodi, F., O'Day, S., McDermott, D., Weber, R., Sosman, J., Haanen, J., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J., Akerley, W., van den Eertwegh, A., Lutzky, J., Lorigan, P., Vaubel, J., Linette, G., Hogg, D., Ottensmeier, C., Lebbe, C., Peschel, C., Quirt, I., Clark, J., Wolchok, J., Weber, J., Tian, J., Yellin, M., Nichol, G., Hoos, A., & Urba, W. (2010). Improved Survival with Ipilimumab in Patients with Metastatic Melanoma New England Journal of Medicine DOI: 10.1056/NEJMoa1003466

Hwu, P. (2010). Treating Cancer by Targeting the Immune System New England Journal of Medicine, 363 (8), 779-781 DOI: 10.1056/NEJMe1006416

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Is the cancer research paradigm changing?

By MaverickNY on August 18, 2010

Over the weekend, a reader (a scientist in translational medicine) kindly sent me the link to a paper on PARP inhibition and asked:

"Is this a sign of the new wave of oncology drug development? Rather than basing treatment on cancer tissue type (eg. breast, prostate, colorectal), the underlying genetic mutation regardless of tissue of origin will be used for targeted agents. Imagine a randomized Ph2 trial of all BRCA1/2 deficient patients vs. non-mutated patients. Of course, this same rationale would have not worked for K-ras mutation patients with EGFR inhibitors in NSLCLC vs. Colorectal."

My short answer is basically, yes.

It may, however, take a while for this to evolve fully clinically, but you can already see the movement starting at AACR meetings, where they organise topics around pathways.

Unfortunately, at ASCO and ASH things are still discussed in cancer specific sessions, which I increasingly find more difficult to follow and plan for. For example, suppose I'm interested in pipeline PI3-kinase inhibitors. There might be something at 8.45am in North Hall A on one tumour type, but another at 9.00am on the other side of the convention centre in Room 330A in the East Building on a different cancer. Ugh, no wonder we all joke about the #blisterwalks and increasingly lack of time for networking at conferences – we're all too busy dashing between sessions in highly frazzled, rather than leisurely fashion!

I do believe the translational medicine and scientists are right in the pathway over tumour approach though and have been advocating for a pathway driven approach for some time on this blog. If you haven't read it yet, the short four part series on pathways and treatment in lung cancer earlier this year may be useful (see posts here, here, here and here) for examples of how lung cancer specialists (translational scientists and clinicians together) are leading the way in pioneering this concept.

In the example my correspondent gave, PARP inhibitors are being tested in BRCA1 and 2 positive tumours for olaparib (AstraZeneca), i.e. breast and ovarian cancers, whereas looking at the clinical trials database, Sanofi-Aventis are taking a more traditional approach with iniparib (BSI-201) and looking at different tumour types without the BRCA mutation.

Meanwhile, Abbott are also taking a very creative approach with their PARPi, veliparib (ABT-888), by not only looking at BRCA-positive cancers but also getting involved in the I-SPY2 neoadjuvant trial in breast cancer, which was a very smart move in my opinion. You can read more about the agents in that groundbreaking study protocol from the interview with Dr Sue Desmond-Hellmann. It's a great example of seeking to treat women diagnosed with early breast cancer with different therapies based on their underlying biology of their tumour, thereby enabling us to see what works and what doesn't earlier than we would normally.

It's going to be interesting to see how all these different R&D strategies work out commercially. For the record, I think olaparib may well be the first targeted agent to show benefit in patients with cancers that result from BRCA1 or BRCA2 gene mutations. That's quite exciting in itself, and hopefully, AZ have also learned considerably from the mistakes made with gefitinib (Iressa). Whether the specific targeted and scientific approach will win over a more commercial strategy, we'll have to wait and see.

The advantage of a specific targeted strategy is that if you get the biomarker right, the people who are most likely to respond to a therapy will more likely receive it plus the response rates and outcomes, in theory, should be better. Those who are less likely to respond are spared of the systemic exposure and false hope.

