252 NATURE CLINICAL PRACTICE ONCOLOGY MAY 2008 VOL 5 NO 5

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Original article Hayes DF et al. (2007) HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med 357: 1496–1506

SYNOPSISKEYWORDS breast cancer, cyclophosphamide, doxorubicin, HER2, paclitaxel

BACKGROUNDPrevious studies have shown that human epidermal growth factor receptor type 2 (HER2) overexpression in breast cancer cells can predict benefit from adjuvant chemotherapy with trastuzumab or standard doses of doxo-rubicin. The relationship between HER2 over-expression and paclitaxel treatment, however, is unclear.

OBJECTIVETo investigate whether HER2 expression in breast tumors identifies patients who are likely to benefit from adjuvant doxorubicin given above the standard dose, the addition of paclitaxel after adjuvant chemotherapy with doxorubicin and cyclophosphamide, or both.

DESIGN AND INTERVENTIONA total of 3,121 women with node-positive breast cancer, who had completed surgery and were appropriate candidates for adju-vant chemotherapy, were enrolled between May 1994 and April 1999. The patients were randomly assigned to receive either doxo-rubicin (60, 75 or 90 mg/m2 body surface area) combined with cyclophosphamide (600 mg/m2) for four cycles, plus four successive cycles of paclitaxel (175 mg/m2) or observation. Tissue specimens were requested for 1,500 of the women who participated in the trial, and immunohistochemical analysis for HER2 was

HER2 positivity predicts a benefit from paclitaxel treatment after adjuvant chemotherapy

performed with the CB11 monoclonal anti-body. Estrogen receptor data were available for 99.4% of patients in the trial.

OUTCOME MEASURESThe primary outcome measure was disease-free survival, defined as the time from enrollment to the first local or distant recurrence or death.

RESULTSNo significant interaction between HER2 over expression and doxorubicin dose above 60 mg/m2 was observed. At 5 years, the rates of disease-free survival for HER2-positive patients who received 60 mg/m2 or 90 mg/m2 doxo-rubicin were both 63%. For HER2-negative patients who received 60 mg/m2 or 90 mg/m2 doxorubicin, the 5-year disease-free-survival rates were 72% and 69%. Multivariate analysis of the interaction between HER2 status and the addition of paclitaxel to treatment revealed a hazard ratio of 0.59 for recurrence (P = 0.01); the hazard ratio for death was 0.57 (P = 0.01). Among patients with HER2-positive tumors, paclitaxel was associated with improved disease-free survival. Patients with estrogen-receptor-positive and HER2-positive tumors seemed to benefit from paclitaxel; however, patients with estrogen-receptor-positive and HER2-negative tumors did not benefit.

CONCLUSIONThe expression of HER2 in patients with node-positive breast cancer was associated with a benefit from the addition of paclitaxel after adjuvant treatment with four cycles of doxo-rubicin plus cyclophosphamide. No relation-ship between HER2 status and doses of doxo rubicin above 60 mg/m2 was observed.

PRACTICE POINT

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MAY 2008 VOL 5 NO 5 NATURE CLINICAL PRACTICE ONCOLOGY 253

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AcknowledgmentThe synopsis was written by Mandy Aujla, Associate Editor, Nature Clinical Practice.

Competing interestsThe author declared no competing interests.

CorrespondenceTata Memorial HospitalDr E Borges RoadParel Mumbai 400012Indiasudeepgupta@tatahospital.net

Received 2 December 2007Accepted 7 February 2008Published online 25 March 2008

www.nature.com/clinicalpracticedoi:10.1038/ncponc1092

COMMENTARY

Sudeep Gupta

A series of randomized studies published in the past 10 years have established taxane-containing anthracycline regimens as a standard adjuvant treatment option in women with high-risk breast cancer. The addition of taxanes (e.g. paclitaxel or docetaxel) to anthracyclines is, however, associated with adverse effects such as myelo suppression, neuropathy and fluid retention as well as additional treatment costs. It is, therefore, of great interest to know which, if any, subgroup of patients would preferentially benefit from the addition of a taxane. A number of correla-tive studies have recently sought to answer the question of preferential benefit from various treatments for breast cancer.1

Berry et al.2 reported their combined analy- sis of three sequential randomized Cancer and Leukemia Group B (CALGB) trials in node- positive breast cancer patients. In the subgroup of patients with estrogen-receptor-positive tumors, the addition of paclitaxel and increasing anthra-cycline dose density resulted in little additional benefit over 3-weekly cycles of anthracycline therapy. Combined analysis of two adjuvant anthracycline–docetaxel trials3 showed that there was no relationship between receptor status and benefit from docetaxel.

In a retrospective analysis of CALGB 9344,4 Henderson et al. randomly selected a subgroup of patients from the original study and reported that the addition of paclitaxel to four cycles of adjuvant chemotherapy resulted in a significant reduction in the hazard of recurrence and death in HER2-positive patients, regardless of estrogen-receptor status. Further exploratory analysis of subgroups divided by both HER2 and estrogen-receptor status, revealed a lack of benefit from additional paclitaxel in HER2-negative, estrogen-receptor-positive patients. Another study5 reported that anthracycline therapy improved relapse-free and overall survival (compared with cyclo-phosphamide, methotrexate and fluorouracil) in HER2- positive patients. The study by Hayes et al. has refined this further by showing that there is no interaction between HER2 status and dose escalation of anthracycline beyond an optimum dose (in this case, doxorubicin 60 mg/m2).

What impact does this study have on clinical practice? Should we stop using taxanes in some node-positive patients? Before answering these

questions several points need to be addressed. First, as also emphasized by the authors, this is a retrospective analysis of a subgroup of patients from a randomized study; all such analyses are essentially exploratory and hypothesis- generating. Second, a large number of comparisons have been performed without statistical adjustment for multiple comparisons, increasing the likeli-hood of the role of chance in the results. Third, since the publication of CALGB 9344, trastu-zumab has been integrated into the adjuvant treatment of HER2-positive patients and adju-vant aromatase inhibitors have largely replaced tamoxifen in the treatment of postmenopausal women. The additional benefit of paclitaxel in the presence of these two agents in the respective subgroups is currently speculative and open to further scrutiny. Fourth, docetaxel is a taxane, but not identical to paclitaxel in its effects. It would be interesting to evaluate the interaction of adju-vant docetaxel with HER2 status. With all these caveats, it must be stated that a consistent finding in many analyses from CALGB has been a lesser benefit of additional or intensified chemotherapy in the estrogen-receptor- positive subgroup of patients.2,4

Given the findings of Hayes et al., it would be reasonable for oncologists to consider taxane-containing anthracycline regimens as the preferred treatment for HER2-positive patients and non-taxane regimens as the preferred option in HER2-negative, estrogen-receptor-positive patients.

References1 Paik S et al. (2006) Gene expression and benefit

of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24: 3726–3734

2 Berry DA et al. (2006) Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295: 1658–1667

3 Andre F et al. (2007) Estrogen receptor expression and efficacy of docetaxel in early breast cancer: a pooled analysis of 3,490 patients included in two randomized trials [abstract]. J Clin Oncol 25 (Suppl): 537

4 Henderson IC et al. (2003) Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21: 976–983

5 Pritchard KI et al. (2006) HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354: 2103–2111

S Gupta is an Associate Professor of Medical Oncology and a Member of the Breast Cancer Working Group at the Tata Memorial Hospital, Mumbai, India.

PRACTICE POINTThe addition of paclitaxel after anthracycline-based chemotherapy should be considered preferentially in the treatment of HER2-positive patients

PRACTICE POINT

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