Get Cancer. Lose Your Job?

 

Let’s start with this fact: If you are employed and get a breast cancer diagnosis, it’s less likely you’ll be working at your job four years later. A newly-published study of women in Los Angeles and Detroit found that among women less than 65 years with limited-stage breast cancer, 76 percent had a paying job at the time of their diagnosis. Based on follow-up surveys of the same women four years later, the number employed was reduced by 30 percent. That’s a huge drop.

The study was just published on-line in the Cancer Journal. The authors, including a corresponding and lead author in a department of radiation oncology at the University of Michigan, make a point in the paper’s title, Impact of Adjuvant Chemotherapy on Long-Term Employment of Survivors of Early-Stage Breast Cancer, that chemotherapy may be to blame. And there’s some truth in this. Chemotherapy causes fatigue and, occasionally lasting problems such as neuropathy, heart weakness and chemobrain that might limit or impair a person’s capacity to work effectively.

On the other hand, the likelihood of developing many of those chemo-related effects depend on the dose and regimen selected. Radiation, often, causes fatigue, and – when administered to the chest, can cause premature heart disease (atherosclerosis) and lung problems, besides secondary tumors as a late consequence of treatment. It happens, though, that hormonal treatments, like Tamoxifen, can cause chemobrain too.

As someone trained to give chemotherapy, I’ll point out that none of these options for adjuvant treatment (what’s given to patients with limited disease to lessen the likelihood of recurrence) is a walk in the park. Each bears the potential for short and long-term toxicity. So I don’t blame chemotherapy in particular, although the study authors emphasized that as a culprit based on a low-level statistical correlation.

More broadly –

This news comes as no surprise. I know too well how women at work may be treated after a breast cancer diagnosis. I am privy to the stories of dozens of women who say they were unduly turned down for promotions or good assignments, opportunities…Upon returning to work, if they took time off (which some didn’t, such as your author, during her BC treatment), they  – if they take pride in their work – find themselves missing their own doctors’ appointments, exercise and other aspects of survivorship care, just to “prove” that they’re still valuable to their office, team, business.

The harsh reality is that people who have had cancer treatment are sometimes perceived as a burden on a working group: a consultant who can’t travel quite so much, a sales rep who looks less beautiful, a nurse who has to take an occasional half-day off for a check-up. Some bosses worry, although you’d be hard-pressed to find this in writing, that an employee who had cancer treatment may suffer a recurrence, and so she can’t be counted on – no matter how capable and motivated she may be – to lead a fellowship program, or to complete an ambitious project.

What would help is for doctors to guide patients with more nuanced advice, to avoid over-treatment. And patients should ask their physicians, based on their circumstances, for the least therapy that makes sense based on the size and molecular details of their tumor, to avoid long-term toxicity. And for employers to treat their workers who have illness – and not just breast cancer – as potentially valuable workers, contributors, over the long haul.

 

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Palbociclib Appears to Prolong Progression Free Survival in Women with Metastatic Breast Cancer

Yesterday researchers at the annual AACR meeting announced the results of a clinical trial of a new drug with activity in some forms of breast cancer. Palbociclib (PD-0332991), a pill developed by Pfizer, was tested in women with metastatic breast cancer cells with estrogen receptors and lacking Her2. These ER+/Her2- tumors represent the most common breast cancer subtype, which is one reason so many people are eying the results of this relatively small, randomized study.

The phase 2 trial, called PALOMA-1 included 165 post-menopausal women with advanced ER+/Her2 negative disease. The research subjects were assigned to take either Letrazole (Femara, an aromatase inhibitor, a drug that inhibits estrogen synthesis) alone, or Letrazole and also the experimental drug, Palbociclib. The study found a highly significant difference in progression free survival (PFS), the intended endpoint: the mean time until disease progressed was 20.2 months among women who took Palbociclib, as opposed to 10.2 months for those assigned to Letrazole alone. The p-value for the difference between the arms (1-sided) was 0.0004. That’s a powerful  result.

