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The Oncologist, Vol. 12, No. 4, 390-396, April 2007; doi:10.1634/theoncologist.12-4-390
© 2007 AlphaMed Press

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Breast Cancer

Achieving Higher Pathological Complete Response Rates in HER-2–Positive Patients With Induction Chemotherapy Without Trastuzumab in Operable Breast Cancer

Frédérique Penault-Llorcaa,c, Catherine Abriala, Marie-Ange Mouret-Reyniera,c, Inès Raoelfilsa, Xavier Durandoa,c, Marianne Leheurteura, Pierre Gimberguesa,c, Jacques Tortochauxa,c, Hervé Curéa,e, Philippe Cholleta,d

aCentre Jean Perrin, Clermont-Ferrand, France; bINSERM U484, Clermont-Ferrand, France; cUniversité d'Auvergne, Faculté de Médecine, Clermont-Ferrand, France; dCentre d'Investigation Clinique, Clermont-Ferrand, France; eCentre Hospitalier Universitaire, Clermont-Ferrand, France

Key Words. Breast cancer • Pathological response • HER-2

Correspondence: Catherine Abrial, Ph.D., Centre Jean Perrin, Bureau de Recherche Clinique, 58, rue Montalembert, BP 392, 63011 Clermont-Ferrand Cedex 1, France. Telephone: 33-4-73-27-80-05; Fax: 33-4-73-27-80-29; e-mail: catherine.abrial{at}tiscali.fr

Received July 13, 2006; accepted for publication February 11, 2007.


   ABSTRACT
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 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 Disclosure of Potential...
 References
 
Recent trials of induction chemotherapy in bulky operable breast cancer have shown much higher pathological complete response (pCR) rates with trastuzumab-driven combinations. However, it is useful to take into account the specific chemosensitivity of HER-2–positive tumors. The aim of this study was to assess the pCR rate according to HER-2 status in response to chemotherapy, without an anti–HER-2 specific biological agent, in 710 operable breast cancer patients. Since 1982, these patients have been treated with several different neoadjuvant chemotherapy combinations. During this period, HER-2 overexpression was most often not assessed. Subsequently, we assessed HER-2 expression using archival paraffin-embedded tissue. A technically usable specimen was available for 413 of the 710 patients. Before treatment, 51 patients were HER-2 positive, 287 patients were HER-2 negative, and the results were inconclusive for 75 patients. Of these patients, a pCR in breast and nodes was obtained in 94 patients (14.3%), but this event was threefold more frequent for HER-2–positive patients (23.5%) than for HER-2–negative patients (7%).

The overall survival (OS) and disease-free survival (DFS) rates at 10 years were 66.6% and 57.4%, respectively. The DFS rate was, as expected, better for HER-2–negative patients, with HER-2 status assessed before as well as after chemotherapy. A significant difference was found for OS in favor of HER-2–negative patients only with postchemotherapy assessment of HER-2, a fact similar to our previous findings. Finally, there was a tendency toward a higher DFS rate for HER-2–positive patients who achieved a pCR compared with HER-2–positive patients who did not.

Disclosure of potential conflicts of interest is found at the end of this article.


   INTRODUCTION
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 Disclosure of Potential...
 References
 
Recent trials have shown higher pathological complete response (pCR) rates in HER-2–positive breast tumors with trastuzumab-driven combinations (66.7% for paclitaxel plus trastuzumab versus 25% for paclitaxel alone [1]). In another study combining paclitaxel and trastuzumab, Burstein et al. [2] reported a clinical objective response rate of 75% and a pCR rate of 18%. Finally, a study combining docetaxel with trastuzumab has shown a clinical objective response rate of 96% and a pCR rate of 47% [3]. These results indicate the high efficacy of trastuzumab combined with chemotherapy. However, it is useful to take into account the specific sensitivity of HER-2–positive tumors. In a database harboring the patients of several prospective phase II neoadjuvant trials based on anthracycline- and/or taxane-driven combinations, pCR rates were studied in 710 women with stage II–III operable breast cancer treated in 1982–2004, according to their HER-2 status. No patient in this series had received an anti–HER-2 treatment, like trastuzumab. Pathological review was conducted to assess residual disease in breast and nodes according to the Chevallier et al. [4] classification. The question of this study was: Are HER-2–overexpressing tumors more sensitive to chemotherapy, even without trastuzumab?


