A Film and Story-Telling Festival Focuses on Disability

Recently I had the opportunity to attend part of the New York ReelAbilities Film Festival. The 6th annual event in New York involved all five boroughs, but was based primarily at Manhattan’s Jewish Community Center. The program featured a dizzying spectrum of disability perspectives and concerns on film. It also included talks, photographs, parties and story-telling in presented by The Moth.

RealAbilities NY Disabilities Film Festival, 2014

RealAbilities NY Disabilities Film Festival, 2014

I liked everything about this festival. Perhaps the best aspect is that individuals with all kinds of issues can come, in real life, and meet other people with similar kinds of concerns. And so might their parents, or spouses and others who want to know, to gain a better sense of the experiences of people with varied physical forms. I don’t know that I could have imagined this kind of event happening, when I was a child or a young doctor.

For this post, I’ll stick to “the Moth” presentations, which numbered five. My instincts tell me not to declare favorites, so I’ll just provide a tidbit about each of the stories:

The first speaker walked onto the stage with just a bit of guidance. He was young, blind, handsome and funny. He spoke of growing up in a suburb. He was assigned chores and minded those. When in his early 20s, he signed up to participate in  a program that involved cleaning on Coney Island, the people in charge tried to keep him standing at the edge of the project, to not let him help out in a meaningful  way. He felt marginalized. By speaking with the other participants, gradually he entered the workspace. He got to get his hands dirty, doing grunt work with the rest of the crew. Happiness ensued.

Next, a dark-haired, smiling woman who has aphasia – difficulty speaking, casually stood as she told her story. Her name is Yvonne Honigburg, and she advocates for the National Aphasia Association. She described growing up with a sometimes secretive mother, of learning she was adopted, and of searching for her biological mother. Eventually the three met in a restaurant in New Haven, CT. Upon meeting Yvonne’s natural mother, the adoptive mother said something surprising. It ended well.

A woman in a wheelchair delivered the third, marvelous story. Millie Gonzalez has long curly reddish hair. She wore a sequined, shiny top and spoke of how she has always loved to dance. Evidently she has spina bifida, and after years of dancing with crutches, as a child and in high school, she’s learned to dance in a wheelchair. A while back she attended a previous ReelAbilities festival and saw the film Musical Chairs. After the event, upon trusting a man, perhaps the film director, he “twirled” her in the air, or something like that. Her heart stopped, momentarily, for the thrill of it all. It was very romantic. After that, she’s gone belly-dancing and advocating for people with disabilities.

The fourth speaker told of a moving story of her life with severe kidney disease and impaired vision. When she was a child, and the doctors finally explained to her what was wrong, she felt a sense of relief, knowing at least that there was an explanation for what she was experiencing. After some dark times, and dialysis, she received a kidney from her mother. Still, she lacked self-esteem, and hibernated. She spoke openly and vulnerably, about what led her to see the value of living. #uplifting

The final speaker walked on stage and, after a few minutes, mentioned that she had a prosthetic arm. She’d spent most of her childhood, adolescence and college years trying to hide her deformity. She didn’t want to be perceived as defective. In becoming a mother, she realized that her child had certain expectations….I cried, just a bit.

Seriously, you should listen to the Moth to find out what happened. And next year, or in your city, check out the ReelAbilities Film Festival.

No favorites. Each story is distinctly beautiful, and instructive (like people…)

All for a while,


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10 Newly-Defined Molecular Types of Breast Cancer in Nature, and a Dream

Breast cancer is not one disease. We’ve understood this for decades. Still, and with few exceptions, knowledge of BC genetics – information on tumor-driving DNA mutations within the malignant cells – has been lacking. Most patients today get essentially primitive treatments like surgical hacking, or carving, traditional chemotherapy and radiation. Some doctors consider hormone therapy as targeted, and thereby modern and less toxic. I don’t.