But there was no statistically significant difference in overall survival between the two groups, a fact that was irksome to some observers, particularly in the biotech investment world, and to some who were reminded of the Avastin story and its fall-out. Most of the women lived for approximately 3 years after enrolling, with a trend of a few months favoring the Palbociclib arm. Another problem is that over half the patients were recruited to the study based on biomarker results, having to do with cyclin D1 amplification and/or loss of p16. So it could be the results are more relevant to breast cancer patients who have those particular changes. How those molecular features, enriched in the final study population, relate to Palbociclib’s usefulness in breast cancer and other tumor types warrants more evaluation, for sure.

My feeling is that this may prove to be a useful drug, not just in breast cancer. Any medication which interferes with cell growth by blocking cyclin-dependent kinases (enzymes) called CDK-4 and -6 could be useful in quite a few malignancies. The main side effect was suppression of the bone marrow (low blood cells). Some questions I’d like to ask the researchers, and which I hope they’ll address in the Phase III study, is if certain types of mets (e.g. lung vs. bone) or certain molecular subtypes are more tempered by this drug.

As for 10 months of PFS – if it pans out in a formal, published work, that’s valuable. Imagine that you’re 55 years old and living with metastatic breast cancer. A drug that is likely to delay, by most of 2 years, your tumor’s expansion into the lungs (causing shortness of breath), or bones (causing fractures and pain) or liver, and elsewhere can be worth a lot. It’s about the quality of life, whether or not it’s extended.

One final concern is that this study wasn’t blinded, so the doctors’ assessment of how the patients were doing, and the patients’ assessment of how they were feeling,  may have been influenced by their knowing which arm they were on. Also, because this new drug is a pill, some insurance may not cover it – a policy issue that applies to many new cancer drugs.

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Questions for ASCO – on Tamoxifen, ATLAS and aTTom

On Sunday in Chicago, oncologists and others at the plenary session of the annual ASCO meeting will be talking about an abstract that matters a lot to women with breast cancer. It’s a study on Tamoxifen that bears on how long women with estrogen-receptor positive (ER+) tumors should take adjuvant hormonal therapy after initial treatment for early-stage BC.

tamoxifen binding an ER receptor (Wikimedia Commons)

tamoxifen binding an ER receptor (Wiki-Commons)

Why this matters so much is that ER+ tumors account for most BC cases. So if you’re a pre-menopausal woman who’s had a tumor removed by surgery, there’s a good chance your doctor will recommend adjuvant (“extra”) treatment with Tamoxifen for 5 or (probably) 10 years. The reasoning behind this recommendation is that the recently-published ATLAS study demonstrated a clear lengthening of life among women with ER+ tumors who took the longer course.

The usual dose of Tamoxifen (Nolvadex) is 20 milligrams per day. The bargain-rate cost is around $9 for a month’s supply GoodRx.com  – so we’re talking just over $110/year x 5 or 10 years. That’s small change as oncology drugs go, although the numbers add up over so many patients affected…

Tamoxifen carries a small but real risk for what most doctors consider side effects, like blood clots and occasional, typically low-grade uterine cancers. The problem with Tamoxifen – which is not so much a risk as a definite consequence of taking this medication – is that it has anti-estrogen effects that many young (and older) women consider undesirable. Already our breasts have been cut. Feeling “feminine” is not trivial. Many don’t want it!

(Mental exercise: imagine hundreds of thousands of men ages 35-55 agreeably accepting a prescription for partial chemical castration to reduce the chances of a tumor recurring, after they’ve already had significant treatment to reduce those odds)

Your author has been in rooms filled with doctors where the overwhelming consensus expressed was that hormonal treatments in women with BC are terrific. Indeed, they extend life and, in some cases – such as those with low Oncotype scores – afford women the option of skipping chemo. But how are they so sure we’d rather take an anti-estrogen for 5-10 years rather than 3-6 months of chemo? Answer: I don’t think anyone knows.

One limitation of the ATLAS study (and as best I can tell the same for aTTom) is that the trial doesn’t distinguish between women who got adjuvant chemo and those who didn’t get chemo. So it’s unclear whether Tamoxifen helps prevent recurrence, or extend life, in women who’ve also received chemotherapy for the disease.

Here are 2 questions for aTTom:

1. How do we know that women with small, node-negative (low risk) tumors who receive chemotherapy, as is standard in many communities, get additional benefit from Tamoxifen after chemo?

