December 13, 2008
Barbara Brenner, Former Executive Director
More on Metastasis
I decided to take the early morning off from this very exhausting meeting, but made it a point to hear what I could of the AACR Distinguished Lectureship in Breast Cancer Research, presented by Joan Massagué. While I had to leave the lecture before it was over, I think I got the gist of it.
Massagué started from the very logical—at least to me—observation that, given the common metastatic sites of breast cancer—bone, brain, liver—and the different natures of those organs, cancer cells need different abilities to penetrate and colonize those sites.
He also pointed out that, unlike other cancers like lung and colon, breast cancer often takes several years (and sometimes much longer) to manifest as metastatic. To him, this means that the primary breast cancer cells can’t colonize initially. They have to develop this ability in the micro-enviro in which they are embedded. Massagué asks what functions cells need to accomplish this? He also noted that, while developing metastasis 2 or 3 years after initial diagnosis may be “early” to an oncologist, to a biologist, it’s a long time.
The question that came to mind as I heard Massagué describe this was: what does the micro-environment have to be to enable this transformation? I don’t think Massagué got to this question.
The balance of Massagué’s talk built on the information being learned through understanding the molecular structure of cancer, and described his development (along with his team) of genetic signatures that predict lung metastases and brain metastases.
This is important work, especially in the ongoing and as yet uncompleted effort to individualize care, and treat only those who need treatment. We’ll keep an eye on it. And we’ll also ask this question: if it turns out that not everyone whose breast cancer has the lung metastasis genetic signature or the brain metastasis genetic signature develops mets, what will that tell us about the human body that will help us develop new approaches for the people who are at greatest risk?
Another Lunch with Big Pharma—Novartis Has Its Hands Full
Today’s lunch time entertainment was a presentation by Novartis to promote Zometa. The program was called “Metastatic Breast Cancer: Why are my bones important?” The company rep started by telling us that this drug is doing great things for women, but that there are still lots of people who are untreated but who need to be. She expressed the hope that we would obtain useful information for the patients we talk to, or, at least, to remember to call Novartis if we have questions.
The first speaker was Marcia Strassman, an actress (Welcome Back Kotter) who was diagnosed with bone mets at her initial diagnoses. She is now partnered with Novartis (and has a Facebook page) to offer support and information to other people with breast cancer about the importance of following prescribed treatment. In the case of Zometa, that’s an infusion every 28 days. Marcia was diagnosed after she found what she called a mound, even though she had been getting regular mammograms and had had one 7 months before her diagnosis. Fortunately for her, she had been involved in a benefit to raise money for cancer research for years, and had access to the best doctors. Unfortunately, a scan revealed bone mets, and we she was placed immediately on Arimidex and Zometa. She said she had an allergic reaction to Arimidex, so was switched to Femara. She was very thankful for the drug, which happens also to be made by Novartis. She wanted us to know that most of her activities have not been affected—she’s living her life, and doing her treatments. In fact, she told the group that she was able to get her Zometa when she traveled.
Turned out when she was asked about getting Zometa on the road that Marcia has a health insurance plan that lets her do things that an HMO or an uninsured person can’t do. Great representative for what happens to people with breast cancer, no?
The next two presenters were both doctors—Adam Brufsky and Hope Rugo. They talked about the importance of bone health, and the powerful effect of Zometa. Neither of them disclosed how much Novartis pays them for their work on behalf of the company. Brufsky wanted us to know that great progress has been made in breast cancer, and that the majority of women diagnosed now will be cured of their disease. He promised that in the next few years we’ll see phenomenal progress. (Where have we heard this before?) And he credited the advocates in the room for raising money for research, and urged us to keep doing that. (I can’t be sure, but I’m betting that most of the women in the room work for organizations that don’t raise money for research.)
Hope Rugo framed her presentation interestingly, pointing out that she would talk about what happens in the real world with Zometa, and noting that clinical trails are, as she put it “a little contrived.” She spoke glowingly of the advantages of Zometa, and stressed at some length how rare osteonecrosis of the jaw is as a side effect.
Then it was question time, and that got interesting. Questions could be posed in writing or verbally. Some questions were about treatment issues. I asked about the fact that the company, which makes all these drugs that are addressing cancer like Zometa and Femara (an aromatase inhibitor), also makes the herbicide atrazine, which stimulates aromatase. There was a question about Evista (raloxifene) for breast cancer, which Hope Rugo handled quite well, pointing out that the drug is not a breast cancer drug, but that she prefers it for “prevention.”
Roberta Gelb, an activist who works with several organizations, pointed out to Dr. Brufsky that, despite his urging, none of the advocates in the room would tell the patients they work with to live their lives and leave their breast cancer to their oncologists. After a defensive response from the doctor, the session ended.
The activists with whom I spoke after this lunch were deeply offended by the presentation. They felt patronized and angry. It’s clear that Novartis did not know who was in the room—very well informed, passionate, and smart advocates and activists who need and demand real information, not pablum sugar-coated by a drug company.