Until there’s a way to prevent BC, we need better ways to treat it. Which is why, upon reading the new paper in Nature on genetic patterns in breast cancer, I stayed up late, genuinely excited. As in thrilled, optimistic..The research defined 10 molecular BC subgroups. The distinct mutations and gene expression patterns confirm and suggest new targets for future, better therapy.

The work is an exquisite application of science in medicine. Nature lists 31 individuals and one multinational research group, METABRIC (Molecular Taxonomy of Breast Cancer International Consortium), as authors. The two correspondents, Drs. Carlos Caldas and Samuel Aparicio, are based at the University of Cambridge, in England, and the University of British Columbia in Vancouver, Canada. Given the vastness of the supporting data, such a roster seems appropriate, needed. The paper, strangely and for all its worth, didn’t get much press –

Just to keep this in perspective – we’re talking about human breast cancer. No mice.

The researchers examined nearly 2000 BC specimens for genetic aberrations, in 2 parts. First, they looked at inherited and acquired mutations in DNA extracted from tumors and, when available, from nearby, normal cells, in 997 cancer specimens – the “discovery set.” They checked to see how the genetic changes (SNPs, CNAs and/or CNVs) correlated with gene expression “landscapes” by probing for nearly 29,000 RNAs. They found that both inherited and acquired mutations can influence BC gene expression. Some effects of “driver” mutations take place on distant chromosomal elements, in what’s called a trans effect; others happen nearby (cis).

Next, they honed in on 45 regions of DNA associated with outlying gene expression. This led the investigators to discover putative cancer-causing mutations (accessible in supplementary Tables 22-24, available here). The list includes genes that someone like me, who’s been out of the research field for 10 years, might recall – PTEN, MYC, CDK3 and -4, and others. They discovered that 3 genes, PPP2R2A, MTAP and MAP2K4 are deleted in some BC cases and may be causative. In particular, they suggest that loss of PPP2R2A may contribute to luminal B breast cancer pathology. They find deletion of MAP2K4 in ER positive tumors, indicative of a possible tumor suppressor function for this gene in BC.

Curtis, et al. in "Nature": April 2012

The investigators looked for genetic “hotspots.” They show these in Manhattan plots, among other cool graphs and hard figures, on abnormal gene copy numbers (CNAs) linked to big changes in gene expression. Of interest to tumor immunologists (and everyone else, surely!), they located two regions in the T-cell receptor genes that might relate to immune responses in BC. They delineated a part of chromosome 5, where deletions in basal-like tumors marked for changes in cell cycle, DNA repair and cell death-related genes. And more –

Cluster Analysis (abstracted), Wikipedia

Heading toward the clinic, almost there…

They performed integrative cluster analyses and defined 10 distinct molecular BC subtypes. The new categories of the disease, memorably labeled “IntClust 1-10,” cross older pathology classifications (open-access: Supplementary Figure 31) and, it turns out, offer prognostic information based on long-term Kaplan-Meier analyses (Figure 5A in the paper: Supplementary Fig 34 and 35). Of note, here, and a bit scary for readers like me, is identification of an ER-positive group, “IntClust 2” with 11q13/14 mutations. This BC genotype appears to carry a much lesser prognosis than most ER-positive cases.

Finally, in what’s tantamount to a 2nd report, the researchers probed a “validation set” of 995 additional BC specimens. In a partially-shortened method, they checked to see if the same 10 molecular subtypes would emerge upon a clustering analysis of paired DNA mutations with expression profiles. What’s more, the prognostic (survival) information held up in the confirmatory evaluation. Based on the mutations and gene expression patterns in each subgroup, there are implications for therapy. Wow!

I won’t review the features of each type here for several reasons. These are preliminary findings, in the sense that it’s a new report, albeit a model of what’s a non-incremental published set of observations and analysis; it’s early for patients – but not for investigators – to act on these findings. (Hopefully, this will not be the case in 2015, or sooner, preferably, for testing some pertinent drugs in at least a subset of the subgroups identified.) Also, some of the methods these authors used came out in the past decade, after I stopped doing research. It would be hard for most doctors to fully appreciate the nuances, strengths and weaknesses of the study.