Some marketers will also argue that it may also, however, limit your market commercially, but my argument is that a highly targeted agent will actually get more prescriptions in the long run because it will be easier for an oncologist to choose therapy accordingly and good results reinforce usage and loyalty. Standing out from the crowd with superior efficacy in a well defined population is a much more elegant approach to this marketer 🙂

In a catch-all strategy, you may believe that by targeting a bigger market you will win more commercially, but the risk is that the response rates will be lower in a heterogeneous population (the wins and losses will cancel out to some extent). Thus if a competitors more targeted approach actually works, they win and you have no biomarker to answer with to allow oncologists to choose between the agents. Increasingly, they are reluctant to treat everyone willy nilly because of high costs, whether in terms of patient co-pays for oral therapies or more draconian restrictions for iv therapies from insurers.

Developing targeted agents is very different from traditional chemotherapy. Oncologists now want to know who is most likely to respond to a given therapy and treat those subsets accordingly rather than randomly treat and expose everyone to not insignificant systemic side effects of therapy. One of the best concepts we have right now is to have multi-functional research and clinical practice that marries identifying the key pathways and mutations with targeted therapies designed to knock out or shutdown the aberrant cell signalling.

We have a ways to go, but the tide is already turning.

Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, & Carmichael J (2010). Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet, 376 (9737), 235-44 PMID: 20609467

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Patterns of expression of DNA repair genes and relapse from melanoma

By MaverickNY on August 17, 2010

Someone kindly sent me this paper on how gene expression can be used to track insufficient DNA repair, which can lead to relapse in melanoma, making it potentially useful as both a prognostic and predictive biomarker for the disease. Regular readers will notice that I am slowly changing my opinion of gene expression studies as a result of articles like this one :-).

According to the researchers:

"Over-expression of DNA repair genes was shown to be associated with reduced relapse-free survival, thicker tumors and tumors with higher mitotic rate.

Preliminary data are also reported suggesting that DNA repair genes are overexpressed in tumors from patients who do not respond to chemotherapy."

Resistance to treatment is one of the biggest ongoing problems associated with treatment of melanoma, both with approved therapies and also pipeline drugs, so finding ways to detect it earlier (and the reasons why) would potentially help in sequencing with different drugs.

So what was involved in this study, which is the largest gene expression study to date in melanoma? The authors decided to see whether formalin-fixed tissue analysis would be useful:

"Gene expression profiles were identified in samples from two studies (472 tumors). Gene expression data for 502 cancer-related genes from these studies were combined for analysis."

The findings were quite interesting.

Basically, the increased expression of DNA repair genes most strongly predicted relapse, and was associated with thicker tumours. Increased expression of RAD51 was the most predictive of relapse-free survival (RFS). In addition, RAD52 and TOP2A were independent predictors of RFS in the analysis.

The authors concluded:

"Over-expression of DNA repair genes (predominantly those involved in doublestrand break repair) was associated with relapse. These data support the hypothesis that melanoma progression requires maintenance of genetic stability."

In the past, we have discussed synthetic lethality and DNA repair on this blog in breast and ovarian cancers, with respect to PARP inhibitors seeking to repair damaged DNA and prolong survival outcomes. Based on the current analysis, it looks as though a similar approach may be useful in melanoma. This may give clues for future pipeline development of new therapeutics designed to tackle the specific underlying biology of the cancer.

It should be noticed, though, that the results are describing the factors contributing to relapse from chemotherapy (dacarbazine, DTIC) rather than current pipeline drugs in development for melanoma such as PLX-4032 (Roche/Plexxikon) or ipilimumab (BMS).

I would be very interested to see whether the biomarkers identified in this research for chemotherapy would also apply to the targeted therapies. It is possible that they may not, or possibly they could help reverse or repair some of the changes occurring. Either way, finding ways to address the DNA repair may be a fruitful area of study.

Jewell, R., Conway, C., Mitra, A., Randerson-Moor, J., Lobo, S., Nsengimana, J., Harland, M., Marples, M., Edward, S., Cook, M., Powell, B., Boon, A., de Kort, F., Parker, K., Cree, I., Barrett, J., Knowles, M., Bishop, T., & Newton-Bishop, J. (2010). Patterns of Expression of DNA Repair Genes and Relapse from Melanoma Clinical Cancer Research DOI: 10.1158/1078-0432.CCR-10-1521

Michael Douglas has throat cancer?