2. Should pre-menopausal women with small, ER+ tumors be given a choice between taking chemo or Tamoxifen?

In other words, is there evidence to support the combination – chemo followed by hormonal Rx – as the standard, adjuvant care for women with early-stage, ER+ tumors? or that women prefer hormonal pills over a short course, like 4 cycles, of chemo?

I’m eager to hear about the updated aTTom (adjuvant Tamoxifen Treatment offers more?) findings, to be published and presented on Sunday. I hope my colleagues – doctors, patients, advocates and journalists will ask good questions!

All for now,

ES

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Contemplating Breast Cancer, Beyond October 2012

It’s foggy today, October 3, ten years since the last mammogram I had and will ever need. I’ve been remiss in updating the blog. The reasons include family concerns and other projects. Meanwhile, I’ve been thinking about the big picture – what’s most important for progress against breast cancer in the decade ahead.

So here’s what I see, now – in terms of three priority areas: improving treatment, prevention, and education to inform treatment decisions.

Pumpkins, organized by subtype (WikiCommons image)

As an oncologist, I perceive huge strides in understanding BC since the time of my diagnosis. But these advances are largely invisible to patients because they’re in the realm of pathology and classification of different subtypes. What was essentially a 3-type malignancy with a handful of treatment options has expanded under the molecular microscope to a spectrum of 4, 10 or – what’s probably most accurate – hundreds or thousands of patient-particular conditions, depending on the level of precision by which you define a disease. I’m optimistic, because it looks as though, in my lifetime, BC treatment will be tailored to each patient. There’ll be less surgery and better drugs.

The hitch, now, is not so much with science as with funding– funding to analyze each patient’s tumor at the genetic and protein levels, funding to pay for treatments selected by patients (which might include less treatment and/or palliative care in advanced cases), and funding to educate doctors about BC subtypes and medical progress, so they might offer “modern” advice to each patient in ordinary clinics, apart from clinical trials and academic centers. Newer is not always better in medical care. Same goes for more treatment (especially when it comes to higher doses). Still, the lag between advances in BC science and application of distinct, targeted and better treatments is frustrating at best.

Some of my colleagues call for patience – emphasizing that studies need be confirmed, drugs tested in mice, etc. Their point is that we can’t jump from pathology research and new BC classifications to new therapy. But one lesson I take from progress against AIDS is that maybe we shouldn’t be so patient. At least not for young people with poor-prognosis BC subtypes or stage. We could do studies and studies of particular BC treatments, and studies of studies (those would be meta-analyses) and debate 8 or 10 years from now whether a particular drug or combination of drugs worked in clinical trials that selected for patients with an antiquated subtype of the disease. Or we could move toward “n=1” trials, with smart, well-trained physicians assessing each patient by a combination of old-fashioned physical exams and the most modern of molecular studies of the tumors, considering the options, and moving forward with individual, mini-experimental treatment plans.

I vote for the latter. If the drug works in a patient with advanced BC and the patient feels better, why not?

For people with early-stage BC, prescribing or taking new and essentially untested drugs makes less sense at first glance. That’s because standard treatments are “successful” – leading to long-term remissions and possible cures in over 80 percent of those affected. But these relatively good results may have, paradoxically, hampered development of better drugs that could obviate the need for breast-deforming surgeries and radiation in many women. The possible application of BC drug cocktails, in lieu of surgery for early-stage patients, is a huge question for the future, and one for which trials would be necessary. Just getting those projects going – applying BC science to treatment of early-stage cases – would be a step in the right direction.

As for BC prevention, of course that would be infinitely better than detecting or treating the disease. Unfortunately, I think we’re farther away from preventing the disease than we are from having effective and less brutal treatments for most patients. The problem with lifestyle modification – like staying active and not obese – is that it’s far from full-proof: You can be seemingly fit as a fiddle and get a lethal case of BC. Still, there are plenty of other health-related reasons for women to exercise and eat sensibly. As for avoiding carcinogens or, first, just knowing what chemicals contribute to BC formation and growth, the science isn’t there yet.  It’ll be a long haul before anyone can prove that a particular chemical causes this disease. That said, I advocate research in the slow-growing field of environmental oncology and wish there’d be more enthusiasm for regulating our exposure to likely-toxic chemicals.