Most readers can’t know how skeptical I was in the 1990s, when grant reviewers at the NCI seemed to believe that genetic info would be the cure-all for most and possibly all cancers. I don’t think that’s true, nor due most people involved with the Human Genome Project, anymore. The Cancer Genome Atlas and Project should help in this regard, but they’re young projects, larger in scope than this work, and don’t necessarily integrate DNA changes with gene expression as do the investigators in this report. What’s clear, now, is that some cancers do respond, dramatically, to drugs that target specific mutations. Recently-incurable malignancies, like advanced melanoma and GI stromal tumors, can be treated now with pills, often with terrific responses.

Last night I wondered if, in a few years, some breast cancers might be treated without surgery. If we could do a biopsy, check for the molecular subtype, and give patients the right BC tablets. Maybe we’d just give just a tad of chemo, later, to “mop up” any few remaining or residual or resistant cells. The primary chemotherapy might be a cocktail of drugs, by mouth. It might be like treating hepatitis C, or tuberculosis or AIDS. (Not that any of those are so easy.) But there’d be no lost breasts, no reconstruction, no lymphedema. Can you imagine?

Even if just 1 or 2 of these investigators’ subgroups pans out and leads to effective, Gleevec-like drugs for breast cancer, that would be a dream. This can’t happen soon enough.

With innovative trial strategies like I-SPY, it’s possible that for patients with particular molecular subgroups could be directed to trials of small drugs targeting some of the pathways implicated already. The pace of clinical trials has been impossibly slow in this disease. We (and by this I mean pharmaceutical companies, and oncologists who run clinical trials, and maybe some of the BC agencies with funds to spend) should be thinking fast, way ahead of this post –

And given that this is a blog, and not an ordinary medical publication or newspaper, I might say this: thank you, authors, for your work.

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Blood and Hip Surgery: New Study Supports Fewer Transfusions

Under the radar, over the holiday week, the NEJM published a report on transfusion requirements in older adults who surgical hip repair. The main finding is that most patients, including the elderly and those at risk for cardiac complications of the procedure, don’t benefit from getting so many red blood cell transfusions as is commonly prescribed.

The study, funded by the NHLBI, involved more than 2000 adults over 50 years of age who underwent hip surgery. Overall the patients were quite elderly, with a mean age above 80 in each group. The trial included patients with heart disease and risk factors for cardiac complications. Participants were randomized to receive red blood cells if their hemoglobin fell to a level below one of either two thresholds: 10 or 8 gm/dl. What happened is that, at the time of discharge from the hospital and by 60 days after the procedure, the rates of death, coronary syndrome and other complications were the same.

An accompanying editorial weighs in on the study and conclusion, that a standard threshold for ordering transfusions in the context of major hip surgery might be lowered. Reducing transfusions would lower demands on the blood supply, lessen the costs of administering these infusions, and reduce complications from infected or otherwise-damaging pints.

The study is important because it bolsters the evidence that too many units of blood are administered routinely.  Sometimes with good reason, busy surgeons recommend a threshold for what’s almost an automatic order that blood to be given. If there is such a threshold in a SICU (surgical ICU), operating room or elsewhere, this report suggests it’s often too high.

It would be better, for sure, if transfusions were ordered on a case-by-case basis, with input by a doctor who would assess each patient’s baseline level of hemoglobin and other relevant factors. For example, a patient who’s been anemic for years may tolerate a lower hemoglobin level than someone who’s never been anemic before, or whose lung function is marginal.

Still, the main take is that many patients undergoing surgery need less blood than their doctors realize, and that we can safely, overall, reduce the number of transfusions ordered for many patients, even in those who are older and with risk of heart disease.

What patients might do: if you’re going to have major surgery, talk with your doctor about whether you might need blood and how the surgeon will decide if you need blood or not, and how much. If you have a strong preference to avoid transfusion, let your doctor know about that and discuss how you might avoid getting unnecessary pints.

