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Provocative findings from two studies of patients in pivotal trials suggest that some women with HER2-negative breast cancer may benefit from trastuzumab.
A retrospective analysis of the phase III Cancer and Leukemia Group B (CALGB) 9840 trial revealed that HER2-negative metastatic breast cancer patients with multiple copies of the chromosome carrying HER2 had significantly better response rates (63% vs. 26%, P = .048) when they were treated with trastuzumab (Herceptin) in addition to paclitaxel.
In the adjuvant setting, another retrospective analysis showed that a small group of HER2-negative patients in the phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial had significantly better disease-free survival with a relative risk of 0.40 (P = .026) when given trastuzumab after completing treatment for early breast cancer.
Both studies drew considerable attention, with investigators and discussants discouraging attendees from using the findings in the clinical setting before they can be verified.
"We emphasize that additional study is needed. At the moment we don't feel that these data should be used clinically," Dr. Peter A. Kaufman said in his presentation of the CALGB data. Dr. Kaufman of the cancer center at the Dartmouth-Hitchcock Medical Center, Lebanon, N.H., stressed that only a small number of patients was analyzed and that trastuzumab did not improve progression-free survival or overall survival for the HER2-negative patients with polysomy of chromosome 17.
Dr. Soonmyung Paik of the NSABP called for a randomized clinical trial to test adjuvant trastuzumab in HER2-negative women. A favorable outcome might lead to expansion of trastuzumab's indication from 20% to about 60% of breast cancer patients, he said.
"The major question raised by this paper is, what now?" Dr. James H. Doroshow said, advising that the NSABP study needs to be confirmed before new standards for HER2 positivity can be developed. "It is critical that all appropriate adjuvant breast cancer sets be reevaluated, so that a new consensus can be established for HER2 testing," said Dr. Doroshow, director of the National Cancer Institute's division of cancer treatment and diagnosis.
Investigators were limited to available tissue blocks in both retrospective studies of completed trials. They also grappled with disparities between local and central laboratories testing for HER2 positivity, and with standards for making the determination by immunohistochemistry (IHC) and/or fluorescent in situ hybridization (FISH).
"This is the bottom line. We couldn't find any subset that didn't benefit from trastuzumab," Dr. Paik said. In patients deemed negative by both IHC and FISH, the relative risk of recurrence was 0.34 (P = .014). Noting that the parameters of HER2 positivity originated in the metastatic setting, he proposed the "definition of HER2 overexpression/gene amplification based on data from advanced disease may need to be modified for the adjuvant setting."
Kaufman P.A. et al. CALGB 150002: Correlation of HER2 and chromosome 17 (ch17) copy number with trastuzumab (T) efficacy in CALGB 9840, paclitaxel (P) with or without T in HER2+ and HER2- metastatic breast cancer (MBC). Abstract 1009.
Paik S. et al. Benefit from adjuvant trastuzumab may not be confined to patients with IHC 3+ and/or FISH-positive tumors: Central testing results from NSABP B-31. Abstract 511.
Commentary |
Testing for HER2 overexpression has been controversial since trastuzumab was first approved to treat advanced breast cancer. These interesting retrospective analyses evaluated the impact of trastuzumab in patients with variable HER2 positivity. The issue of whether or not polysomy of chromosome 17 (multiple copies of the chromosome on which HER2 is located) can predict response to trastuzumab in HER2 negative women is still highly debatable, and additional studies are necessary. Very small numbers of patients are represented in the analysis of Cancer and Leukemia Group B (CALGB) 9840. The data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) adjuvant trial is complementary to the presentation by Dr. Edith Perez (abstract 512) in that patients found to be negative for HER2 overexpression by central testing appeared to benefit from the addition of trastuzumab to adjuvant chemotherapy. It is important to remember that all of these patients' tumors tested positively for HER2 at their local institutions, as this was a major eligibility requirement for the trial. It may be that the results of testing are more variable than currently thought, and that any positive value at any site predicts potential benefit from adjuvant trastuzumab. Repeat testing of the "negative" samples at another pathology laboratory may help to elucidate this question. If these data stand up to additional review, and data from other trials demonstrate similar benefits in the HER2-negative population, it may be that the only way to understand the appropriate criteria for determining benefit from adjuvant trastuzumab is to conduct a randomized trial. — Hope S. Rugo, M.D.
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