HER-2 and choice of adjuvant chemotherapy in breast cancer

HER-2

and Choice

of Adjuvant Soonmyung

The amplification ognized prognostic survival for patients

Chemotherapy Paik and Chanheun

or overexpression of HER-2 is a recmarker that is associated with poor with node-positive breast cancer.

Several studies have demonstrated that HER-2 may serve to direct the selection of optimal adjuvant chemotherapy. This article provides a critical review of the studies

that

predictor

of response Oncol 28:332-335.

Semin Sounders

offer

evidence

for

the

to chemotherapy. Copyright

role

of HER-2

as a

2001

by

T

HE HER-2 GENE encodes a 185kd protein that belongs to the transmembrane type I tyrosine kinase receptor family, which includes the epidermal growth factor (EGF) receptor, HER-3, and HER-4.1 Because HER-2 overexpression can cause NIH3T3 cells not only to transform,2 but also to become resistant to tumor necrosis factoralpha,3 there has been considerable interest in linking it to clinical drug resistance. However, between 1988 and 1992, many laboratories, including our own, attempted to correlate HER-2 overexpression with response to chemotherapeutic agents using cell line models and could not find a consistent link. Although the results of most of these studies were not published, three articles from one laboratory reported in vitro work that linked HER-2 overexpression with resistance to doxorubicin in non-small cell lung cancer cell lines.+6 Despite generally discouraging in vitro study results, several investigators have continued to pursue this line of thinking in clinical studies that can be largely placed into two groups: those that examine the role of HER-2 as (1) a marker of resistance to the cyclophosphamide, methotrex-

From the Division of Pathology, National Surgical Adjutant Breast and Bowel Project, Pittsburgh, PA. Supported by Public Health Sewice Grants No. LJIO-CA12027, LJI O-CA-69651, LJJ O-CA-373777, cd LJJ O-CA69974. Current address for C.P. : Department of Surgery, Kungdong Sacred Heart Hospital, Hallym University Medical School, Seoul, Korea. Address reprint requests to Soonmyung Paik, MD, Division of Pathology, National Surgical Adjutant Breast and Bowel Project, Four Allegheny Center, 5th Floor, East Commons Professional Building, Pittsburgh, PA 15212. Copyright 0 2001 by W.B. Saunders Company 0093-7754/01/2804-0003$35.00/O

332

ate, and fluorouracil (CMF) regimen, or (2) a marker of sensitivity to doxorubicin. For historical reasons, it makes sense to examine these two groups of studies separately. HER-2

OVEREXPRESSION THE

AND

CMF

RESPONSE

REGIMEN

W3.

Cornpony.

doi:10.1053/sonc.2001.26144

Cancer

Park

TO 0

in Breast

Two early studies by Allred et a17 and Gusterson et al8 published in 1992 suggested that HER-2 overexpression might be a marker of reduced benefit obtained from the CMF regimen. In Allred’s study,5 node-negative patients at high risk for recurrence were randomized to no treatment versus CMF. Any benefit that occurred in the CMF group was restricted to the HER-2-negative cohort. Those who were HER-2-positive demonstrated a worse outcome than whose who were HER-2negative, despite having received CMF. Although the researchers suggested a possible interaction between chemotherapy and HER-2 status, a statistical analysis was not performed to examine this possibility. Gusterson et al performed a retrospective study of patients enrolled in the International Breast Cancer Study Group (IBCSG) Trial V, in which node-positive patients were randomized to perioperative single-cycle therapy (PeCT) or full cycles of postoperative CMF plus prednisone (CMFP).~ The benefit from CMFp over PeCT was more pronounced in the HER-a-negative cohort (relative risk [RR] = 0.57; P < .OOOl for 6-year disease-free survival [DFS]) compared to the HER2Lpositive cohort (RR = 0.77, P = .21), suggesting that HER-2-positive tumors are relatively resistant to the CMFp regimen compared to HER2-negative tumors. Again no formal test for statistical interaction between HER-2 and treatment was presented in this study. Two recent studies, however, have challenged the idea of HER-2 as a marker of resistance to CMF. Miles et al examined 274 patients randomized to either adjuvant CMF (n = 129) or no chemotherapy (n = 146) who were a subset of patients enrolled into the Guy’s/Manchester Trial.9 Women with HER-d-negative tumors who received CMF had a median overall survival of 12.7 years, compared with women with HER-2negative tumors in the control group, who had a median survival of 7.3 years. Improvement in surSeminars