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New Music from an Orchestra of Radioactive Isotopes

For the weekend –

A tweet led me to a fantastically inventive kind of music. The Radioactive Orchestra comprises 3175 radioisotopes. From the website: “Melodies are created by simulating what happens in the atomic nucleus when it decays from its excited nuclear state…Every isotope has a unique set of possible excited states and decay patterns…”

image from the Radioactive Orchestra project

The project, sponsored by a Swedish nuclear safety organization, KSU, encourages visitors to select among the graphed isotopes, listen and learn. You can try composing music on your own, or you can check out a production by DJ Alex Boman on YouTube:


h/t: Maria Popova, @brainpicker, who picked up on this last August at Brainpickings. And to @JohnNosta, who sent yesterday’s tweet.


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Cervical Cancer Screening Update: on Pap Smears, Liquid-based Cytology and HPV

The latest issue of the Annals of Internal Medicine contains 2 noteworthy papers on cervical cancer screening. The first, a systematic review of studies commissioned by the USPSTF, looked at 3 methods for evaluating abnormalities in women over 30 years:

high-grade cervical cell dysplasia (Dr. E. Uthman, Wikimedia Commons)

1. Conventional cytology (as in a Pap smear; the cervix is scraped and cells splayed onto a microscope slide for examination);

2. Liquid-based cytology (for LBC, the NHS explains: the sample is taken as for a Pap test, but the tip of the collection spatula is inserted into fluid rather than applied to slides. The fluid is sent to the path lab for analysis);

3. Testing for high-risk HPV (human papillomavirus). Currently 3 tests have been approved by the FDA in women with atypical cervical cells or for cervical cancer risk assessment in women over the age of 30: Digene Hybrid Capture 2 (manufactured by Quiagen), Cobas 4800 HPV (Roche) and Cervista HR HPV (Hologic); another Roche Diagnostics assay, Amplicor HPV, awaits approval.

These HPV assays use distinct methods to assess DNA of various HPV strains.

There’s a lot of jargon here, and I have to admit some of this was new to me despite my nearly-due diligence as a patient at the gynecologist’s office and my familiarity as an oncologist with the staging, clinical manifestations and treatment of cervical cancer. Who knew so many decisions were made during a routine pelvic exam about which manner of screening?

The main points I took away from this paper:

1. Liquid-based cytology is similar to conventional Pap smear cytology for detecting high-grade dysplasia (abnormal cells) and cervical cancer.

2. It seems that at some medical centers, and possibly overall, there’s a lower proportion of inadequate cell specimens when practitioners skip the slides and use the liquid method. This means that fewer women need be called back for another procedure.

3. Finding HPV sequences in the cervix yields many false positives, in terms of malignancy.

The researchers conclude that further studies are needed to sort out how HPV testing can improve or supplement cervical cancer screening. The main limitation is that many young women are infected with potentially cancer-causing strains of HPV, but most don’t get cervical cancer. When cervical cancer does develop that’s usually later on, a decade or longer after the relevant viral infection.

The second Annals article, a helpful narrative review, considers the practical implications of the above findings. The authors state that over 40 types of HPV can infect the cervix. They review that progression to cancer occurs along these 4 steps: HPV transmission, acute infection, persistent infection causing precancerous changes and eventually, in a subset of those infected, invasive cervical cancer.

Figure 1 is remarkably clear:

Prevalence of high-risk HPV and incident cases of cervical cancer in the U.S., 2003–2005. Surveillance Epidemiology and End Results (SEER) data for incident cases among females aged 15 to 19 years and 50 to 64 years.

The graph shows that the prevalence of HPV infection is highest among teens and women in their early 20s, and decreases in older women. By contrast, the incidence of cervical cancer rises steadily in women over 30 years and remains elevated among women in their 40s. The authors show, separately, that the rate of cervical cancer in older women is low.

The central point is that high-risk HPV infection and associated inflammation of the cervix are common in young women, but cervical cancer is rare among those under 30 years. The investigators conclude that cervical cancer screening in women younger than 20 years may be harmful. They also state that evidence supports discontinuation of cervical cancer screening in most women who are over 65 years old.

