Selection for Herceptin by FISH Improves Survival

February 1, 2002

SAN ANTONIO-A retrospective study presented at the 24th Annual San Antonio Breast Cancer Symposium (abstract 18) has shown that breast cancer patients selected for treatment with trastuzumab (Herceptin) combination therapy on the basis of HER-2 gene amplification by fluorescent in situ hybridization (FISH) may have improved clinical benefits.

SAN ANTONIO—A retrospective study presented at the 24th Annual San Antonio Breast Cancer Symposium (abstract 18) has shown that breast cancer patients selected for treatment with trastuzumab (Herceptin) combination therapy on the basis of HER-2 gene amplification by fluorescent in situ hybridization (FISH) may have improved clinical benefits.

"I think the data really point toward changing our approach to detection with FISH," said the study’s lead author Robert D. Mass, MD, associate director of oncology, Genentech, Inc.

It has been nearly 15 years since Slamon and his colleagues described the characteristic molecular alteration that leads to overamplification of HER-2. This work led to the pivotal trial of trastuzu-mab plus chemotherapy vs chemotherapy alone as first-line treatment of metastatic breast cancer, which demonstrated an improved response rate with trastuzumab: 50% vs 32%, respectively.

To qualify for enrollment, patients had to overexpress HER-2 at the 2+ or 3+ level. The investigators used a standardized, semiquantitative immunohistochemistry (IHC) assay to screen for enrollment. A previous analysis demonstrated HER-2 amplification in 89% of 3+ tumors and in 24% of 2+ tumors.

Accuracy Issues

"Since trastuzumab was approved some 3 years ago to treat advanced breast cancer, we have come to realize that IHC as a detection method has some significant accuracy issues. These issues led us to evaluate a more precise and accurate way to measure overexpression," Dr. Mass said.

He explained that FISH technology has a built-in control mechanism that prevents some of the false-negatives that occur with use of IHC.

"To establish the accuracy of FISH, we retrospectively evaluated the pathology data that were established from the trastuzumab trials," Dr. Mass said.

Histologic material for FISH testing was available from 458 of 469 patients enrolled in the pivotal trial of trastuzumab combination therapy. The material consisted of archived, unstained tissue sections (44%) or previously immunostained tissue sections (56%).

"When we looked at the baseline characteristics of the two randomized groups, they were quite similar with two exceptions," he noted. "The amplified patients were much more likely to overexpress at the 3+ level, and, to some extent, they were much less likely to be estrogen-receptor positive. The rest of the baseline demographics and prognostic characteristics were similar in the two groups."

Results With FISH

FISH results using the PathVysion test were obtained in 451 patients, and HER-2 amplification was detected in 76% of the study population. The addition of trastuzumab to chemotherapy in the FISH-positive subgroup significantly improved the response rate (54% vs 30.8%, P < .0001). No such improvement was seen in the FISH-negative subgroup (38% vs 37.5%).

The addition of trastuzumab in the FISH-positive group also provided a significant survival benefit (OR, 0.71, P = .009) that was not detected in the FISH-negative group.

"You can see by the response rates in the amplified patients that there was a very large improvement in overall response rate from 31% to 54%. However, for the 106 patients who lacked gene amplification, there appears to be no gain from the addition of trastuzumab," Dr. Mass concluded.

Thus, he said, "patient selection based on HER-2 amplification by FISH may provide improved clinical benefit from trastuzumab, compared with selection by IHC. This can also confer a substantial survival benefit."