By MaverickNY on August 16, 2010

This afternoon I was chatting with a Pharma friend via IM when she sent me a surprise link:

Michael Douglas to Undergo Chemo for Tumor in Throat Cancer

Oof, he was one of my favourite actors growing up as a child – I just loved the Streets of San Francisco! He also made Gordon Gekko famous in Wall Street.

There's a lot of throat cancer in the news lately. The most recent was Alex Higgins, the incredible Irish snooker player who was a truly sensational player from my childhood.

I wrote about him recently here. Be warned – the before and after pictures are a little shocking.

A recent photo of Michael Douglas on ABC News was also a shock, as he looks much more haggard than I remember 🙁

Lately, I've been watching re-runs in the evenings of the classic gritty but violent English detective drama from the 1970's, The Sweeney, starring John Thaw and Dennis Waterman. Idly clicking through to IMDB, I wondered what had become of Thaw, who also starred in Inspector Morse, only to discover that he, too, had passed away in 2002 – from throat cancer.

What is common with these three men? Well, alcohol and cigarette smoking contributed no doubt, as the American Cancer Society lists both of these as two of the potential risk factors for laryngeal and hypopharyngeal cancer, the medical term for throat cancer, which is often referred to as oesophageal cancer in the UK. The median age of diagnosis is round 65, so Douglas, Thaw and Higgins were all around the peak of the age range bell curve (60-65).

Hopefully, Michael Douglas's cancer has been picked up early and he will make a full recovery from chemotherapy. I really hope so, it's very sad to see one's favourite childhood heroes dropping 🙁

Photo Credits:

Manny the Movie Guy

The Sweeney Info

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Circulating IGF-I levels and pancreatic cancer risk

By MaverickNY on August 16, 2010

A couple of new papers will be reviewed this week, thanks to everyone who sent in links and suggested topics for discussion. I'll try and cover one a day, although there were so many worthy of consideration! Please do keep the ideas coming, they are much appreciated.

For today, here's one I came across last week in one of the American Association of Cancer Research (AACR) journals, Cancer epidemiology, biomarkers & prevention. The article discusses the evidence surrounding overexpression of insulin-like growth factor (IGF)-I and how that is implicated in human pancreatic tumours. To look at this concept further, the researchers decided to use longitudinal data from a study involving 187 cases and 374 controls, a not insignificant number as a starting point:

"We conducted a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort of men and women 55 to 74 years of age at baseline to test whether prediagnostic circulating IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 molar ratio concentrations were associated with exocrine pancreatic cancer risk."

For those needing some background, I've covered the IGF pathway and some of the therapeutic inhibitors being developed in cancer before (see here, here, here and here for examples).

Michael Pollak, one of the authors from McGill University in Montreal, is a recognised authority on the subject and gave a fascinating talk on the science and biology behind the topic at the AACR Lung cancer meeting back in January this year. It's a particularly interesting pathway, not only because of the potential for cross-talk between pathways, but also feedback and feedforward loops, especially with the insulin receptor (IR), as Pollak elegantly illustrated.

It was therefore with great curiousity that I downloaded and read the paper (see the clickable journal link in the reference below), wondering what they found in the broader study. Essentially, they concluded that:

"A higher IGF-I/IGFBP-3 molar ratio represents increased free IGF-I, which may be a risk factor for pancreatic cancer."

Thus, rather than the absolute levels per se, the ratio may turn out to be a useful biomarker of the disease because the individual levels were not found to be helpful by the researchers, who:

"confirmed the nonsignificant associations for IGF-I, IGF-II, and IGFBP- 3 and risk of pancreatic cancer from previous studies."

As many of you know, pancreatic cancer is rather nasty, typically being diagnosed late because the symptoms can be subtle to detect and diffential diagnosis from other conditions associated with general malaise is hard. A new biomarker would be clearly be helpful, although the findings will need to be validated in future large scale longitudinal studies or from pooled analysis from other prospective trials.

Mind you, this research on pancreatic cancer reminded me of the phase I Merck study in the same tumour type, reported earlier this year, with a combination of different therapies including IGF-1R and EGFR inhibitors.