Two asides on this otherwise non-bloggy topic –

It’s great that the Annals provides the full text of these papers open-access, free of charge to the public.

Amazing how well-accepted is the concept of some viruses causing cancer, today. This was a heretical idea 25 years ago in academic medicine; now it’s dogma.

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New Study, Presented at a Meeting of Breast Surgeons, Supports that Mammograms Save Lives of Women in Their 40s

The American Society of Breast Surgeons held its 2011 annual meeting in D.C. from April 27 – May 1. Among the papers presented was Abstract #1754: “Mammography in 40 Year Old Women: The Potential Impact of the U.S. Preventative Services Task Force (USPSTF) Mammography Guidelines.” You can find the press release, followed by the abstract, here. The main result was that screening women ages 40-49 by mammography was associated with finding smaller tumors, with less spread to the lymph nodes, than clinical breast exams alone, and this correlates with improved survival at 5 years.

The study, put forth by a group at the University of Missouri-Columbia in Columbia, MO, is  based on a 10-year retrospective chart review, from 1998 – 2008, of 1581 women treated for breast cancer at that institution. In this author’s opinion, a retrospective, chart-review type analysis of a medical intervention is about as low as you can get on the quality-of-data scale in a medical study. And, as emphasized by Dr. Otis Brawley, chief medical officer of the ACS as quoted in HeathDay’s report on the matter, these are tentative findings, presented in abstract form at a meeting. He suggested that the 5-year follow-up is too short.

That said, I think the findings are significant and likely reflect what happens when mammography screening is done right, which is that it saves lives in women 40 and older.

The results focused on the 320 women – 20% of all those treated for breast cancer at the institution – between the ages of 40 and 49 at the time of breast cancer diagnosis. Among those, mammography detected the tumors in just under half (47%) of the cases; in 53%, there was a palpable mass – the “clinical detection” group. In those with cancers were detected by mammography, the average tumor size was 2 cm in diameter; in the clinical detection group, the average size was 3 cm. (From an oncologist’s perspective that’s a huge difference; for most breast cancer subtypes that 1 cm difference in diameter portends a distinct prognosis.) What’s more, the frequency of lymph node involvement in the clinical detection group was 56%, more than twice that in the mammography group (25%), another prognosis-changer. These findings were highly significant from a statistical perspective, with p-values <0.0001.

The researchers confirmed that negative lymph nodes and smaller tumors were associated with longer survival. They estimated that disease-free survival, at five years, was 94 percent for women under 50 who received mammograms and 78 percent for those who did not receive the screening exams. Five year overall survival rates for each group were 97% and 78%, respectively.

These figures have huge implications, especially if you multiply the potential survival benefit – on the order of 20 percent at 5 years, or greater, depending on how you look at it – across over some 21.5 million women in the U.S. between the ages of 40 and 50, approximately 1.5 in 1000 of whom will be found to have invasive BC per year.*

Reuters ran this story on April 29  as did HealthDay. Both ran quotes by Dr. Paul Dale, chief of surgical oncology at the University of Missouri School of Medicine and lead author of the abstract. The findings suggest that adherence to the updated U.S. Preventive Service Task Force (USPSTF) guidelines, which do not recommend screening mammography for most women between the ages of 40 and 49, would lead to preventable deaths.

One thing the author of ML learned this morning is that Dr. Virginia Moyer, the new chair of the USPSTF and who is quoted in the HealthDay coverage, is a pediatrician and professor with a public health degree.

*based on U.S. Census data of 2000 and SEER data incidence (BC, all races, by age) accessed 5/2/11

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When Less Chemo is Just As Good, In Treatment for Acute Myeloid Leukemia (AML)

Today’s issue of the New England Journal of Medicine includes an article with the bland title Cytarabine Dose for Acute Myeloid Leukemia. AML is an often-curable form of leukemia characterized by rapidly-growing myeloid white blood cells. Cytarabine – what we’d call “Ara-C” on rounds  – has been a mainstay of AML treatment for decades.