   PATIENTS AND METHODS
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 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 Disclosure of Potential...
 References
 
Patient Population
In the present study, 710 operable stage II–III breast cancer patients received neoadjuvant chemotherapy. Patients with primary inflammatory or nonoperable carcinoma were excluded. The majority of these patients (500) had been treated at Centre Jean Perrin (Clermont-Ferrand) and the others were treated at Centre Hospitalier Universitaire (Tours), Centre Paul Papin (Angers), and Centre Hospitalier (Brive-la- Gaillarde), France.

The baseline workup included a complete history and clinical examination, bilateral mammography, and, for most of the patients, bilateral breast ultrasound. The diagnosis of carcinoma was established through fine-needle aspiration or needle core biopsy of the primary tumor and palpable lymph nodes. When invasive adenocarcinoma was demonstrated, the tumor was evaluated for Scarff Bloom Richardson (SBR) grading and hormone receptors (HRs) were assessed by radioimmunology or immunohistochemistry. Laboratory assessment consisted of a complete blood count, blood chemistry analysis, and tumor markers (carcinoembryonic antigen and cancer antigen 15.3). The absence of distant metastases was confirmed by chest x-ray, bone scan, and liver ultrasound. This series has been already published in part [5, 6].

Treatment Modalities
Between 1982 and 2004, the 710 patients were treated by different protocols of neoadjuvant chemotherapy: doxorubicin, vincristine, cyclophosphamide, and 5-fluorouracil (5-FU) with or without methotrexate (AVCF/M); theprubicin, vinorelbine, cyclophosphamide, and 5-FU (TNCF); vinorelbine, epirubicin, and methotrexate (NEM); vinorelbine, epirubicin, and paclitaxel (NET); docetaxel; 5-FU, epirubicin, and cyclophosphamide (FEC), with epirubicin doses of 50, 75, or 100 mg/m2; 5-FU, doxorubicin, and cyclophosphamide (FAC) 50; and docetaxel plus theprubicin, vinorelbine, cyclophosphamide, and 5-FU (TNCF). Most of these were in successive phase II trials published separately [7–9]. Table 1 gives the precise protocols for each regimen. Patients received a median number of six cycles of neoadjuvant chemotherapy (range, 1–9). Chemotherapy was administrated i.v. at 21- or 28-day intervals. After primary chemotherapy, patients underwent appropriate surgery according to the size of their residual tumor. Nevertheless, we have to emphasize that 27% (n = 42) of the patients who received AVCF/M did not undergo surgery and received radiotherapy directly. Radiotherapy was applied after the completion of surgery or chemotherapy, if adjuvant chemotherapy was given. Postoperative irradiation treatment was delivered to the chest wall, internal mammary lymph nodes, and supraclavicular/axillary lymph nodes. In cases of important residual disease, patients could receive additional courses of chemotherapy. Finally, menopausal patients with HR-positive tumors received tamoxifen for 5 years.


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  		Table 1. Dosing for the different neoadjuvant chemotherapies used (n = 710 patients)

 
Assessment of Response
Clinical, mammographic, and ultrasound measurements were recorded before treatment, every two or three cycles during neoadjuvant chemotherapy, and at the end of cytotoxic treatment before surgery. Clinical, mammographic, and echographic responses were evaluated separately by the decrease in tumor and node volumes (the product of the two greatest perpendicular dimensions), and were classified as follows: complete response, partial response (>50%), moderate response (25%–50%), no change (±25% with no new lesions), and progression (>25% or the appearance of new lesions).

