Barbara Brenner, Former Executive Director

Tamoxifen: still looking for answers

I decided early on at this conference that I was going to skip the many presentations on molecular pathways. They are very interesting to doctors, and to folks doing drug development, but they are, by themselves, meaningless to patients. I also decided that I would only sit through presentations on Phase III drug trials, because those are the ones of most interest to patients, since they are closet to FDA approval.

So the first sessions I attended this morning were two about our old friend, tamoxifen. This is at drug that has been in use for more than 30 years in the breast cancer context, and you might think that we know all we need to know about it, but not so.

The first presentation was the one that interested me most. Abstract 33 focused on CYP2D6, the gene that may control the body’s ability to metabolize – and benefit from – tamoxifen. While the presenter touted the data collection, there was so much missing information as he described those data that its hard to know what, if anything the study means. With the weak data presented, no association of CYP2D6 to invasive breast cancer was seen.

The other presentation on tamoxifen was of Abstract 34, looking at the effects of tamoxifen for women with locally excised DCIS. The presentation by Jack Cusick was of long term (median 12.7 years) trial follow up. Cusick pointed out several times that long time follow up with DCIS patients is necessary because the risk of death from the disease is so low.

The trial looked at patients treated with just radiation, those treated with just tamoxifen, and those treated with both. Radiation reduced recurrences in the affected breast by 60%. Longer follow up of patients who received tamoxifen showed benefit, with a 29% reduction in all recurrences, mostly in the unaffected breast.

Cusick noted that the benefits of tamoxifen were much stronger in low and intermediate grade tumors than in high grade tumors, and that analysis is ongoing to try to determine who is most likely to benefit from treatment

There was no significant difference in deaths among the arms of the trial, a result that Cusick found surprising.

A question asked after this presentation revealed that a substantial number of patients in the trial did not have clear tumor margins. This may confuse the results, since clear margins might make less treatment necessary.

Cusick answered the final question posed to him saying that there is “undoubtedly overtreatment of DCIS”.

Avastin: In search of a survival advantage

This afternoon we heard two presentations about two big Avastin (bevazicumab) trails: AVADO (Avastin as first line treatment for metastatic breast cancer) and RIBBON II (Avastin as second line treatment for metastatic disease). Avastin was given fast track approval by the FDA based on data showing that the drug improved Progression Free Survival (PFS) of patients. At the time, there was no evidence that the drug improved overall survival of patients. And in neither study presented today did patients on Avastin survive longer than patients who do not receive the drug.

David Miles presented Abstract 41, the final overall survival results from the AVADO trial. In the trial, there were two dosing schemes for Avastin. The data he presented showed that the higher dose of Avastin arm improved PFS (from 8.2 months to 10 months) and the Objective Response Rate (ORR) (a combination of complete response [tumor disappears], partial response [tumor shrinks] and stable disease [tumor doesn’t shrink, but doesn’t grow[.. There was no survival advantage with either dose of Avastin.

A woman whose name I didn’t get presented Abstract 42, the results of RIBBON II, testing Avastin as a second line treatment for metastatic disease in combination with four different chemotherapy agents. The results provided were those based on median 7.2 months of follow up. The primary endpoint of the trial was PFS, and the final PFS results showed a 22% reduction in risk of progression for all the chemo cohorts. The difference in Objective Response Rates was not statistically significant. And the interim overall survival data showed no advantage for Avastin. There were more adverse events with Avastin.

Most revealing statement made by the presenter of the RIBBON II information was her conclusion that Avastin provides “clinically meaningful” benefit for patients. When I posed the question of what she meant by “clinically meaningful,” she acknowledged that this is “somewhat subjective,” but that, for her as treating oncologist, the number of trials showing PFS benefit for Avastin justifies it use in patients.

A word on PFS: A question and answer exchange in another presentation was revealing about how different doctors see data. Someone asked about quality of life data in a trial where PFS advantage for the drug in question was 2 months. The person asking the question thought the quality of life issue was large because the amount of time gained was small. The response he received was that 2 months was 40% improvement in Progression Free (not overall) Survival , and that was very significant. It was great to hear quality of life raised here. To bad the presenter didn’t think it was so important.

Avastin and Surgery
In one of the few surgical studies presented here, Abstract 43 looked at surgery complications from using Avastin as neoadjuvant treatment. The study suggests that surgery involving tissue expanders or implants may be problematic for women who receive neoadjuvant Avastin.

Drug company sponsorship of trials

Most of the trials presented here – including all the Avastin ones – were sponsored by the companies that make the drugs. Usually, that goes without comment here, at least without public comment. But after the presentation of Abstract 46, Dr. Vogel from New York stood up and asked whether the reason that the presenter didn’t say that the trial of sunitinib was definitive and a definitive failure was because Pfizer was the study funder. The presenter didn’t bite on that question, he punted.

Heard In the Halls

If you keep your ears open, you learn things here. Today I learned that

  • Italy won’t pay for drugs in its health care system unless the drug extends life by at least 3 months more than do other available treatments.
  • The National Comprehensive Cancer Network (NCCN) is considering setting suggested prices for new cancer drugs.
  • In Japan and India, surgeons are oncologists. There is no separate medical oncology specialty
  • The Susan G. Komen for the Cure Foundation did not have their usual dinner honoring their scientist awardees here this year. Instead, they  had an invitation only reception. We weren’t invited.
  • The leadership at the Komen Foundation don’t believe that over-treatment happens in breast cancer