The new report* covers a fairly large, multicenter, randomized trial of adult patients with AML. The researchers, based in the Netherlands, Switzerland, Belgium and Germany, evaluated 860 patients who received either intermediate or high doses of Ara-C in their initial, induction chemotherapy. According to the journal, “this investigator-sponsored study did not involve any pharmaceutical companies.”

The main finding was that at a median follow-up of 5 years there were no significant differences between the groups in terms of complete remission rates, relapses or overall survival. The high-dose Ara-C offered no clear advantage in any prognostic subgroup, including those with genetic changes that bear a poor risk. Not surprisingly, Grade 3 and 4 (severe) toxicities were more common in the patients who received higher doses of Ara-C. Those patients also had lengthier hospitalizations and prolonged reduction in their blood counts.

Why am I mentioning this report, besides that it hasn’t received any press coverage? First, because the findings might matter to people who have AML and are contemplating treatment options. But mainly it’s an example of how carefully dialing down some chemotherapy doses could reduce health care costs and lessen untoward effects of cancer therapy – in terms of early toxicities and, possibly down the line, fewer secondary malignancies – without compromising long-term outcomes.

*subscription required: N Engl J Med 364: 1027-36 (2011). The free abstract includes some details on the chemo doses.

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Radiologists’ Experience Matters in Mammography Outcomes

There’s a new study out on mammography with important implications for breast cancer screening. The main result is that when radiologists review more mammograms per year, the rate of false positives declines.

The stated purpose of the research,* published in the journal Radiology, was to see how radiologists’ interpretive volume – essentially the number of mammograms read per year – affects their performance in breast cancer screening.  The investigators collected data from six registries participating in the NCI’s Breast Cancer Surveillance Consortium, involving 120 radiologists who interpreted 783,965 screening mammograms from 2002 to 2006. So it was a big study, at least in terms of the number of images and outcomes assessed.

First – and before reaching any conclusions – the variance among seasoned radiologists’ everyday experience reading mammograms is striking. From the paper:

…We studied 120 radiologists with a median age of 54 years (range, 37–74 years); most worked full time (75%), had 20 or more years of experience (53%), and had no fellowship training in breast imaging (92%). Time spent in breast imaging varied, with 26% of radiologists working less than 20% and 33% working 80%–100% of their time in breast imaging. Most (61%) interpreted 1000–2999 mammograms annually, with 9% interpreting 5000 or more mammograms.

So they’re looking at a diverse bunch of radiologists reading mammograms, as young as 37 and as old as 74, most with no extra training in the subspecialty. The fraction of work effort spent on breast imaging –presumably mammography, sonos and MRIs – ranged from a quarter of the group (26%) who spend less than a fifth of their time on it and a third (33%) who spend almost all of their time on breast imaging studies.

The investigators summarize their findings in the abstract:

The mean false-positive rate was 9.1% (95% CI: 8.1%, 10.1%), with rates significantly higher for radiologists who had the lowest total (P = .008) and screening (P = .015) volumes. Radiologists with low diagnostic volume (P = .004 and P = .008) and a greater screening focus (P = .003 and P = .002) had significantly lower false-positive and cancer detection rates, respectively. Median invasive tumor size and proportion of cancers detected at early stages did not vary by volume.

This means is that radiologists who review more mammograms are better at reading them correctly. The main difference is that they are less likely to call a false positive. Their work is otherwise comparable, mainly in terms of cancers identified.**

Why this matters is because the costs of false positives – emotional (which I have argued shouldn’t matter so much), physical (surgery, complications of surgery, scars) and financial (costs of biopsies and surgery) are said to be the main problem with breast cancer screening by mammography. If we can reduce the false positive rate, BC screening becomes more efficient and safer.

Time provides the only major press coverage I found on this study, and suggests the findings may be counter-intuitive. I guess the notion is that radiologists might tire of reading so many films, or that a higher volume of work is inherently detrimental.