As far as I can remember, Merck also included the use of metformin in the protocol to manage hyperglycemia, which would also potentially block the IGF-1R – IR feedback loop seen in the figitumumab trial. Still, it would be interesting to know whether the IGF-I/IGFBP-3 molar ratio and free IGF were higher in the people with pancreatic cancer in that study.

Clearly, if IGF-I/IGFBP-3 turns out to be a valid biomarker of disease risk then it may be possible to identify, monitor and ultimately treat people with pancreatic cancer earlier, as well as develop better pipeline drugs, since we learn more about the biology of the disease in the process.

That can only be a great thing in the long run for improved outcomes.

Douglas JB, Silverman DT, Pollak MN, Tao Y, Soliman AS, & Stolzenberg-Solomon RZ (2010). Serum IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 Molar Ratio and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology PMID: 20699371

Chemoprevention in Prostate Cancer – do 5alpha-reductase inhibitors make things worse?

By MaverickNY on August 12, 2010

There's a lot of media coverage today surrounding use of 5alpha-reductase inhibitors such as finasteride (Merck) and dutasteride (GSK) and their generic equivalents for chemoprevention of prostate cancer following publication of a study on finasteride by the American Association of Cancer Research (AACR) and one earlier this year on dutasteride in the New England Journal of Medicine (see references below for sources and the journal articles).

So what do these drugs do?

The drugs in the 5alpha-reductase class were developed for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to:

Improve symptoms
Reduce the risk of acute urinary retention
Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy.

Fair enough, but how does this relate to prostate cancer?

Well, testosterone is the major circulating androgen in men and is converted to the major intracellular androgen, dihydrotestosterone, by steroid 5alpha-reductase isoenzymes, designated as type 1 and type 2. Finasteride inhibits the type 2 isoenzyme, whereas dutasteride inhibits both.

Many of you will be aware that in early stage prostate cancer, most men are hormone sensitive and respond to androgen deprivation therapy (ADT), which effectively acts as chemical castration to suppress the growth of the tumour of the prostate. Later, when castration resistance sets in (CRPC), the disease is more advanced. These days, if they are asymptomatic or mildly symptomatic, then a vaccine called sipuleucel-T (Provenge) can be considered or if metastatic and symptomatic, then chemotherapy with docetaxel (Taxotere) can be considered as a first-line option or cabazitaxel (Jevtana) after docetaxel has failed.

The goal of using the 5alpha-reductase inhibitors early was therefore to prevent or at the very least delay the development of malignant prostate cancer, essentially reducing the risk of developing the disease later. Several studies have been published over the last decade to answer this question.

The big question is does this approach actually work?

My thinking was if it was that obvious, then surely urologists and primary care physicians would be rushing to prescribe either therapy? Trouble is, they're not, as this succinct AACR press release shows.

One of the problems is that the original Prostate Cancer Prevention Trial (PCPT) study back in 2003, a large randomized controlled trial consisting of 18,000 men, appeared to have conflicting results, since it showed:

a 25 percent reduced risk of prostate cancer.
a 27% increased risk in high-grade tumours, which was highlighted in the accompanying editorial.

This fact seems to have created doubt and concern amongst urologists and PCP's.

Subsequently, there have been other reported studies with finasteride in 2008 (reanalysis of the 2003 data) and with dutasteride in the NEJM earlier this year, suggesting in both cases that the risk did not exist. The doubt, however, still lingers as the AACR press release highlighted:

"64 percent of urologists and 80 percent of primary care physicians never prescribe finasteride for chemoprevention.

When asked for reasons for their decision, 55 percent said they were concerned about the risk of high-grade tumors and 52 percent said they did not know it could be used for chemoprevention."

Another issue is the conflicting consequence of PSA suppression, which is still used by many urologists as the main biomarker for diagnosis and ADT treatment. The NEJM editorial earlier this year noted the challenge:

"Among men without cancer, both finasteride and dutasteride treat lower urinary tract symptoms, produce dramatic prostate shrinkage, and reduce serum levels of PSA by 50% or more.

However, for the patient who believes that he is taking a drug to prevent prostate cancer, this decline in PSA level can lead to a false sense of security."

Why is this? The editorial went on to explain:

"Data from the PCPT indicate that finasteride produces a progressive suppression of PSA for the duration of treatment. To estimate what the “true” PSA level would be if finasteride were not taken, it is necessary to multiply the PSA level by 2.0 for the first 2 years, by 2.3 for years 2 through 7, and thereafter by 2.5.

