Tag Archives: cancer research

“It really shouldn’t be up to a patient to know….”

Today was a slightly less busy Monday than usual since I was at lab for a gazillion hours this weekend (ok slight exaggeration but longer than usual, and got a bit ahead of usual). This meant not only I had time to mull some things over while doing cell culture less hurriedly than usual on a Monday, but I had a little half hour or so before lunch to look at my weekly pubmed email updates.

A new paper in the Annals of Oncology caught my attention since it was a large population on IBC patient outcomes study regarding ~7700 patients diagnosed between 1990 and 2010. This caught my attention because there hasn’t been much written on this lately outside of single institution studies (such as MDACC’s own experience) – which have limitations including positive bias (places with terrible outcomes less likely to write academic papers vs centers of excellence with nuggets to share). Intrigued I read over most of it, and scrutinized the figures/tables. The purpose of the paper was to investigate whether overall outcomes of IBC have improved over time using a national healthcare database called SEER, focusing on stage 3 patients. Just to share a piece of the promising data they show, figure 1 shows a nice positive trend in 2-year overall survival that goes from 50% in 1990 to ~70% in 2010. However as I dug deeper, a few things disturbed me. The data in most of the tables is stratified by year of diagnosis…..a few things that stood out to me.

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Figure 1: 2 year overall survival and the years in which selected drugs became used in IBC.

Ok first I have to explain a few things– today’s definitive treatment for stage 3 IBC given with curative intent includes upfront (neoadjuvant) chemotherapy, then a modified radical mastectomy followed by radiation. If HER2 positive, 1 year of Herceptin is included starting concurrently with chemotherapy (finished after surgery). If ER+, 5+ years of adjuvant endocrine therapy appropriate to menopausal status (tamoxifen or aromatase inhibitor) is given after radiation.

Going back to the SEER data – what do these data show? In the most recent 5 year period specifically, only 82% of patients received a mastectomy. 18% rate of breast conserving surgery is unacceptable when IBC is an absolute contraindication to lumpectomy (the reason being since the disease by definition involves the skin, it must go as well as the whole breast!). These surgeries also were not done to today’s standard. In the table there is a section on number of nodes examined. Shockingly, 20.5% had ZERO nodes examined. Mind boggled! Axillary nodal dissection is an important component of comprehensive staging and is considered a very standard step during surgery. While sentinel node dissection (SLND) is becoming more and more considered in other locally advanced breast cancers treated by mastectomy, the role of SLND is still under investigation in IBC. The MDACC surgical team is trying to identify a subset of patients who can be spared the morbidity from axillary dissections yet adequately stage their axilla. However as of today, every patient should have 1 or more nodes examined. Preferably all the level 1 and 2 nodes that the surgeon finds.

Next up – only 51% of patients received radiation. This should be 100%. No excuses – radiation is a very important form of local therapy that has been proven to make a difference in outcomes. Studies of many high-risk breast cancer patients have demonstrated that radiation decreases the risk of loco-regional recurrence by 50-66% – which is a lot when your baseline recurrence risk is as high as it is for most IBC patients.

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Figure 2: Data showing less than optimal treatment provided.

Lastly, but not of least importance, is an analysis of outcomes by race. For white patients diagnosed between 2006 and 2010 – the 2-year OS is 75%, whereas among black women it is only 61%. Why is this? Complicated topic – likely both underlying biology as well as factors relating to access to good quality care. Another topic for another day, but just another statistic from the paper that bothered me, and barely commented on by the authors.

So back to the original question are we doing better? Yes statistically the p-values for all the comparison show an increase in outcomes over time. But there is still a lot to do. Clearly triple-negative IBC still lags behind – less than 15% have a pathological complete response and this leads to a median overall survival around 2 years. To do better in TN-IBC, we will not only need to increase pCR rates (perhaps by adding targeted agents to chemotherapy or changing cocktails to take advantage of new knowledge) but also find some adjuvant therapy that is useful to mimic the benefits from endocrine therapy in ER+ disease. What about a vaccine or similar immunotherapy approach as well.

Perhaps it would be best to start with applying what we already know though. Outcomes are best with a multi-disciplinary team working together – good upfront staging (radiologists working hand-in-hand with pathologist to get enough of the correct tissue), optimal chemotherapy (anthracycline+taxane or otherwise) upfront with a competent medical oncologist closely following response. The medical oncologist then handing the patient off to trusted surgical oncologists who will do the CORRECT surgery, get clean margins and then of course a radiation oncologist to mop up any residual local disease with an appropriate dose, frequency and fields based on the individual patients risk factors. It really shouldn’t be up to a patient newly diagnosed with an uncommon, rapidly progressing life-threatening disease to know this stuff. Are you with me?

 

Source: Dawood S et al, “Survival of women with inflammatory breast cancer: A large population based study”. Annals of Oncology 2014 (in press), article link

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SABCS 2013: What I’m most looking forward to seeing this year

Well the annual San Antonio Breast Cancer Symposium is here and I’m very excited to be here to learn what’s new and upcoming in the world of research and clinical care. I meant to get this post up before I left, but my lab work this weekend had other ideas.   Just a quickie post from the hotel this morning before the sessions start for real this afternoon.

