Sometimes Science Is Not Convenient: Avastin® In The (Very) Early Treatment Of Breast Cancer

Sometimes science is not as convenient as we would like it to be. We want answers, we want clarity, we want direction--especially when it comes to the treatment of patients with cancer.

So when I read two articles and an editorial released Wednesday in the New England Journal of Medicine, I was struck as to how studies seeking to answer similar questions could come to different conclusions. And, as I struggled to explain the research findings to reporters prior to their release to the general public, I found myself searching for words that would adequately explain the message of the research. Quite frankly, determining that message proved to be difficult. 

The studies were done by well-recognized and accomplished researchers, one group from Germany and one from a group based in the United States. The goals of the studies were to demonstrate whether or not the addition of Avastin®(bevacizumab) to chemotherapy treatment given before a woman with breast cancer had surgery improved the rate of complete response of the cancer at the time of surgery (meaning that when the surgeon did the surgery and the pathologist reviewed the specimens there was no evidence of cancer in the breast). Both studies rely on the premise that achieving a complete response in this fashion improves the outlook for women with breast cancer. In addition, the American study sought to answer the question as to which of several chemotherapy regimens were better than the others.

In the German study, women with HER-2 negative breast cancer received this treatment program (called neoadjuvant chemotherapy, meaning before surgery) using a combination of drugs including epirubicin and cyclophosphamide, followed by docetaxel. Half the women were also treated with Avastin®, and half were not.  The women who received the additional Avastin® did have a higher rate of complete response in the breast as determined at the time of surgery, particularly in women with so called "triple negative" breast cancers (which means that they were not only HER-2 negative, but also didn't have evidence of hormone receptors in their cancers). These cancers are considered to have a poorer outlook. Women who did have hormone sensitive cancers did not do better with the addition of Avastin®, and their rate of response to the treatment was less than the triple negative group. As might be expected, the addition of Avastin® increased the number of toxic side effects of the treatment.

In the American study, women were randomly assigned to one of three treatment groups, one receiving only docetaxel, another receiving docetaxel plus gemcitabine and a third group receiving the docetaxel with capecitabine. All women received additional treatment with doxorubicin and cyclophosphamide. Within each of the three treatment groups, half the women also received Avastin® and half did not. 

The addition of gemcitabine or capecitabine did not improve the complete response rate of the tumors when evaluated at the time of surgery, so there was clearly no benefit to adding either drug to docetaxel. However, in the women who also received Avastin®, there was a higher complete response rate (34.5%) compared to no Avastin® (28.2 %). However, unlike the German study where women who had hormone negative tumors did better, in the US study those with hormone sensitive tumors had a more pronounce benefit from the addition of Avastin®. And, when the three "basic" chemotherapy groups were evaluated, the addition of Avastin® to the docetaxel/capecitabine arm was beneficial, but there was no effect on docetaxel alone group or the docetaxel/gemcitabine group. Once again, as in the German study, the side effects were more pronounced with the addition of Avastin®.

If all of this discussion leaves you scratching your head (assuming you have waded through the dense and very condensed descriptions of the trial above) you are not alone.

In the editorial that accompanied the research articles, the authors write:
"Subgroup analysis in the (US) and (German) trials revealed contradictory results. In the (German) trial, the rates of pathological complete response were significantly increased with bevacizumab therapy in patients with hormone-receptor-negative ("triple negative") breast cancer, whereas in the (US) trial, there was only a trend favoring bevacizumab in that population. In contrast, the (US) trial showed a significant increase in the rate of pathological complete response in patients with hormone-receptor-positive cancer, whereas in the (German) trial, no differences were noted in that population."

The writers go on to explain why those differences may have been observed, and how further studies and research may help us understand the differing results. They conclude:

"However, in the context of unsustainable expenditures for cancer care in the United States, any survival benefit of bevacizumab, or other molecularly targeted drugs, will be balanced against the considerable development costs of modern molecularly targeted oncology drugs."

So where does that leave us, when we try to explain to patients how this research might impact their lives?

First, I think it is fair to say that based on these results there is not going to be a rush to change current practice by most oncologists. There is no clear direction here, the side effects are greater, the cost not inconsiderable, and the results are in conflict. This is clearly a situation where--as noted in the editorial--we need to see further results over time, and additional research to help us understand which patients are in fact most likely to benefit from the addition of Avastin® to breast cancer treatment for women before surgery.

But to me there is a larger lesson, namely that as I mentioned earlier science and research are not always convenient. Sometimes research gives conflicting results, and sometimes the direction we need to take is not clear once the results are available. We sometimes find that research raises as many--if not more--questions than it answers. And sometimes that research cannot be easily translated into convenient sound bites (or as I like to say these days, Twitter bites since so much of our information is conveyed in messages of 140 characters or less).

It is in circumstances such as these that the thoughts of experts are important in putting research into perspective. And, for patients with cancer facing decisions about what treatment they should undertake, this type of situation underscores how important their care can be in the hands of a knowledgeable oncologist, especially one who carefully reads and understands the literature, is able to discuss the information intelligently with their patients, and is willing to spend the time to do so. It still comes down to the relationship between you and your doctor to understand what all of this means, and what is best for you. And I don't expect that truism to change any time soon, no matter how sophisticated our research may be now or in the foreseeable future.

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