However, if the PSA level ever begins to rise at all, a biopsy should be performed, because with an increase in PSA level, the risk of cancer is increased by a factor of 3 and the risk of high-grade disease is increased by a factor of 6.

In the Finnish study, men who received finasteride for more than 4 years had a risk of high-grade disease that was increased by a factor of 2.6."

After reading all of the evidence in the various studies (cited below), I can see why physicians might be:

Confused
Concerned

It's hard to make solid sense of the real impact of all the research, even as an unbiased scientist given the data that has emerged. My overall takeaway from all the articles was as follows:

Dutasteride and finasteride do not prevent prostate cancer.
They do shrink tumours that have a low potential for being lethal.
They do not reduce the risk of a positive biopsy in patients who have an elevated PSA level or an abnormal digital rectal examination.
Use of these drugs for prevention may be controversial because PSA levels are suppressed, giving a false sense of security.
If prostate cancer develops, the diagnosis may be thus delayed (by artificially low PSA levels) until they have high-grade aggressive disease that may be more difficult to cure.

My final observation is that perhaps we should be monitoring other markers of disease such as circulating tumour cells (CTCs) in the blood rather than PSA. Whether this would be a better measure of disease or not remains to be elucidated, but would certainly be worth looking at in future studies to see if it is a more accurate biomarker in early prostate cancer.

Hamilton RJ, Kahwati LC, & Kinsinger LS (2010). Knowledge and Use of Finasteride for the Prevention of Prostate Cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology PMID: 20699373

Andriole, G., Bostwick, D., Brawley, O., Gomella, L., Marberger, M., Montorsi, F., Pettaway, C., Tammela, T., Teloken, C., Tindall, D., Somerville, M., Wilson, T., Fowler, I., & Rittmaster, R. (2010). Effect of Dutasteride on the Risk of Prostate Cancer New England Journal of Medicine, 362 (13), 1192-1202 DOI: 10.1056/NEJMoa0908127

Walsh, P. (2010). Chemoprevention of Prostate Cancer New England Journal of Medicine, 362 (13), 1237-1238 DOI: 10.1056/NEJMe1001045

Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, & Coltman CA Jr (2003). The influence of finasteride on the development of prostate cancer. The New England journal of medicine, 349 (3), 215-24 PMID: 12824459

Lucia, M., Darke, A., Goodman, P., La Rosa, F., Parnes, H., Ford, L., Coltman, C., & Thompson, I. (2008). Pathologic Characteristics of Cancers Detected in the Prostate Cancer Prevention Trial: Implications for Prostate Cancer Detection and Chemoprevention Cancer Prevention Research, 1 (3), 167-173 DOI: 10.1158/1940-6207.CAPR-08-0078

Murtola, T., Tammela, T., Määttänen, L., Ala-opas, M., Stenman, U., & Auvinen, A. (2009). Prostate cancer incidence among finasteride and alpha-blocker users in the Finnish Prostate Cancer Screening Trial British Journal of Cancer, 101 (5), 843-848 DOI: 10.1038/sj.bjc.6605188

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Why do some cancer drugs work and others don't?

By MaverickNY on August 12, 2010

The news yesterday from Amgen that panitumumab (Vectibix) failed in Head and Neck cancer got me thinking. Why did it fail where cetuximab (Erbitux) succeeded? They're both monoclonal antibodies to EGFR, so that makes it rather interesting.

Many of you will remember that bevacizumab (Avastin) and Erbitux were both approved within a month of each other for colorectal cancer, both monoclonals, to VEGF and EGFR respectively. That was after a long string of failures for anti-angiogenesis compounds. Subsequently, vatalanib (PTK787), a small molecule tyrosine kinase inhibitor (TKI) of VEGF from Novartis failed in the same indication and did not achieve statistical significance in survival.

