After attending my fifth San Antonio Breast Cancer Symposium it seems, once again, that we are inching forward ever so slowly in improving survival for some women, but at a great cost to many. Much effort is going towards breast cancer research, but these efforts seem diffuse, with a hit or miss strategy. Many results never reach the clinic. Those that do may or may not lead to marginal improvements for some, but most often add risk of toxicities for many. Thousands of researchers and oncologists once again gathered to hear about studies focused on comparing different doses, different schedules, different combinations of treatments, with some showing marginal improvements in survival, most showing no difference. Very few presentations focused on how to reduce the risk of toxicities from treatment for the increasing numbers of women being diagnosed with early breast cancer, many of whom may have been fine with no treatment at all. Almost no presentations focused on preventing the disease in the first place.
I like to imagine how different it could be if there was a mission-driven approach to breast cancer research, and everyone was coming together to strategize about achieving very specific goals, rather than diffuse pursuits in many directions. What if there was a coordinated effort throughout the year to answer a few directed questions that could lead to understanding how to prevent deaths from the disease? How exciting it would be to come together each year to hear about that kind of progress.
Instead, the presentations I heard often seemed driven by the needs of pharma or business, but not women. How can we recapture the market for a drug going off patent? Or how do we move the drug to another stage of the disease and capture a new market? Or the needs of scientists. Many presentations this year looked at associations between genomic profiles and various factors of the disease or treatments. This is elegant science, which leads to papers and new lines of laboratory research for next year, but I didn’t hear much evidence that this work was leading to benefits for women.
A few presenters said we may be going about it all wrong. Dr. Fatima Cardoso, in a presentation on treatment guidelines for women with metastatic breast cancer, said we need to think of metastatic disease as a different disease and study it as a different disease, not as grounds for studying adjuvant treatment of early breast cancer. The current model is to develop a drug that shrinks tumors, prove its efficacy in the metastatic setting, and then move it into the adjuvant setting to prevent recurrences. And add it on to existing standard of care to see if it improves survival. The problem, said Dr. George Sledge in a presentation on tumor dormancy, is that agents that can halt progression in a metastatic setting may be completely different from those that can remove residual disease after surgery for early breast cancer, or that maintain tumor dormancy and prevent a reemergence of the disease. I would also say that another problem of this add-on approach to breast cancer treatment is that while sometimes bringing marginal benefit, this approach continues to escalate the risk of treatment toxicities.
Our work must continue as advocates for women, to right this ship, getting researchers to focus on the appropriate questions that will lead to meaningful progress and lower toxicities. This year, we remain hopeful that a new class of drugs, antibody-drug conjugates (ADCs), will alter cancer care, bringing greater efficacy and at the same time greatly reducing the harms of treatment. These ADCs can deliver chemotherapy directly to cancer cells, resulting in cell death, while avoiding harm to normal cells. But they must be evaluated on their own, and not simply added to regimens of systemic chemotherapy. We continue to advocate for the company (Genentech), that developed an ADC for HER2+ breast cancer called T-DM1, to evaluate the new drug in early breast cancer without systemic chemotherapy, to finally give the promise of targeted breast cancer treatment, with lower toxicity, a chance to be achieved.
Specific findings reported at this year’s symposium:
This was one bright spot at the meeting. Encouraging results were presented from a small study of a new agent, done in two parts, with just under 200 women who had ER+ advanced breast cancer. The agent, which is identified as PD 0332991, was developed from the work of Dr. Dennis Slamon and colleagues, funded by a DOD Innovator Award. It is an inhibitor of cyclin-dependent kinases (CDK), necessary for DNA synthesis. In the first part of the study, women were randomized to receive PD 0332991 with letrozole, or to receive letrozole alone. In the second part of the study women were screened for a biomarker, abnormal levels of the CDK protein. The good news is that women who took the CDK inhibitor had a median progression free survival of 26.1 months, compared to 7.5 months for the women who took letrozole alone. The disappointing news was that the effort to identify a biomarker of response beyond ER was not successful. More low white and red blood cell counts were reported with the new drug, but were readily managed and produced few complications for the women. A phase III trial of the CDK inhibitor begins in 2013.