in Oncology, Vol 28, No 4 (August),

2001:

pp 332-335

HER-2

AND

CHEMOTHERAPY

333

viva1 was less marked when women with HER-2positive tumors were considered; median overall survival for those who received CMF among these women was 6.1 years, compared with 4.4 years for women in the control group. However, the improvement in survival in both cohorts was statistically significant, with no evidence of treatmentby-HER-2 interaction upon formal statistical test. In a recently presented study,10 Menard et al of the Istituto Nazionale Tumori, Milan, Italy, examined 337 of 386 cases from their first CMF trial. Node-positive breast cancer patients who had undergone radical mastectomy were randomly assigned to receive no further treatment (179 women) or 12 monthly cycles of adjuvant CMF (207 women) and were monitored for 20 years. HER-2 was overexpressed in 16% of tumors. An analysis of DFS and cancer-specific survival (CSS) indicated that the prognostic contribution of HER-2 in multivariate models was significant for the untreated patients (DFS: P = .042, CSS: P = .0035), but not for the treated patients (DFS: P = .86, CSS: P = .96). Analyses of treatment effect by HER-2 status indicated a clinical benefit from CMF for patients with HER-2-positive as well as HER-2-negative tumors. The RR for recurrence was 0.48 in HER-2-positive patients treated with CMF versus no adjuvant therapy. The same RR was 0.64 in HER-2-negative patients treated with CMF versus no adjuvant therapy. There was no evidence of statistical interaction between HER-2 status and treatment. Therefore, studies carried out thus far indicate that patients with HER-2-overexpressing tumors do gain benefit from the CMF regimen, although that benefit may be of a lesser magnitude when compared with that gained by patients with HERd-negative tumors. HER-Z OVEREXPRESSION AND RESPONSE TO DOXORUBICINCONTAINING REGIMENS

THE

Our interest in HER-2 and the response to doxorubicin-containing regimens stemmed from results we obtained in a retrospective study of gastric cancer conducted at Yonsei Medical School in Korea.11 Of 109 cases of primary gastric cancer treated with curative resection either with or without adjuvant fluorouracil/doxorubicin (EA), HER-2 overexpression did not demonstrate a sig nificant effect on outcome when all patients were

considered. However HER-2 was an indicator for poor DFS (P = .0474), local relapse-free survival (I’ = .0293), and overall survival (P = .0310) in patients treated with surgery only (n = 5 1). There was no effect on outcome in patients who underwent surgery and treatment with adjuvant FA (n = 58). Furthermore, the apparent therapeutic benefit from the FA regimen was restricted to patients with HER-2-positive tumors. These data suggest that HER-2 may be associated with an improved response to the FA regimen. In 1994, results from the Cancer and Leukemia Group B (CALGB) 8869 trial were published.12 Trial 8869 was a retrospective study of a cohort of 442 cases from CALGB protocol 8541, in which 1,550 node-positive patients were randomized to three different doses (high, moderate, and low) of a cyclophosphamide/doxorubin/fluorouracil (CAF) regimen with dose intensification of all three drugs.13 With a median of 3.5 years of follow-up, the overall survival of HER-2-positive patients in the high-dose arm of this study was almost double that in the low-dose arm. In contrast, the HER-2-negative group experienced no benefit from the CAF dose escalation. Results of the tests for interaction between HER-2 and dose intensification were statistically significant. A validation study for CALGB 8869 also confirmed the originally observed interaction, this time with more than 900 cases.14 Although the authors speculated that the interaction observed in trial 8869 could be due to the doxorubicin dose increase, this study did not provide clear evidence of that since the doses of all three drugs in the CAF regimen were increased in this study. The National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-l 1 provided a nearly ideal study cohort in which to test the hypothesis that HER-2 is a marker of doxorubicin response. Patients were randomized to melphalan (L-PAM)/fluorouracil (PF) or L-PAM/doxorubicin/fluorouracil (PAF) so that the only treatment variable was the addition of doxorubicinis Of 638 patients, 239 (37.5%) were scored as positive for HER-2 protein overexpression. After a mean time on study of 13.5 years, clinical benefit from the addition of doxorubicin to PF was apparent only for HER-2-positive patients (DFS: RR = 0.60, P = .OOl; survival: RR = 0.66, P = .Ol; relapsefree survival: RR = .58, P = .002; distant DFS: RR = 0.61, P = .OO3). The outcome of HER-2negative patients treated with PAF was not signif-