Global clinical response was estimated using the mean of the response percentages obtained by the three methods of measurement in the majority of cases. In other cases, the global clinical response corresponded to the responses obtained by the two other methods of measurement if one was not available.

Pathologic response was independently evaluated after surgical resection of the remaining tumor and nodes. Pathologic responses were classified as follows, according to Chevallier et al. [4]:

Class 1: disappearance of all tumor either on macroscopic or microscopic assessment;
Class 2: presence of in situ carcinoma only in the breast, without invasive tumor and tumor cells in the lymph nodes;
Class 3: presence of invasive carcinoma with stromal alteration, such as sclerosis or fibrosis;
Class 4: no or few modifications of the tumoral appearance.

Statistical Analysis
Response rates are presented with their 95% confidence intervals (CIs).

Relations between all the parameters studied were evaluated using the {chi}2 test. p values < 0.05 were considered significant.

Results were last updated in January 2006. The DFS duration was defined as the time elapsed between the date of first diagnosis and the date of first relapse, wherever this relapse might be. The OS duration was the time between the date of initial diagnosis and the date of the last status report, with the patient being alive or dead, whatever the cause of death. Survival curves were established according to the Kaplan–Meier method [10].


   RESULTS
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 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 Disclosure of Potential...
 References
 
Table 2Go summarizes tumor characteristics for the 710 patients. The median age was 49.5 years (range, 26–81) and 324 of the 710 patients (45.63%) were menopausal.


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  		Table 2. Patient characteristics, response to neoadjuvant chemotherapy, and adjuvant treatments

 


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  		Table 2. Continued

 
Tumor Parameters
The median largest diameter of the primary tumor was 4 cm (range, 1–13). In all, 417 of 710 patients (58.73%) had clinical lymph-node involvement. The pathological diagnosis gave 554 of 710 (78%) as invasive ductal and 91 of 710 (12.8%) as invasive lobular carcinomas. In all, 181 of 553 patients (32.7%) had an SBR grade III tumor and HRs were positive in 60% (380/635) of the tumors. Finally, 51 (7.2%) patients were HER-2 positive and 287 (40.4%) patients were HER-2 negative. The results were inconclusive for 75 (10.6%) patients, and because the database consists of archival tissue, data were missing for 297 (41.8%) patients. After chemotherapy, 35 (4.9%) patients were HER-2 positive and 325 (46%) patients were HER-2 negative. The results were inconclusive for 19 (2.7%) patients. We have no data for the 331 other patients: 54 (7.6%) patients did not undergo surgery, 103 (14.5%) patients were in pCR, and for the remaining 174 (24.3%), we no longer had paraffin-embedded tumor samples. These results concerning the HER-2 assessment were given for the whole population, that is, 710 patients, but in Table 2, HER-2 results are also given for the 656 operated patients.

Clinical Responses
Because of technical reasons or incomplete treatment, 10 patients were not evaluable for global clinical response. Response was consequently assessed in 700 patients. The objective response rate was 70.28% (95% CI, 66.9%–73.7%), of which 16.14% were complete.

Pathological Responses
Fifty-four patients were not included in the pathological evaluation after chemotherapy: 44 did not undergo surgery and were treated with radiotherapy alone and 10 were either in progression or presented with an allergy or a toxicity, or refused surgical treatment. Hence, 656 patients underwent surgery and were evaluable for pathological response. According to the Chevallier et al. [4] classification, 59 patients were class 1 and 35 patients were class 2; thus, the overall pCR rate in breast and nodes was obtained for 94 patients (14.3%; 95% CI, 11.6%–17.0%). However, this rate was threefold higher for HER-2–positive patients (n = 12/51; 23.5%) than for HER-2–negative patients (n = 20/287; 7%) (p = .0008).

Therapeutic Care
Of the 656 operated patients, 471 (71.8%) underwent conservative surgery and 185 (28.2%) underwent modified radical mastectomy.