Though FDA approval for Avastin in the metastatic breast cancer setting was revoked last year, clinical trials of the drug are continuing, and we continue to get reports. I wonder how many women are still receiving this drug and what it would take for researchers to stop these trials. Two studies were presented this year – the BEATRICE trial, looking at Avastin to prevent recurrence in women with triple negative disease, and the LEA trial, looking at Avastin in combination with hormonal treatment for first line treatment of metastatic breast cancer. In BEATRICE, a trial of over 2500 patients, the three year recurrence rate was virtually the same for both arms of the study, with greater toxicity in the Avastin arm. In LEA, investigators were hoping to show that Avastin if given without chemotherapy, would be more beneficial. But results from the trial of 380 women showed no differences in overall survival, and in fact, there was a trend toward lower survival in the Avastin arm, though this wasn’t statistically significant.
Results were reported from a phase III trial of eribulin mesylate for women with previously treated metastatic breast cancer, showing no significant improvement in overall survival, when compared to capecitabine.
Letrozole for Lobular Carcinoma
Lobular carcinoma accounts for approximately 10% of invasive breast cancer, and is usually ER+. An analysis from BIG I-98, a study comparing letrozole with tamoxifen for preventing recurrences in post-menopausal women, was presented showing that women with lobular cancers were deriving greater benefit from letrozole, than women with invasive ductal carcinoma. Previous results had failed to demonstrate an overall survival advantage with letrozole for all of the women in the study, but this subset analysis did find a greater overall survival advantage with letrozole vs. tamoxifen for women with invasive lobular carcinoma.
Results from CONFIRM, a study of different doses of Faslodex for recurrent or metastatic breast cancer, were presented showing a median overall survival of 26.4 months for the higher 500 mg dose of Faslodex compared to 22.3 months for the smaller dose of 250mg. At least one serious adverse event was experienced by 8.9% of the women receiving the higher dose, compared to 6.7% receiving the lower dose.
Dose Dense Chemotherapy
A ten-year follow-up analysis of adjuvant dose dense chemotherapy, given every two weeks and at a higher dose, instead of the standard dose every three weeks, showed a benefit in overall survival. In this study of over 1200 women with 4 or more positive lymph nodes, 10 year OS rates were 69% for those on the dose dense regimen, compared with 59% for those receiving the standard regimen. Nine cases of leukemia were reported in the dose dense arm vs. two in the standard arm.
Leukemia risk from treatment for early breast cancer
From clinical trials results we know that adjuvant treatment for breast cancer increases the risk of developing leukemia. A review of the records from over 20,000 women treated for early breast cancer found an overall cumulative risk of developing leukemia after ten years of 0.27%. The women who developed leukemia tended to be older, and the risk increased in those receiving chemotherapy vs. no chemotherapy, and for any radiotherapy vs no radiotherapy. No increased risk was observed if a taxane was added to an anthracylcine chemotherapy regimen.
Results were presented at this symposium and earlier this year at a European meeting on the optimal duration of Herceptin treatment for HER+ early breast cancer. The HERA trial found no difference in recurrence or survival between one or two years of treatment, and the PHARE trial, which was designed to determine if six months did not give a worse outcome, had results that were inconclusive. One year of Herceptin treatment remains the standard of care.
The ATLAS study (Adjuvant Tamoxifen – Longer Against Shorter) was the one most covered by the media this year. In this study, over 6800 women who had completed five years of treatment with tamoxifen for early breast cancer were randomized to continue tamoxifen for five more years or to stop treatment. It’s worth noting that there was not a placebo for the group who stopped treatment, weakening the design of the study. Compliance was approximately 80% and a benefit was found for the longer treatment, but it didn’t show up until after it was completed, in years 10-15 following diagnosis. The benefit was modest and the risk of side effects did increase. Breast cancer mortality was 15% for those women who stopped tamoxifen at five years, compared to 12.2% for those who continued for ten years. The cumulative risk of recurrence was 21.4% for women who took tamoxifen for ten years, compared to 25.1% for those who stopped. The rate of endometrial cancer was 3.1% in the ten year group, compared with 1.6% in the group that stopped at five. There was also an increased risk of pulmonary embolism in the ten year treatment group, though there were no differences in the risk of stroke.
Several studies on radiotherapy were presented. Most notably, ten year follow-up from the START trial demonstrated that three weeks of treatment is at least as safe and effective as the standard five-week schedule of treatments. Researchers with the TARGIT-A trial, looking at a single dose of radiation delivered internally vs. whole breast externally delivered radiation, presented preliminary results showing no differences in breast cancer deaths but a decreased mortality with the single dose from cardiac related deaths and second cancers.