It gets even more interesting when you consider prostate cancer as another example:

Abbott's atrasentan got villified at it's ODAC meeting and never received approval. In a few months, however, we will hear what happens in the phase III trial for another endothelin-A inhibitor, zibotentan (AstraZeneca). The phase II data showed a difference in OS, but not PFS, so who knows what will happen with the phase III study?
Avastin also failed to achieve a survival advantage in prostate cancer, but does that mean that other VEGF inhibitors, such as sanofi-aventis/Regeneron's aflibercept (VEGF-Trap), will fall the same fate? We don't know yet, but as far as I know, that one's still alive and kicking.

I find it fascinating trying to work out why some drugs work and some don't even in the same class in the same indication. It could be all sorts of reasons:

Dosing
Scheduling
Patient population
Study design
Drug combinations
Compound structure
Availability of suitable biomarkers
Indications

Or one of many many other things or combination of reasons.

And there there is the related issue of 'pure' inhibitors (single target such as VEGF or BCR-ABL) versus multi-kinases or monoclonals (more than one target such as VEGF, EGFR, PDGF or FGFR, for example). Does it make a difference in efficacy and tolerability, will they affect outcomes differently?

Hopefully, we can learn from the failures to date for the future, allowing us to design better drugs and trials that have a more positive impact on outcomes.

Curiousity is killing this cat… R&D is such a crapshoot sometimes.

Diet and alcohol alter epigenetics of breast cancer and might predict severity of disease

By MaverickNY on August 11, 2010

Recently, I chanced upon a paper in the PLoS Genetics journal by two research groups from Brown University and the University of California San Francisco. Their findings suggest that epigenetic changes to DNA in breast cancers are related to environmental risk factors and tumour size. The information gleaned might also help predict the severity of the disease.

According to Wikipedia:

"Epigenetics is the study of inherited changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence, hence the name epi- (Greek: επί- over, above) -genetics."

Personally, I think of it in more simple lay terms as the control of patterns of gene expression in cells.

In this research, epigenetic profiles in stage I to IV breast tumours from 162 women were measured. A detailed assessment of individual demographic and dietary information was recorded, as well as breast cancer tumour characteristics. The tumour epigenetic signatures were used to provide more detailed staging, and eventually, prediction of prognosis, although further work was encouraged for the latter.

What was interesting was the study found that alcohol consumption, folate intake (vitamin B9), and tumour size are each independently associated with epigenetic profiles of tumours:

"In fact, strong evidence of an etiologic role for alcohol in breast cancer has been reported in multiple meta-analyses of prospective and case-control studies with an excess risk for each alcoholic drink per day of about 10%."

While alcohol had a negative effect, folate consumption appeared to have a positive effect:

"Yet, metaanalysis of case control studies of dietary folate, including results from the Shanghai Breast Cancer Study (whose participants are not regular alcohol drinkers) generally support a protective role for folate."

The data in this study confirmed previous research on the effects of alcohol and folate on breast cancer risk by comparing the DNA methylation patterns:

"Breast cancer prognostic characteristics and risk-related exposures appear to be associated with gene-specific tumor methylation, as well as overall methylation patterns."

Christensen, B., Kelsey, K., Zheng, S., Houseman, E., Marsit, C., Wrensch, M., Wiemels, J., Nelson, H., Karagas, M., Kushi, L., Kwan, M., & Wiencke, J. (2010). Breast Cancer DNA Methylation Profiles Are Associated with Tumor Size and Alcohol and Folate Intake PLoS Genetics, 6 (7) DOI: 10.1371/journal.pgen.1001043

Shrubsole MJ, Jin F, Dai Q, Shu XO, Potter JD, Hebert JR, Gao YT, & Zheng W (2001). Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer research, 61 (19), 7136-41 PMID: 11585746

Menopausal hormone therapy and subsequent risk of invasive breast cancer subtypes

By MaverickNY on August 10, 2010

There has been much conflicting evidence out there on risk factors associated with various cancer types that it is sometimes hard to remember what’s important.

A press release from the American Association of Cancer Research (AACR) on menopausal hormone therapy and the risk of developing breast cancer therefore caught my attention with these highlights:

Risk varied according to BMI, with greater risks for thinner women.
Longer duration of hormone therapy increased breast cancer risk.

The latter was no surprise at all, but seriously, I thought I had read before that a higher not lower BMI was associated with an increased breast cancer risk, but on reflection, that may have been in pre-menopausal not menopausal women.