As adjuvant treatment, 673 (94.8%) patients received radiotherapy, 122 (17%) patients received chemotherapy (AVCF mainly for patients who received AVCF/M as neoadjuvant treatment; 5-FU, vinorelbine, and cyclophosphamide mainly for patients who received docetaxel as neoadjuvant treatment; docetaxel mainly for patients who received FEC as neoadjuvant treatment), and 372 (52.4%) patients with HR-positive tumors received tamoxifen for 5 years.

DFS and OS
The study was terminated in January 2006, with a median follow-up of 108 months (range, 24–288 months). The OS and DFS rates for the whole population (n = 710 patients) are shown in Figure 1 and demonstrated an OS rate at 10 years of 66.6% and a DFS rate at 10 years of 57.4%.


Figure 1
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  		Figure 1. Overall survival (OS) and disease-free survival (DFS) in 710 patients treated with neoadjuvant chemotherapy for operable breast cancer.

 
Next, we focused our analysis on the subset of patients for whom we have HER-2 assessment available, that is, 338 patients before chemotherapy and 360 patients after chemotherapy. When we compared DFS according to HER-2 expression, there was a significant difference in favor of HER-2–negative patients, both when HER-2 assessment was done before chemotherapy (Fig. 2, p = .0073) and when HER-2 assessment was done after chemotherapy (Fig. 3, p = .00015). No significant difference was found for OS when assessing HER-2 before chemotherapy, but a significant difference was found in favor of HER-2–negative patients when comparing post-treatment HER-2 (Fig. 4, p = .0029). These results confirm those of our previous publications: multivariate analysis with factors studied after chemotherapy showed their significant prognostic value compared with multivariate analysis with the same factors or other factors studied before chemotherapy [6, 11, 12].


Figure 2
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  		Figure 2. Disease-free survival in human epidermal growth factor receptor 2 (HER-2)–positive and HER-2–negative patients pretreatment, who were treated with neoadjuvant chemotherapy for operable breast cancer (p = .0073).

 


Figure 3
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  		Figure 3. Disease-free survival in human epidermal growth factor receptor 2 (HER-2)–positive and HER-2–negative patients post-treatment, who were treated with neoadjuvant chemotherapy for operable breast cancer (p = .00015).

 


Figure 4
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  		Figure 4. Overall survival in human epidermal growth factor receptor 2 (HER-2)–positive and HER-2–negative patients post-treatment, who were treated with neoadjuvant chemotherapy for operable breast cancer (p = .0029).

 
Finally, we have to emphasize that there was a tendency toward a higher DFS rate for HER-2–positive patients who achieved a pCR compared with HER-2–positive patients who did not (p = .092). No significant difference was found for OS (p = .18).


   DISCUSSION
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
Disclosure of Potential...
 References
 
Adverse survival factors can also become favorable predictive factors when a specific treatment becomes available; this is the case for HER-2 –positive tumors treated with trastuzumab [13–15].

It is known that HER-2 positivity is an adverse prognostic factor, but it came to light recently that it is also a factor of greater chemosensitivity. In particular, pCR rates reached unprecedented levels >50% in two different studies [1, 3]. This is also why we looked for this parameter as a predictive and prognostic factor in our already published neoadjuvant database. According to our results, the pCR rate was threefold higher for HER-2–positive patients. According to this classic adverse factor, the DFS rate was lower for these HER-2–positive patients. Nevertheless, among HER-2–positive patients, those who were in pCR showed a trend toward a higher DFS rate (p = .092). We have to emphasize that these patients had never received an anti–HER-2 treatment like trastuzumab, but when the HER-2–positive tumor gave evidence of chemosensitivity, the prognosis improved. This work is extended from a previous study reported by Penault-Llorca et al. [16], with a greater time span. It corresponds to our previous findings that prechemotherapy factors have to be retained as predictive, and postchemotherapy factors as prognostic. An adverse prognostic factor can greatly improve when efficacy is met (pCR in this case).