The third priority is for improving education in math and science, starting at the elementary school level. Doctors need to understand statistics, but many don’t. They need to know about genomics and basic science in medicine. Patients need this kind of knowledge if they want to have a clue, if they want to engage meaningfully in decisions about which antibody to take, or pill, or whether they want to participate in a clinical trial of pills instead of surgery for a Stage II tumor with high levels of Her2, for example. That’d be a tough decision for an oncologist. I only wish that we could reach the point where we could have those kinds of truly informed conversations about clinical treatment of breast cancer, which happen every day.

We’ve got a lot of information in hand, but we need to learn how to apply that to more patients, faster and more openly.

All for a while. I’m open to ideas on this. Happy October!

ES

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How Much Do You Want Your Doctors To Say About Risks of Treatment?

When I was diagnosed with breast cancer, I was working as a board-certified oncologist. The initial decisions most patients face – which doctor to see, what kind of doctor to see, and at which medical center to see them – were basically non-decisions. I knew, within an instant of my diagnosis, who I’d ask to be my oncologist, surgeon and plastic surgeon. Those choices were straightforward, because I knew what those physicians were like in terms of how they cared for patients, their knowledge and other aspects of their practices and personalities.

The harder decisions were what treatment to take, or not, for my early-stage breast cancer. I was perhaps the most informed cancer patient who could walk into an oncologist’s office. I was familiar with the different regimens. I knew that adjuvant chemotherapy would, roughly and over the long haul, reduce my odds of recurrence by a third. I was aware that, if I opted for a lumpectomy, radiation treatment would reduce the local recurrence rate but was unlikely to affect my long-term survival. I understood that dose-intense regimens were more likely to make me sick and more likely to cause problems down the road.

And yes, in the back of my head I knew that chemotherapy can cause another cancer. Did I think about that possibility? The best answer is, probably, not so much. I was coping with the present.

But that knowledge did influence the decision I made to take a relatively “light” dose of chemotherapy. I was lucky, also, in that I understood my pathology. My tumor, at 1.5 cm, with a negative sentinel node and generous expression of hormone receptors, was a good-prognosis tumor. I was 42 years old, and wanted to live for a few more decades if I survived my spine surgery (another story). I chose the minimal amount of chemo that had been shown in clinical trials to reduce the odds of recurrence.

Last week, I wrote a piece for the Atlantic on how doctors and patients talk about the risks of chemotherapy, or not, and whether patients listen or necessarily want to listen. The reason I put it out there is because I’ve seen doctors shy away from this part of the conversation about cancer treatment. I’m a firm believer in informed consent, and in patients’ access to as much information as they choose to have. If you get chemotherapy, you have the right to know about these risks, and to ask your doctor about them.

I’ve been there with patients who’ve said: “please, don’t tell me this. I can’t deal with it.” Some might even consider it cruel to tell patients with a serious, urgent and treatment-needing condition details of all the possible side effects. Many ask, “what would you do, doctor, if it were someone in your family?” And if they like and respect you, they go with your recommendation.

This kind of paternalism, when a doctor assesses the risks and benefits, and spares the patient’s “knowing” seems anachronistic. But it may, still, be what many people are looking for when and if they get a serious illness. Not everyone wants a “tell me everything” kind of physician. What do you think?

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This Week’s Triple, Tough Dose of Real Stories on Women with Cancer

Dear Readers,

It’s been a tough week on the breast cancer front.

Many in the community first learned that Ellen Moskowitz, a former leader at the Metastatic Breast Cancer Network (MBCN), died. Ellen was a funny, articulate woman who lived with MBC. When I interviewed her for an article on the value of a day designated to awareness about metastatic disease, she kept me laughing.