But I wasn’t at all surprised, nor do I find the results counter-intuitive: the more time a medical specialist spends doing the same sort of work – say examining blood cells under the microscope, as I used to do, routinely – the more likely that doctor will know the difference between a benign variant and a likely sign of malignancy.

Finally, the authors point to the potential problem of inaccessibility of specialized radiologists – an argument against greater requirements, in terms of the number of mammograms a radiologist needs to read per year to be deemed qualified by the FDA and MQSA. The point is that in some rural areas, women wouldn’t have access to mammography if there’s more stringency on radiologists’ volume. But I don’t see this accessibility problem as a valid issue. If the images were all digital, the doctor’s location shouldn’t matter at all.


*The work, put forth by the Group Health Research Institute and involving a broad range or investigators including biostatisticians, public health specialists, radiologists from institutions across the U.S., received significant funding from the ACS,  the Longaberger Company’s Horizon of Hope Campaign, the Breast Cancer Stamp Fund, the Agency for Healthcare Research and Quality (AHRQ) and the NCI.

**I recommend a read of the full paper and in particular the discussion section, if you can access it through a library or elsewhere. It’s fairly long, and includes some nuanced findings I could not fully cover here.

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More News On Lymph Nodes and Breast Cancer Surgery

Last week the New England Journal of Medicine (NEJM) printed a major research article on lymph node dissection in breast cancer surgery. When I first saw the Times’ recent headline, I thought it would cover this paper: Effect of Occult Metastases on Survival in Node-Negative Breast Cancer.*

It turns out there were separate articles on axillary node dissection after sentinel node biopsy in breast cancer – one in JAMA and one in the NEJM – published a week apart. For some reason, the NEJM paper got little attention in the media.

In the work reported in the NEJM, investigators based at the Univ. of Vermont evaluated if the presence of occult metastases – cancer cells found upon further examination of dissected lymph node specimens after the sentinel nodes were deemed negative – affects survival in women with early-stage breast cancer. What they found was that yes, it does: there’s a small but significant reduction in overall survival and disease-free survival at 5 years in women who have “negative” sentinel nodes but turn out, upon more detailed path inspection, to have some malignant BC cells in the armpit.

Kinda scary for someone like me, who had a negative sentinel node. The Vermont investigators determined that 16% of us have occult mets. Of those, 11.1% would be isolated tumor-cell clusters (less than 0.2 millimeters in greatest dimension), 4.4% micrometastases (between 0.2 and 2 millimeters) and 0.4% macrometastases (larger than 2 millimeters), all as classified by the American Joint Committee on Cancer.

On the other hand, the results were generally favorable all-around:

“The 5-year Kaplan-Meier survival estimates for patients in whom occult metastases were detected were 94.6% for overall survival, 86.4% for disease-free survival, and 89.7% for distant-disease–free interval; the survival estimates for patients in whom occult metastases were not detected were 95.8%, 89.2%, and 92.5%, respectively.”

Some details on the well-done study I feel compelled to insert here, a vestige of my thrice-weekly-journal-clubs-in-academic-medicine days:

The Vermont study is strong from a statistical standpoint: The researchers examined stored pathology samples from 5611 women with operable, clinically node-negative BC who were already registered in a large multicenter clinical trial (NSABP B-32). The study participants were randomized to receive either sentinel node dissection or sentinel node dissection followed by full axillary lymph node dissection.

It was a prospective analysis, and the median time on study was just under 8 years. Of the 5611 women enrolled, 3887 (~70%) had negative sentinel nodes and sufficient pathology material available for evaluation. Oncologists treating the patients were “blinded” to the data regarding occult mets, so that they wouldn’t be influenced in their treatment decisions. Among the women with negative sentinel nodes, 1927 underwent sentinel node dissection followed by axillary node removal and 1960 got sentinel node dissection only (based on the earlier randomization).