334

PAIK

icantly improved over that of those treated with PF (DFS: RR = 0.96, I’ = .74; survival: RR = 0.90, I’ = .47; relapse-free survival: RR = .88, P = .37; distant DFS: RR = 1.03, P = .84). Statistical tests for the interaction between doxorubicin treatment and HER-2 overexpression were significant for DFS (P = .02) and distant DFS (P = .02). Interaction tests for survival (P = .15) and relapse-free survival (P = .06) were suggestive but not statistically significant.16 These data suggest that HER-2-positive patients did obtain preferential benefit when doxorubicin was added to less efficacious regimens. PREOPERATIVE

TRIALS

Preoperative chemotherapy trials in breast cancer provide a window of observation for responsiveness to specific therapies. Although results from such trials are few, they are generally congruent with a model of HER-2-induced resistance rather than one of selective sensitivity. One study of 90 patients with operable breast cancer who were treated with four 3-weekly cycles of chemotherapy with mitoxantrone and methotrexate with or without mitomycin C, plus tamoxifen prior to surgery showed a 93% response rate in HER-2negative tumors, whereas only 57% of HER-2positive tumors showed a response (P = .007).i7 Jarvinen et al examined 55 patients with advanced breast cancer treated with epirubicin as first-line cytotoxic chemotherapy. The response rate in those with HER-2-overexpressing tumors was 32%, compared with 65% in those with no HER-2 overexpression (P = .0058).is Miller et al also reported on a cohort of 80 patients with unspecified preoperative chemotherapy. In these patients, HER-2 overexpression was a predictor of poor response (P = .009).19 NSABP B-I 5: DOXORUBlClN/CYCLOPHOSPHAMlDE VERSUS CMF The data discussed thus far suggest the existence of a differential dose-response curve for chemotherapy according to HER-2 status. The HER-2negative tumors are hypothesized to have a steeper dose response to chemotherapy than do the HER2-positive tumors. Although both share the same “limit of cytoreduction,” or maximally achievable benefit, HER-d-negative tumors arrive at this limit with PF, CMF, or low-dose CAF, while HER-

AND

PARK

d-positive tumors do so only with more treatmentintensive regimens such as standard-dose doxorubicin/cyclophosphamide (AC) or CAF. It could also be hypothesized that what is responsible for the lack of a differential response according to HER-2 in the studies by Menard et a110 and Miles et al9 is that the 12-cycle regimen of CMF used is more treatment intense than is the six-cycle CMF regimen that was used in the IBCSG Trial V. If this hypothesis is correct, standard AC should be better than six cycles of CMF only for HER-2positive tumors, and the addition of paclitaxel to AC should be beneficial only for patients with HER-2-positive tumors. Materials from NSABP B-15 provided us with a way to test this hypothesis directly.20 In that study, standard 3-month AC was compared directly with standard 6-month CMF. Overall results showed no differences in clinical outcome between the two regimens. Data from the analyses of HER-2 status in B-15 were presented at the 1999 San Antonio Breast Cancer Meeting. Immunohistochemistry for HER-2 was performed on pre-hematoxylin and eosin (H&E)-stained sections from 2,034 (89%) of 2,295 eligible cases from B-15. While a superiority of AC over CMF in this analysis was shown for HER-2-positive patients, these differences did not reach statistical significance, with an adjusted RR of failure of 0.80 for relapse-free survival (95% confidence interval, 0.62 to 1.04; P = .lO). Tests for interaction between HER-2 and treatment response were suggestive of trends for treatment by HER-2 status interaction but also were not statistically significant (P = .08 for relapse-free survival). More importantly, however, no difference was found between AC and CMF in the HER-d-negative patients. These data, interpreted within the context of previous studies, suggest that AC is a better regimen with which to treat HER-2-positive patients, whereas both CMF and AC are recommended for HER-2-negative patients. CONCLUSION Data available thus far suggest that for HER-2positive tumors, doxorubicin-based regimens offer a better therapeutic choice than do CMF-based regimens. For HER-2-negative tumors, the two types of regimens appear to have equal efficacy. Several adjuvant therapy trials are currently evaluating the additional effect of taxanes when given in combination or in sequence. If an advantage is

HER-2

AND

CHEMOTHERAPY

335

consistently demonstrated with this approach, it would be important to examine whether the advantage is restricted to HER-2/neu-positive patients. ACKNOWLEDGMENT The NSABP

author acknowledges Barbara for her role as scientific editor

C. Good, PhD, of the manuscript.

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