Robin Roberts, a co-host of Good Morning America who was treated for breast cancer less than 5 years ago, announced that she’ll be getting a bone marrow transplant for MDS. The blood condition is, in some cases, a complication of chemotherapy. I wrote a piece about this for the Atlantic Health. This unfortunate news reminds us an aspect of cancer treatment some of us would rather put out of our heads. The main message – which I hope came through editing – is that all cancer patients should take careful notes on their planned treatments and ask their doctors about the long-term consequences of therapy. Not all chemo is the same; the risks vary among regimens and doses. The reality is that some of us – patients and doctors – prefer not to think about late, long-term, possible effects of treatment, like secondary tumors, when there’s a life-threatening condition in hand. This doesn’t mean chemo isn’t the right choice. Often it is, but it should be weighed out, carefully.

Finally, we learned that Dr. Susan Love, a breast surgeon and professor at UCLA, and leader of an Army of Women, has leukemia. Dr. Susan Love’s Breast Book is a reference my friends and patients turned to in the 1990s, before the Internet was so loaded with cancer info, and many still do. She has, through that book and through her Foundation, besides through her work as a surgeon, helped an army of women to heal, and more.

My thoughts are with each of these remarkable women, and their loved ones, now.

ES

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FDA Approves Pertuzumab for Advanced, Her2+ Breast Cancer

We’re on a roll for new treatments of the Her2+ form of breast cancer. On Friday the FDA approved Pertuzumab, a monoclonal antibody, for advanced cases. As indicated, the drug would be given along with another monoclonal antibody, trastuzumab (Herceptin) and a chemotherapy, docetaxel (Taxotere) to patients with advanced breast tumors with high levels of Her2.

The new treatment’s brand name is Perjeta. Like Herceptin, this reagent works by attaching to the Her2 receptor on a cancer cell’s surface. But it differs by binding a distinct part of the molecule; its mechanism of action is said to complement that of Herceptin.  You might recall that HER protein family members are complex signaling molecules that span cell membranes. Her1 is the Epidermal Growth Factor Receptor; it’s turned on when bound by its partner, or molecular ligand, Epidermal Growth Factor(EGF). The others are Her2, -3 and -4.

EGFR (Her1) signaling, Wiki-Books image

The science behind drugs that interfere with Her2 receptors and signaling is nicely summarized in a recent, open-access Nature Reviews Clinical Oncology article. Herceptin binds a particular segment of Her2 on the outside of the cell; this leads to failed signaling on the inside, including cell division signals, and causes cell death by several mechanisms. Pertuzumab binds a distinct segment of Her2 in such a way that it can’t form a complex with the related Her3 molecule; this interaction is needed for Her2 to stimulate cell growth.

The FDA’s approval rests largely on results of the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) study, published earlier this year in the NEJM. In that Phase III study, just over 800 patients were randomly assigned to receive a standard regiment – Herceptin in combination with Taxotere plus a placebo infusion, or the Herceptin-Taxotere combination plus Pertuzumab.

The patients who received Pertuzumab did better in terms of Progression Free Survival (PFS, 18.5 months vs. 12.4 months; this difference holds strong statistical merit). There is a trend, also, in terms of Overall Survival: at a median follow-up point of 19.3 months, there were more deaths in the placebo group. But a statistically significant difference was not reached. Toxicity was reported as “generally similar” in the two groups, but there was more diarrhea, dry skin and rashes among those who got Pertuzumab (Table 3). Heart problems, a known toxicity of the Herceptin-Taxotere regimen, were slightly less common with Pertuzumab. Hair loss, presumably from the chemotherapy part of the regimen, was common in both groups.

One curious thing I noticed, in re-reading the January report, is that although the median age for both patient groups was 54 years, the control patients ranged from 27 – 89 in age; those who got Pertuzumab ranged from 22 – 82 years. Although the younger “shift” of Pertuzumab-receiving patients relative to the controls is unlikely to affect the PFS, it’s odd to include an 89 year old patient on an experimental protocol involving infusions of two monoclonal antibodies along with chemo.

This is a super-costly regimen. Like Herceptin, and like the experimental compound antibody, DM1, about which I wrote last week, Perjeta is manufactured by Genentech. As detailed by Andrew Pollack in the NY Times: the wholesale price for Perjeta will be $5,900 per month for a typical woman; Herceptin costs $4,500 per month. So we’re talking about a treatment in which the monoclonal antibodies alone cost over $10K per month. “A typical 18-month course of treatment would be more than $187,000,” he indicated. But if you add on the costs of the Taxotere, drugs like Benadryl and Decadron to minimize allergic reactions, anti-nausea meds, charges for the infusion and monitoring…It’ll be a lot more than that.