One result not emphasized in the paper was that removing additional nodes, after the sentinel lymph node exam, didn’t affect the clinical outcome in women with or without occult mets. This finding ties in with this week’s JAMA report, covered separately.

It’s a long article, probably of more interest to pathologists and BC oncologists than to the average reader here. There’s a lot interesting detail, including subtle results of planned subgroup analyses, on the prognostic significance of different kinds (sizes) of occult mets.

I know from my experiences – mainly lately as a friend of people with BC who, in the past few years since sentinel node studies have become the norm – that these issues regarding the significance of occult mets bear on everyday decisions patients make together with their oncologists: how much chemo to take?; should I get radiation to the axilla if there’s a tiny cluster of cells found?; should we add Taxol to the regimen? etc.

These are very real, every-day questions in oncology, and the answers aren’t obvious. But I do think the carefully-established findings reported in this paper will shed light, in an incremental sort of way, on how to best treat BC in women who have negative sentinel nodes at surgery.

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Cautious Optimism for a New Melanoma Treatment

This morning’s news feed delivered some seemingly excellent news for some people with melanoma. At least until now, this form of skin cancer has been considered incurable when metastatic. In the last year, we heard details about the ups and downs of ongoing clinical trials of new drugs to treat the disease.

The Times reports that Roche’s experimental drug prolongs life in patients with metastatic melanoma whose tumors have B-Raf mutations. The new findings, based on a randomized phase III, open-label and industry-sponsored trial, BRIM 3, were first communicated in a press release yesterday. The company indicates that the study met its primary endpoints: Patients taking the experimental pill, RG7204, lived longer, and went longer without disease progression, than those patients in the control arm who received standard chemotherapy (dacarbazine) injections every three weeks.

The new drug – a pill usually given at a dose of 960 milligrams twice daily – goes by several names:

RG7204 (Genentech is a Roche subsidiary)

PLX4032 (Plexxikon has a partnership with Roche to commercialize and develop PLX4032)

RO5185426 (as listed at ClinicalTrials.gov and the NCI thesaurus)

Since the Phase III study opened in January 2010, investigators recruited patients at numerous medical centers worldwide. According to the Roche press release, nearly subjects were randomized to receive either the experimental pill (960 mg) twice daily or dacarbazine (1000 mg/m2) by intravenous every 3 weeks. Patients continued on their assigned drug until the disease progressed or they experienced unacceptable toxicity. The most frequent severe adverse events were skin-related, including another, less-aggressive form of skin cancer, and mild, reversible liver abnormalities. The most common reported side effects were rash, joint pain, hair loss and fatigue.

What I can’t find are published details, such as by how long life was prolonged in patients receiving the experimental drug. The NIH Clinical Trials site indicates the investigators aim to recruit 680 patients, and the Times indicates that since the trial opened, 338 patients were assigned to the chemotherapy arm of the trial, while another 338 received the Roche drug.

According to Amy Harmon’s report in the Times:

About half of the 68,000 Americans who develop melanoma every year have a mutation in a gene, called B-RAF, that goes awry, for reasons not well understood, signaling cells to grow uncontrollably. The Roche drug works by blocking a malfunctioning protein the gene produces in cancer cells, but leaving the functioning proteins in noncancerous cells alone.

Roche, in its press release, indicates that: “based on these interim analysis results, patients on the control arm of the study will have the option to crossover to receive RG7204.” The results will be presented formally at a medical meeting this year. (Presumably that would be the annual ASCO gathering in June.)

I’m eager to see the findings, the extent and duration of remissions, degrees of toxicity, and more. This could be another good example of targeted therapy – giving a treatment that’s designed to block a known molecular defect in a tumor – that might dramatically alter the prognosis, and way of life, for some patients with malignant melanoma. But I am cautious in my enthusiasm, as the reports so far, and data interpretation, come from the company that sponsored the clinical trial and would sell the drug if approved.

(all links accessed 1/20/11)


addendum/clarification, Aug 2011: PLX-0432 was renamed vemurafenib.

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