There was a whole afternoon devoted to imaging in breast cancer, but I only attended the presentation on ultrasound, because this is a technology that many people find valuable and friendlier than mammography.
The presentation focused mostly on the use of ultra sound as screening intervention. Starting from the premise that mammography is the gold standard (the presenter, Wendie Berg, is a radiologist after all), Dr. Berg noted that there are some subgroups of women who may not benefit from mammography: women with dense breasts and women at high risk of breast cancer. In both groups, there are likely to be more years of screening (since dense breast tissue is most common in younger women) or more frequent screening.
In high risk women, Dr. Berg deferred to the ACS guidelines on use of MRI for screening, and noted that if women are doing MRI and mammography, they don’t need to do ultrasound as well.
But for women at intermediate risk, Dr. Berg saw insufficient evidence for or against MRI, noting that it is both very expensive and not well tolerated by many women. In this group, she finds lots of things to favor ultrasound: cost, availability, it’s not radiation based, and it’s well tolerated. The trial that is ongoing of ultrasound for screening—ACCRIN 666—which published it’s first results in JAMA in May, 2008, shows that ultrasound is good at finding small lesions, node-negative disease, but there are a lot of false positives, leading to a number of unnecessary biopsies.
Dr. Berg noted that ultrasound is not good at determining whether tiny masses are solid or fluid filled, but that there are some efforts to develop technologies to solve this problem.
The take-home here was that it is practical to use ultrasound to screen high-risk women who cannot tolerate MRI, but the high false-positive rate has to be dealt with, as do issues of technologist training and reimbursement.
And, as is always the case when the discussion is about screening, Dr. Berg pointed out that ultrasound supplements, but it doesn’t replace mammography.
Breast Density and Breast Cancer Risk
Jack Cuzick presented Abstract 61 from the IBIS-1 trial—a tamoxifen for risk reduction trial. This study looks at whether a change in breast density functions as a biomarker risk reduction from the use of tamoxifen. While there were over 7,000 women in the original trial, the breast density study was a nest case-control study of only 126 cases. Cuzick concluded that reduction in density over 12 to 18 months is an excellent predictor of subsequent benefit of tamoxifen for risk reduction (which Cuzick insists on calling “prevention.” But the doctor next to whom I was sitting during this presentation pointed out that the study was not sufficiently powered to learn anything meaningful. Small studies, meaningless results.
Benign Breast Disease and Breast Cancer Risk
Presenting Abstract 62, Dr. Ghosh described looking for risk factors for breast cancer among women diagnosed with benign breast disease (BBD). BBD, which for this study had to be biopsy confirmed, includes ATH, non-proliferative disease, proliferative disease without atypia, and atypical hyperplasia (AH). Dr. Ghosh concluded that young women with benign breast disease are at elevated risk, which is elevated most for women with AH. She found that risk is not elevated for young women with non-proliferative disease and with no family history, and that lobular involution reduced risk. When I asked whether breast biopsies had been looked at as increasing the risks in the patients, Dr. Ghosh did not understand my question. Maybe I didn’t state it clearly.
Hormones and Breast Cancer
There were three studies presented on this subject. The first, Abstract 63, looked at correlation of plasma estradiol levels with expression of estrogen receptor genes. The study was inspired by the observations that tumor estrodial is higher in breast tumors than in plasma, and that plasma levels of estrogen and androgenic precursors are significantly associated with breast cancer risk in post-menopausal women. In this small study (N=122), Dr. Dunbier found that tumor expression of estrogen-dependent genes is correlated with plasma estradiol levels. From this, she infers that circulating estrodial could have a substantial impact on the biology of ER+ breast cancer.
The second study presented, Abstract 64, had more of an impact, at least on me. Dr. Chleblowski presented analyses of the data from the Women’s Health Initiative Trial on breast cancer in the women who had been on the combined hormone therapy in that trial: estrogen plus progestin. He showed both a decline in breast cancer following the termination of the WHI, and that mammography screening patterns did not change in these women between when the trial started and when it was stopped. Will this end the debate about why breast incidence declined after the termination of the WHI? I’m not sure I’d bet on it, especially given Wyeth’s attempts to convince people that the decline has nothing to do with the decline in hormone use.
In answering questions after his presentation, Dr. Chlebowski stated that it’s not possible to define a safe interval of hormone therapy use. He also agreed with a questioner that it’s possible that low dose estrogen after a period of deprivation may be useful. There has been other information presented at this meeting about showing that estrogen can benefit patients with metastatic disease.
The last presentation that I listened to was of Abstract 65 about hormone therapy use prior to diagnosis and its impact on breast cancer survival in the California Teacher’s Study. Dr. Marshall reported a statistically significant 5% improvement in breast cancer mortality for women who had used hormone therapy prior to their diagnoses.
I’m looking forward to being home, and away from so much talk about so little that matters to patients’ lives now.