The authors of this particular research noted that:

“There is substantial epidemiologic, experimental, and clinical evidence that the risk of breast cancer is elevated with the use of menopausal hormone therapy (HT), with formulations containing estrogen and progestin (EPT) resulting in a substantially higher risk than formulations containing estrogen only (ET).”

Despite this evidence, many physicians (PCP’s and gynaecologists) still prescribe different formulations of hormone therapy for treatment of menopausal symptoms:

“It remains unclear whether the number of days per month of progestin use affects risk, specifically whether the continuous-combined EPT regimens (e.g. Prempro) differ from sequential regimens. Continuous combined HT was associated with the highest risk of hormone-sensitive breast cancer in some, but not all studies.”

Breast cancer is clearly getting increasingly more complex these days with many subsets to consider based on numerous biomarkers and risk factors:

“Some evidence supports a selective increase in risk of particular breast cancer subtypes associated with EPT use, i.e., the estrogen receptor–positive and progesterone receptor–positive subtypes (ER+/PR+).”

This additive effect with EPT can be explained by an increased mitogenic effect of progesterone in the breast tissue. There is also a need to understand what happens in poor prognosis subsets such as women with triple negative breast cancer (i.e. ER-/PR-/HER2-).

The authors thus reported on the California Teachers Study, a longitudinal epidemiologic trial, which looked at hormone replacement therapy use among 2,857 women for almost 10 years.

Overall, the AACR press release I received summarised the findings nicely:

Breast cancer risk seemed dependent on body mass index (BMI).
Those with a BMI less than 30 appeared to have an increased risk of breast cancer with combined hormone therapy; the risk was strongest among women with BMI less than 25.
In contrast, obese women (i.e. BMI of 30 or more) had no further increase in risk associated with using combined hormone therapy.
The risk of breast cancer was confined to tumors that were positive for both estrogen and progestin receptors. The risk was somewhat weaker for HER2 negative tumors.

Overall, as we have seen with other studies, the research demonstrates that there is a consistent increased risk of breast cancer from hormone therapy use, but it also underscores the need for individual risk-benefit discussions before women begin such therapy, because some subgroups may have different risk profiles.

{UPDATE: the DOI link is not yet working in research blogging so here is the direct link to the abstract and article for now. Will edit the link later once it has been processed.}

Saxena, T, Lee, E, Henderson, KD, Clarke CA,, West, D, Marshall, SF, Deapen, D, Bernstein, L, & Ursin, G (2010). Menopausal Hormone Therapy and Subsequent Risk of Specific Invasive Breast Cancer Subtypes in the California Teachers Study Cancer Epidemiology, Biomarkers & Prevention, 19 (9) :10.1158/1055-9965.EPI-10-0162

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Tufts and raising funding for pediatric cancer research

By MaverickNY on August 10, 2010

This year I'm participating in the 14th Annual Cycle for Life on Saturday 11th September, which benefits the Floating Hospital for Children's Cancer Center. The basic idea is that the fundraising from the riders provides direct support for young patients and their families.

The organisation is based at Tufts Medical Center and offers a unique approach, which appeals to me:

"The pediatric cancer program at Floating Hospital for Children offers complete hematology and oncology services for children. Floating Hospital physicians have developed novel protocols for the aggressive treatment of cancer, including autologous bone marrow transplantation and new approaches to administering chemotherapy.

Floating Hospital for Children's Cancer Center stresses a team approach to the management of pediatric cancer patients, working closely with pediatric surgeons and radiation oncologists. The Center has received national recognition for its innovative patient and family support programs and provides state-of-the-art cancer treatment."

Source: Cycle for Life

Over the last couple of years, my Twitter buddy Alicia Staley has organised a team and off they go in their free time one Saturday morning in the fall, 25 or 50 miles round Marblehead, Massachusetts.

The last two years have seen a bit of rain, so I'm hoping the weather Gods will play nicely this year since I rashly agreed to join the Staley's Riders team, as did Marian, one lunchtime when we all met up in NY :).

To date, I'm about a third of the way towards my target, so if any of you readers or your organisation would like to chip in for a good cancer cause, here's the link.

It will be interesting to see how effective social media is at helping to fund raise. All donations are warmly appreciated in advance!

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