Primecuts – This Week In The Journals

August 2, 2010

By Deborah Hemel, MD

Faculty Peer Reviewed

One of the many advantages of being on elective this week was that I finally had the pleasure of spending time outside and experiencing the heat wave with millions of other sweaty, malodorous New Yorkers. Our sultry plight, however, was dwarfed by far graver weather problems in other parts of the world: record floods in Iowa, Pakistan, Afghanistan, and China have killed hundreds, if not thousands of people, while a destructive heat wave has swept over Russia, a country better known for its lethal winters (1)(2)(3)(4)(5).  Returning to news at the local level, New York veterans were left out of a decision by the Department of Veterans Affairs to allow patients treated at its hospitals and clinics to use medical marijuana (6). The decision does not apply to patients at our VA since medical marijuana is not legal in New York, but for once a small state west of the Hudson may save the day…medical marijuana is legal in New Jersey. Lest you start to feel depressed about the state of our state, Chelsea Clinton and Marc Mezvinsky chose to marry in the great state of New York this weekend even though neither are native New Yorkers (7). Mazel tov to the happy couple; may neither of you follow in your fathers’ missteps.

Medical news this week is a hodgepodge of topics as always, but several interesting oncology articles made headlines in major medical journals. In honor of this August being the 90th anniversary of the passage of the 19th amendment (giving women the right to vote), this week’s Primecuts will continue in the tradition of gender equality by giving equal attention to developments in the diagnoses and treatment of prostate and breast cancers.

 Prostate Cancer

 And the controversy continues…

A large, retrospective study published in the Archives of Internal Medicine this week should raise the eyebrows of male patients and urologists alike (8). In this study, 66% of men ages 65 to 74 who had low-risk disease and PSA values below 4.0 ng/mL were treated with either a radical prostatectomy (RP) or radiation therapy (RT). However, these men with low risk disease…have low risk disease. If the side effects of RP and RT were minimal, such vigilance might be appropriate since early intervention has led to a significant decline in deaths from prostate cancer. Unfortunately, such procedures have serious, and not uncommon, side effects such as impotence and incontinence. While this article does not comment on whether men should still undergo annual PSA testing, it emphasizes the importance of counseling male patients appropriately regarding the risks and benefits of aggressive interventions. While this study does not cast doubt on the seriousness and potential lethality of high grade prostate cancer, it does strengthen the argument that prostate cancer as a whole is overdiagnosed and overtreated in this country. 

 Progress in prostate cancer care?

In other prostate-related news this week the New England Journal of Medicine published the results of a randomized, placebo-controlled trial of a therapeutic cancer vaccine for the treatment of treatment-resistant prostate cancer (9). The study enrolled over 500 men with minimally symptomatic, metastatic prostate cancer whose disease was refractory to androgen-deprivation therapy.  Men who received three rounds of the vaccine, known as sipuleucel-T, had a median survival of 4.1 months longer than those who received the placebo. While these results are exciting and may offer the hope of longer survival to a subset of prostate cancer patients, the feasibility of making this vaccine widely available is questionable. While the nitty-gritty details behind the vaccine’s procurement are enough to make a clinician’s head spin, it is important to note that making the vaccine is a labor-intensive process: each vaccine dose is patient-specific since it is made using the patient’s own antigen-presenting cells, and each round of vaccine takes two to three days to develop.  The cost of the vaccine remains to be seen, but it is likely to be very high. In an age of spiraling healthcare spending, particularly at the end of life, the cost of this vaccine may turn out to be a limiting factor in its use.

 Breast Cancer

 Ma’am, you may need that mammogram…in the future

What if a genetic test could stratify women into risk groups and tailor breast cancer screening recommendations accordingly? Such recommendations already exist for carriers of highly-penetrant BRCA1 and 2 genetic mutations, but such women make up a small minority of breast cancer patients.  A study published in JAMA this week attempted to identify the odds ratios for breast cancer associated with 14 individual single-nucleotide polymorphisms (SNPs) that have been linked to breast cancer in previous studies (10). This study compared the genotypes of over 10,000 women who had been diagnosed with breast cancer to those of over 10,000 women who had never been diagnosed with breast cancer. The study confirmed statistically significant, but not clinically significant, associations with breast cancer risk for 7 of the 14 SNPs examined.  When the effects of the 7 SNPs most strongly associated with breast cancer risk were combined using a polygenic risk score, the cumulative incidence of breast cancer among women in the top fifth was twice that in the bottom fifth, though still quite low (8.8% vs 4.4%). Although polygenic risk scores are not useful for stratifying breast cancer risk among women at this juncture, it is a tool that may prove clinically useful in the future.

 A PARP-inhibitor shows promise

A proof-of-concept trial published in The Lancet this week showed encouraging results for a new drug intended to treat advanced breast cancer in patients who carry a BRCA1 or 2 mutation (11). The drug, called Olaparib, is a member of a class of drugs known as poly(ADP-ribose) polymerase inhibitors, a.k.a. PARP-inhibitors. While a detailed description of Olaparib’s mechanism of action is beyond the scope of this article (and perhaps beyond the scope of its author), at a very basic level Olaparib is thought to induce synthetic lethality in BRCA-deficient cells by preventing PARP proteins from repairing single stranded DNA breaks. In this particular study, the primary endpoint was defined as the objective response rate (ORR) as measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Patients who received 400mg of Olaparib twice daily had an ORR of 41% and a median progression-free survival of 5.7 months, while those who received 100mg of Olaparib twice daily had an ORR of 22% and a median progression-free survival of 3.8 months.  The results of future phase 3 trial(s) will make or break the future of this potentially exciting new drug.

 Dr. Hemel is a first year resident at NYU Langone Medical Center

Peer reviewed by Mike Poles, Section Editor, Clinical Correlations

References:

1. http://www.nytimes.com/2010/07/26/us/26iowa.html

2. http://www.nytimes.com/aponline/2010/07/31/world/asia/AP-AS-Pakistan-Floods.html

3. http://www.reuters.com/article/idUSTRE66U0PM20100731

4. http://www.bbc.co.uk/news/world-asia-pacific-10784666

5. http://www.nytimes.com/2010/07/30/world/europe/30moscow.html

6. http://www.nytimes.com/2010/07/24/health/policy/24veterans.html

7. http://www.nytimes.com/2010/07/18/fashion/18CHELSEA.html

8. Shao YH, Albertsen PC, et al. Risk Profiles and Treatment Patterns Among Men Diagnosed as Having Prostate Cancer and a Prostate-Specific Antigen Level Below 4.0 ng/mL. Arch Intern Med. 2010;170(14):1256-1261.

9. Kantoff PW, Higano CS, et al. Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer. N Engl J Med 2010; 363:411-422.

10. Reeves GK, Travis RC, et al. Incidence of Breast Cancer and Its Subtypes in Relation to Individual and Multiple Low-Penetrance Genetic Susceptibility Loci. JAMA. 2010;304(4):426-434.

11. Tutt AT, Robson M, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. The Lancet. 2010;376(9737):235-244.

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