As the FDA notes in its press release, production of Perjeta is currently limited due to a technical issue at the Genentech manufacturing plant. Meanwhile, investigators, doctors and patients will have to sort out the relative value of this drug, on top of the others – including pills – for Her2+ disease.

My opinion is not quite formed on this new antibody. The FDA’s decision was based on results from one trial of 808 patients, half of whom didn’t get the experimental drug. Accrual began in 2008; its broad clinical effects, and long-term toxicities, can’t be established yet. It may be, ten years from now, that Perjeta will be used routinely in patients with other, Her2+ kinds of cancer. Or it may be a toxic bust.  How (and if) we’ll test and compare different doses of Perjeta and potential combinations with other drugs, small pills and traditional chemotherapies – which are many – is not clear. You could, for example, combine one or both of the antibodies with a drug like Lapatinib (Tykerb), that inhibits Her2-triggered growth signals inside the cell.

The problem is that oncologists, and facilities including academic centers where revenue is generated by giving drugs by infusion, now have a huge financial incentive to give the Herceptin-Perjeta-Taxotere regimen. This regimen is approved for first-line treatment of metastatic, Her2+ breast cancer; you don’t have to have “failed” another regimen, as was required for the EMILIA trial. As I understand this approval, an oncologist seeing a woman with recurrent or metastatic Her2+ breast cancer could, immediately, prescribe the 3-drug combination.

It’s impressive that the CLEOPATRA folks included an 89 year old patient in the study. But at some point, you have to wonder where we might draw lines. I’ve no answers on that.

All for now, maybe for the week,

ES

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EMILIA Trial: T-DM1 Appears Helpful in Women with Her2+ Metastatic Breast Cancer

This weekend the American Society of Clinical Oncology (ASCO), to which I belong, is holding its annual meeting in Chicago. Some of the biggest buzz has to do with a new breast cancer drug called T-DM1. ASCO just lifted embargo of the relevant abstract.

The new agent is a hybrid of an old monoclonal antibody, Herceptin, that’s chemically attached to DM1, a traditional kind of chemotherapy. The chemo part, DM1 – also known as emtansine – is manufactured by ImmunoGen. It’s derived from maytansine, a compound that binds tubulin, a protein critical for microtubule formation in dividing cells. According to the NCI website, this chemical, which has antibiotic properties, was extracted from an Ethiopian plant, Maytenus serrata.

T-DM1 was designed by linking the DM1 compound to the trastuzumab (Herceptin) antibody. Trastuzumab is old news in breast cancer. It binds a signaling molecule, Her2, that’s expressed at high levels in approximately 1 in 5 breast tumors. The FDA approved Herceptin for use in patients with metastatic, Her2+ breast cancer in 1998 and, for some women with localized, lymph node positive disease, in 2006. In this new, hybrid drug, the antibody works like a tagged, toxic messenger. In effect, the antibody delivers and inserts the chemo into the malignant cell, where it causes cell death.

The new data, from the Genentech-sponsored EMILIA trial, were presented today:

The Phase III study evaluated 991 women with metastatic breast cancer. All participants had tumors with high levels of Her2 (confirmed in a central pathology lab, for the trial). All had disease that progressed despite treatment with Herceptin and, in most cases, other drugs too. After randomization, 978 women received either of two treatments: the experimental agent, T-DM1, every 3 weeks, by intravenous infusion, or a combination of two pills, “XL” – Xeloda (capecitabine) and Tykerb (lapatinib). Median follow-up was just over 1 year – not bad for a study of MBC, but not great, either.

The big news is this: Among the patients who got the experimental drug, T-DM1, the median time until disease progressed was 9.6 month; for those who took the XL pill combination, it was 6.4 months. This different was statistically significant. Although a difference of 3 months may not sound like much – and isn’t – each regimen in the study held the women’s disease in check for over half a year.

It’s striking that T-DM1 was used as a single agent. Most chemotherapy drugs, like those for HIV, work best in combination; it could be that we’ll see more powerful results in a few years, once we learn how to optimally combine drugs for women with Her2+ breast cancer.