To conclude, we have to emphasize that our previous findings on pre- and postchemotherapy factors were based on the results obtained with univariate and multivariate analyses. We agree that our conclusions here are founded on the results of a univariate analysis. But, as we said in the introduction, first, our aim was to study HER-2 in a patient population who did not receive trastuzumab. Second, we intend to extend our analysis on several factors with a multivariate analysis. Indeed, we agree with the fact that several factors interact and are either predictive or prognostic or both, and that a multivariate analysis could allow a stronger conclusion.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Disclosure of Potential...
References
 
The authors indicate no potential conflicts of interest.


   REFERENCES
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Disclosure of Potential...
 References
 

  1. Buzdar AU, Ibrahim NK, Francis D et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: Results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 2005;23:3676–3685.[Abstract/Free Full Text]
  2. Burstein HJ, Harris LN, Gelman R et al. Preoperative therapy with Trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: A pilot study. J Clin Oncol 2003;21:46–53.[Abstract/Free Full Text]
  3. Coudert BP, Arnould L, Moreau L et al. Pre-operative systemic (neo-adjuvant) therapy with trastuzumab and docetaxel for HER2-overexpressing stage II or III breast cancer: Results of a multicenter phase II trial. Ann Oncol 2006;17:409–414.[Abstract/Free Full Text]
  4. Chevallier B, Roche H, Olivier JP et al. Inflammatory breast cancer. Pilot study of intensive induction chemotherapy (FEC-HD) results in a high histologic response rate. Am J Clin Oncol 1993;16:223–228.[Medline]
  5. Abrial C, Mouret-Reynier MA, Amat S et al. Tumor parameters, clinical and pathological responses, medical management, and survival through time on 710 operable breast cancers. Med Oncol 2005;22:233–240.[CrossRef][Medline]
  6. Amat S, Abrial C, Penault-Llorca F et al. High prognostic significance of residual disease after neoadjuvant chemotherapy: A retrospective study in 710 patients with operable breast cancer. Breast Cancer Res Treat 2005;94:255–263.[CrossRef][Medline]
  7. Chollet P, Charrier S, Brain E et al. Clinical and pathological response to primary chemotherapy in inoperable breast cancer. Eur J Cancer 1997;33:862–866.[CrossRef][Medline]
  8. Van Praagh I, Curé H, Leduc B et al. Efficacy of a primary chemotherapy regimen combining vinorelbine, epirubicin, and methotrexate (VEM) as neoadjuvant treatment in 89 patients with operable breast cancer. The Oncologist 2002;7:418–423.[Abstract/Free Full Text]
  9. Amat S, Bougnoux P, Penault-Llorca F et al. Neoadjuvant docetaxel for operable breast cancer induces a high pathological response and breast-conservation rate. Br J Cancer 2003;88:1339–1345.[CrossRef][Medline]
  10. Kaplan EL, Meier P. Non parametric estimation from incomplete observation. J Am Stat Assoc 1957;53:457–471.[CrossRef]
  11. Curé H, Amat S, Penault-Llorca F et al. Prognostic value of residual node involvement in operable breast cancer after induction chemotherapy. Breast Cancer Res Treat 2002;76:37–45.[CrossRef][Medline]
  12. Chollet P, Amat S, Belembaogo E et al. Is Nottingham prognostic index useful after induction chemotherapy in operable breast cancer? Br J Cancer 2003;89:1185–1191.[CrossRef][Medline]
  13. Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353;(16):1673–1684.[Abstract/Free Full Text]
  14. Perez EA, Suman VJ, Davidson N et al. NCCTG N9831 Update. Proc Am Soc Clin Oncol 2005;23:556–17.
  15. Procter M, Leyland-Jones B et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353;(16):1659–1672.[Abstract/Free Full Text]
  16. Penault-Llorca F, Cayre A, Bouchet-Mishellany F et al. Induction chemotherapy for breast carcinoma: Predictive markers and relation with outcome. Int J Oncol 2003;22:1319–1325.[Medline]



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