The biggest, most exciting news is that Inflammatory Breast Cancer (IBC) will have its first education session ever at SABCS. It is today at 5:30pm, and is being chaired by MD Anderson’s awesome Dr Wendy Woodward. The other IBC expert speakers are Massimo Cristofanilli and Sofia Merajver.

Looking through the rest of the program briefly, a few themes popped out at me about this meeting. One – this will be a big meeting for TNBC biology. We are no doubt going to hear about new developments in finding new targets, including following up on the relevance of JAK2 mutations (as reported last year), targeting the folate receptor, and cancer stem cell pathways. In addition, we will be hearing more about Celldex’s antibody-drug conjugate, Glembatumumab vedotin(also known as CDX-011) that is being studied in metastatic TNBC, in their new randomized METRIC study. CDX-011 targets TNBCs that overexpress glycoprotein gpNMB, which is involved in aggressiveness of TNBCS (resistance to standard chemotherapy, increased invasion and metastasis.).

Today as expected there is a session on the DNA damage response, another hot area of research in TNBC biology, and we will be also hearing about progress with CDK4/6 inhibitors in ER+ disease, now that there are at least 2 good agents available (Pfizer’s Palbociclib and Novartis’s  LEE011).

Other than TNBC biology, looking forward to hearing the updates on the big multi-center adaptively-designed I-SPY2 study. I-SPY2 is a neoadjuvant trial looking at whether adding novel drugs to standard chemotherapy improves outcomes, and hopefully how specific biomarkers correlate or not with responsiveness to these agents.  And finally, there is an adoptive T-cell session – an area of intense interest after the recent promising results in other tumor types. Hopefully we can figure out how to make breast cancer cells as susceptible to the immune system as other cancers.

So that’s what’s up folks! More later.

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Emotional investment in cancer research – how much is necessary for good research?

One of the thought-provoking articles that has come up repeatedly in my twitter feed this week, is an article in the NY Times about (and written by) a young woman who found out that she carries a BRCA1 mutation. After discussing the reasons behind wanting to know whether she carried the gene mutation, she mentions enrolling in a cancer biology class taught by a

“professor [who] filled his slides with dark oncological puns, lecturing with the almost robotic detachment I sometimes see in those who work closely with cancer”…

Reading this paragraph as a cancer researcher, I asked myself to what extent do I portray the robotic detachment she mentions, and does this lead to better research?  Its now a few days after I read the article but I don’t think I really have an answer yet.

To elaborate, my work now is really translational – if you ask me what the measure(s) of my success over the next few years is, here’s my answer: I would have designed a biomarker-driven treatment strategy for IBC patients that still appears promising after rigorous preclinical work including animal model testing and a clear understanding of mechanism. My data so far on my main project is coming along very nicely!

In addition, because I am in the TRIUMPH postdoctoral training program, I have the unique opportunity to be exposed to clinical issues at a deeper level than virtually any other PhD-track program in the country.  This year, in parallel with my lab research, I am engaging in rotations with various specialties within MDACC (pediatrics, medical oncology, radiation therapy, phase 1 trials, surgical oncology). In reflecting on my experiences so far, and talking with my peers, it is crystal clear to us why we are here.  Papers in nice high-IF journals, awards, invited talks etc are nice (and desirable qualifications for those of us who want to stay in academia), but at the end of the program, many of our goals include being able to see our work translate directly into patient care.

On top of these IRL opportunities, I have enjoyed interacting with a group of cancer survivors and patient advocates on social media and reading blogs, which has given me a deeper understanding of the impact of cancer on people’s lives than the average lab scientist, and made me even more driven to do clinically-relevant work. Time will tell whether time invested in such activities above and beyond my long days in lab, will actually make me a better researcher – but I have my suspicions it will.

In contrast, when thinking back to my PhD which was in a much more basic science-driven department, my success was measured by how elegantly I could prove a mechanism for some biological process (in my case how oxidative stress and DNA damage signals to particular pathways to regulate cell survival/death), and by most people’s definition, I was successful in this endeavor. Looking back at some of my peers I have to admit that I saw some of the “robotic detachment” mentioned in the article, not only from those who worked in cell lines/yeast on fundamental biology questions (like understanding all the binding partners of protein X or what genes ABC transcription factor regulates). Perhaps it was just such fundamental (and SLOW!) research combined with the struggles of grad school that made even the brightest students to sometimes appear uninspired.  However, even some of my colleagues who worked on mouse models of XYZ cancer seemed to care only enough to do their project to their committee’s satisfaction.  To be fair, some superficial level of detachment is probably necessary for working with animals that have to be sacrificed during/after the study, especially after the researcher induced disease (in the most humane way possible).  However deep down, I think that most cancer researchers aren’t very detached from their work. After all, cancer touches us all at some point whether individually or people close to us.  heart-robotMaybe its just a question of degree instead of a black-and-white detached or not attitude. Hey, maybe we can be robots WITH hearts – if that’s what it takes to make a real difference!

*****

What do you think fellow biomedical researchers? Do you feel detached from your work i.e. is it mainly just a fun/interesting way to make a living or are you deeply invested in the broader implications of your work?  Or is the reality of the disease you are working on so depressing that you need some objectivity to survive.

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