As far as overall survival, the initial results seem quite favorable. Among women on the study for 2 years, 65 percent were alive who received T-DM1; among those taking the XL regimen, 47 percent were alive at 2 years. (The statistical details for this comparison are not available; evidently it was of weak significance.) The problem is – if only a few patients were analyzed “so far out” on the survival curves, the difference observed between the two study arms might be random. Still, and independently of the comparison, survival of 65 percent at 2 years in this patient group is (sadly) impressive, especially if it comes by a single agent with comparatively few side effects.

The main T-DM1 toxicities were low platelets and abnormal liver function, which were, reportedly, reversible. The XL combination caused more toxicity, overall, including diarrhea, hand-foot syndrome and nausea.  A much greater fraction of women on the XL arm (53 and 27 percent, respectively for Xeloda and lapatinib) needed dose reductions, as compared to the T-DM1 (16 percent had dose reductions due to toxicity). Evidently hair loss isn’t an issue for women who get T-DM1, which is nice.

My main, initial concerns are two:

First, the study, though randomized, is not “blinded,” and can’t be.  It’s impossible for women who are getting an intravenous drug, and their doctors, not to know that they’re not on the pill study arm. Although there were independent evaluators of progressive disease, which is a far more subjective measurement than overall survival, progression free survival can be influenced by the doctors’ and patients’ knowing they’re getting the T-DM1. That said, the initial, observed difference in overall survival – a clear, objective measurement – is impressive.

If these trial results, published in abstract form, pan out, and the quality of patients’ lives is maintained, that’d be helpful to as many as 1 in 5 women with MBC. It is plausible that an antibody like Herceptin that targets the tumor cells could, in fact, “deliver” the chemo effectively into the cancer cells with relatively low toxicity. And if the women are feeling better, which is hard to know from an abstract, great.

My second concern is how this drug will mesh with others now available and in the pipeline for patients with Her2+ disease. In a December, 2010 editorial in the JCO, two clinical investigators wrote: “the unique aspect of T-DM1 is clearly its high clinical activity by itself, without the need of concomitant additional systemic chemotherapy.” They’re right. The question – as considered by those authors – is how T-DMI will be used in the context of expanding treatment options for women with Her2+ breast cancer. This is an expensive (price not yet known) monoclonal antibody-conjugate that’s necessarily given by infusion. Testing this drug against all the other current and up-and-coming alternatives, in varying combinations and doses, will be tricky. The trials alone will cost big bucks, besides toxicity and women’s lives.

These EMILIA results are promising for some women with MBC and, possibly, patients with other cancer forms in which Her2 is expressed. Unfortunately, it’s unlikely to help those women with breast cancer whose tumors that lack Her2+.

I’ll write soon about this new class of oncology drugs – antibodies conjugated to chemotherapies, as a group.

All for now,

ES

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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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The Outlier’s Message, and Evolutionary Science in Breast Cancer

This past week I read several attitude-altering articles about breast cancer.

Kathy Rich, as featured in ‘O’ Magazine

The first lesson, if I might call it that – in the way an oncologist can learn from variations in her patients’ pathology and clinical outcomes – comes from the case of Katherine Russell Rich, who died last week at the age of 56. As reported by Katherine O’Brien in the I Hate Breast Cancer Blog, Rich lived with metastatic BC (MBC) for 18 years. That’s phenomenal, was my first reaction to this news. The prognosis for MBC is said to be around 3 years, and Rich lived for 18 years beyond her tumor’s recurrence with stage IV disease.

As sad and unsatisfactory as this outcome may seem, and it is, Rich’s story offers hope for life beyond the 3 or 4 or 5 years some women with MBC pray, “ask” or otherwise bargain for, fingers-crossed…

As she detailed in an O article, Rich’s initial diagnosis came when she was 32 years old, in 1988. The Times, in an obituary, tells of her lumpectomy, chemo and radiation. In 1993 her cancer came back in bones including her spine. She had a bone marrow transplant, but the disease progressed. Ultimately, she coursed through various and some archaic hormone treatments.

