HER2 Status Affects Chemotherapy Benefit for Node Positive Breast Cancer

ANN ARBOR, Mich., Oct. 10 -- The addition of paclitaxel (Taxol) to adjuvant chemotherapy may hold little benefit for women with the most common type of lymph node positive breast cancer, researchers found.

Women with human epidermal growth factor receptor type 2 (HER2) negative, estrogen receptor positive, lymph node positive breast cancer had no disease-free survival advantage (P=0.71) from adding paclitaxel after adjuvant doxorubicin (Adriamycin) plus cyclophosphamide (Cytoxan).

This group represented more than half the patients in the retrospective analysis of the Cancer and Leukemia Group B (CALGB) 9344 trial reported in the Oct. 11 issue of the New England Journal of Medicine.

Earlier reports from that trial established taxane-containing chemotherapy in routine practice for women at high risk of relapse.

But, if confirmed in other studies, the new findings suggest some of these patients could avoid the toxic effects associated with adjuvant paclitaxel, said Daniel F. Hayes, M.D., of the University of Michigan Comprehensive Cancer Center here, and colleagues.

But, Dr. Hayes cautioned, "right now we are not encouraging patients or doctors to change their practice. We think that would be premature."

In an accompanying editorial, Anne Moore, M.D., of Cornell University Medical Center in New York, reaffirmed that the study "is not a call to abandon taxanes" for these patients.

Rather, she said, it signals "the days of 'one size fits all' therapy for patients with breast cancer are coming to an end."

The use of chemotherapy has been based on risk of recurrence rather than tumor biology, but increasing evidence has suggested that estrogen receptor positive tumors are less responsive to chemotherapy.

To see what role tumor biology played in outcomes for women in the CALGB 9344 trial, the researchers went back and tested HER2 positivity of stored tumor tissue blocks from 1,322 women with node-positive breast cancer. Participants had been randomized to doxorubicin (60, 75, or 90 mg/m² body surface area) plus cyclophosphamide (600 mg/m²) for four cycles, then four cycles of paclitaxel (175 mg/m²) or observation.

Among the study participants, 61% were premenopausal, 57% to 62% had estrogen receptor positive tumors, and more than half had tumors that were both estrogen receptor positive and HER2 negative.

HER2 status appeared to have little impact on the benefit of higher doses of doxorubicin. Five-year disease-free survival among HER2 positive women was 63% whether they had received the highest or lowest dose and was statistically similar between HER2-negative dose groups as well (72% low dose and 69% high dose).

However, HER2 status interacted significantly with the addition of paclitaxel in multivariate analyses.

HER2 positive tumors treated with paclitaxel were 41% less likely to recur than those treated without paclitaxel (hazard ratio 0.59, P=0.01). The risk of death was likewise 43% lower with paclitaxel than without it for women with HER2 positive tumors (HR 0.57, P=0.01).

Patients with HER2 positive breast cancer benefited substantially from paclitaxel regardless of estrogen receptor status, but the same was not true for HER2 negative cancers.

When stratified by both estrogen receptor and HER2 status, the disease-free survival findings were:

• HER2 positive, estrogen receptor negative cancer was associated with significantly better survival through 10 years with the addition of paclitaxel (P=0.001).
• HER2 positive, estrogen receptor positive cancer tended to yield better survival through 10 years with the addition of paclitaxel (P=0.058).
• HER2 negative, estrogen receptor negative cancer showed significantly longer survival with paclitaxel (P=0.001).
• HER2 negative, estrogen receptor positive cancer showed no benefit with paclitaxel (P=0.71).

Although it was reassuring that some women do benefit from the current clinical practice of adding paclitaxel to doxorubicin and cyclophosphamide, finding out who doesn't benefit was the more important point of the trial, Dr. Hayes said.

"We can begin to identify the patients who, shouldn't be exposed to chemotherapy if it's not going to work for them, even if they do have a higher odds of recurrence" he said.

Sparing patients from paclitaxel would avoid its unique toxicity, Dr. Moore said. This includes hypersensitivity reactions and neurotoxicity, which was reported by 18% of patients who received it in the trial.

"For some patients, numbness and tingling in the hands and feet last for months or even years after treatment is completed," she noted.

However, retrospective analysis of other large trials will be important in determining which patients are so unlikely to benefit from chemotherapy that they shouldn't take it, Dr. Hayes concluded.

Further study is also needed to see how other taxanes and dose schedules interact with HER2 status, Dr. Moore said.

Some of the researchers reported receiving consulting fees from Bristol-Myers Squibb or Abbott and clinical research support from Bristol-Myers Squibb. Dr. Moore reported no conflicts of interest.