Along the way, she lost or quit a job in publishing, or both, and traveled to India, and authored two books. In a 2010 first-person story about her case, she told of updating her status – of being alive – at Breastcancer.org each year. She wrote:

…I tell the women how deeply I believe there’s no such thing as false hope: all hope is valid, even for people like us, even when hope would no longer appear to be sensible.

Life itself isn’t sensible, I say. No one can say with ultimate authority what will happen — with cancer, with a job that appears shaky, with all reversed fortunes — so you may as well seize all glimmers that appear.

My take, as an oncologist and former clinician, is that patients sometimes surprise you. Hard to know which woman will respond to a non-targeted treatment, or even a drug like an estrogen modulator, without trying. And I wonder – and this is speculative, but maybe, likely, the two together – doctor and patient – worked together to see what worked in Rich’s case over nearly 2 decades, and what didn’t work.

A Bell Curve

If a drug helps, keep it going; if it hurts, stop. There are so many algorithms in medicine, and molecular tools, but maybe the bottom line is how the, one, your patient is doing.

Which leads me to another post, by Dr. David Gorski, a breast cancer surgeon and researcher who blogs as Orac – what once was imagined as a fabulously capable information processor, at Respectful Insolence. He describes how tough it can be to define, and thereby target or destroy, any individual patient’s breast tumor because the cancer cells are constantly changing. Within each woman’s tumor, an evolution-like process is ongoing, leading to selection of treatment-resistant cells. This is not news in oncology; the concept has been understood for years as it applies to “liquid” tumors like leukemia, as he points out.

In breast cancer, understanding the complexity of each case is more recent. Gorski considers a genetic analysis of 104 triple negative breast cancer (TNBC) cases presented at the recent AACR meeting and published last week in Nature:

“…The 59 scientists involved in this study expected to see similar gene profiles when they mapped on computer the genomes of 100 tumours.

But to their amazement they found no two genomes were similar, never mind the same. “Seeing these tumours at a molecular level has taught us we’re dealing with a continuum of different types of breast cancer here, not just one,” explains Steven Jones, co-author of this study.

…TNBC is not a single disease. In fact, even an individual TNBC tumor is not a single disease. Tumor cells evolve as they proliferate, so that the cells in them are genetically heterogeneous. The cells growing in one area of a tumor can and often do harbor markedly different genetic mutations from the cells growing in another part of the tumor…

The team found that each tumor displayed multiple “clonal genotypes,” suggesting that the cancer would have to be treated as multiple diseases, rather than a single entity.

So besides that there are distinct subtypes of breast cancer, those labeled as TNBC are diverse and contain variation within; each patient harbors sub-clones of malignant cells that, in principle, respond differently to treatment.

Orac, the fictional supercomputer (Wiki-Commons image)

Putting these links together –

The message from Katherine O’Brien, who lives with MBC and blogs about it, is that one outlier – like Katherine Russell Rich – can provide hope to other patients and, maybe, clues for scientists about why she lived for so long with metastatic BC. The message from Orac, a physician-scientist blogger, is how hard it is to pinpoint an individual breast tumor’s molecular aspects, because the disease is so mutable and diverse.

The problem, and this reflects evolution in my thinking over a long while, is that published data – the gold standard, what supports EBM – are largely limited to findings based on trials of groups. We understand now, better than we did 10 or 20 years ago, that each patient’s tumor is unique and can evolve over time, naturally or in response to therapy. Clinical trials, though rigorously planned and elaborately structured, are incredibly expensive and flip-floppy, disappointing overall.

What I’m thinking –

Algorithms – except in the broadest sense – may not offer the optimal approach to cancer treatment. Maybe the median doesn’t matter so much as we’d thought.

Here’s a ~retro idea: In 2012, maybe the ideal and most cost-effective oncology practice would blend low-tech observations – like findings on physical examination and how the patient’s feeling – with occasional, high-tech analyses – like markers for genetic drift within a tumor. If doctors are well-trained and non-robotic, in either the literal or figurative sense, and if they lack COIs regarding treatment decisions, they’d provide better, more effective and personalized treatments than what’s typically offered based on evidence reached through elaborate, costly clinical trials of many patients with similar but non-identical cancers.

All for now,

ES

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