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Division of Hematology/Oncology, New York University Cancer Institute, New York, New York
Corresponding author: Francisco J. Esteva, MD, PhD, Division of Hematology/Oncology, New York University Cancer Institute, 160 E 34th St, New York, NY 10016; Fax: (212) 731-5342; Francisco.firstname.lastname@example.org
The purpose of the current study was to describe the outcomes of patients with human epidermal growth factor receptor 2 (HER2)-overexpressed/amplified (HER2+) early breast cancer who received adjuvant or neoadjuvant trastuzumab-based therapy and were subsequently retreated with trastuzumab for metastatic disease.
A total of 353 patients with metastatic HER2+ breast cancer who were treated with trastuzumab as part of their first-line treatment for metastatic disease were identified. A total of 75 patients had received adjuvant or neoadjuvant trastuzumab-based therapy for early breast cancer, and 278 had not. Clinical outcomes of patients who had or had not received prior trastuzumab were compared using Cox proportional hazards regression and logistic regression analyses. Survival was estimated using the Kaplan-Meier method.
The clinical benefit (complete response, partial response, or stable disease of ≥ 6 months) rates were 71% in the group who did not receive prior trastuzumab and 39% in the group previously treated with trastuzumab. The adjusted odds ratios were 0.28 (95% confidence interval [95% CI], 0.13-0.59; P = .0009) for clinical benefit rates and 0.39 (95% CI, 0.18-0.82; P = .038) for objective (complete or partial) response rates. In the univariate analysis, the median overall survival rate was longer in the group who did not receive prior trastuzumab (36 months vs 28 months) (hazards ratio, 1.47; 95% CI, 1.07-2.01 [P = .022]). The multivariate analysis found no significant difference in overall survival.
The human epidermal growth factor receptor 2 (HER2, also known as ERBB2) gene encodes a growth factor tyrosine kinase receptor that belongs to a family of 4 transmembrane receptor tyrosine kinases that mediate cell growth, differentiation, and survival. The HER2 protein is overexpressed in 20% to 25% of invasive breast cancers,[2-4] and its overexpression portends an unfavorable prognosis because of its inherently more aggressive biology.[5, 6] HER2 protein overexpression or HER2 gene amplification is associated with an increased metastatic potential and a decreased overall survival rate. Previously, the most effective adjuvant systemic regimen for patients with HER2-positive breast cancer was a combination of anthracyclines and taxanes. To our knowledge, trastuzumab was the first humanized monoclonal antibody that directly targeted the extracellular domain of the HER2 receptor. Some of trastuzumab's antitumor effects are antibody-dependent cellular cytotoxicity, inhibition of HER2 extracellular domain cleavage, activation of phosphatase and tensin homolog, and inhibition of phosphatidylinositol 3-kinase/AKT survival signaling.
Trastuzumab was first approved for the treatment of metastatic HER2-positive breast cancer because it provided remarkable improvements in response rate, time to disease progression, duration of response, and overall survival when combined with chemotherapy. Because of its usefulness in the metastatic setting, trastuzumab was studied in the adjuvant setting, in which it resulted in improvements in clinical outcomes when given in combination with or after chemotherapy. Five randomized, phase 3 clinical trials demonstrated significant improvements in disease-free and overall survival rates when trastuzumab was administered in conjunction with adjuvant chemotherapy for patients with early-stage HER2-positive breast cancer.[11-14] The integration of trastuzumab-based therapy into the adjuvant setting changed the course of the disease in women with HER2-positive early-stage breast cancer. Despite this success, trastuzumab resistance still represents a clinical challenge. The majority of patients with metastatic breast cancer whose disease initially responds to trastuzumab develop resistance within 1 year of treatment initiation, and approximately 5% to 15% of patients with HER2-positive early-stage breast cancer who receive adjuvant trastuzumab-based therapy develop recurrent disease.[15-17]
Several clinical trials have shown clinical benefit in continuing or resuming trastuzumab-based treatment despite disease progression during or after treatment with trastuzumab, suggesting that resistance may be partially overcome by changing chemotherapy agents in the metastatic setting.[18, 19] The results of the Retreatment after HErceptin Adjuvant (RHEA) study demonstrated that in patients with HER2-positive metastatic breast cancer, the combination of trastuzumab plus a taxane is clinically efficacious as a first-line treatment at the time of disease recurrence after trastuzumab-based adjuvant therapy. There is also evidence indicating that patients previously treated with trastuzumab and lapatinib derive clinical benefit when retreated for metastatic disease with trastuzumab-based therapy. Despite the identification of trastuzumab resistance as a significant clinical problem, continued blockade of the HER2 pathway at the time of disease progression has been used in the clinic as an efficacious treatment strategy.
To the best of our knowledge, limited information is available outlining the outcomes of patients who receive adjuvant trastuzumab for HER2-positive early-stage breast cancer and then go on to develop metastatic HER2-positive disease and receive retreatment with trastuzumab. The current study reviewed the outcomes of patients who were treated with trastuzumab in the first-line metastatic setting and evaluated whether these outcomes differed between patients who received trastuzumab in the adjuvant/neoadjuvant setting and those who did not.
MATERIALS AND METHODS
We conducted a retrospective review of patients with HER2-positive breast cancer treated at The University of Texas MD Anderson Cancer Center with trastuzumab as part of their first-line treatment for metastatic disease. Patients were identified through the Breast Cancer Management System database, which is managed by the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center. Patients were included in the analysis if they met the following criteria: female sex, age ≥ 18 years, diagnosis of metastatic HER2-positive breast cancer between April 1998 and November 2010, and treatment with trastuzumab-based therapy in the first-line metastatic setting. Patients who had previously received neoadjuvant or adjuvant trastuzumab-based therapy for HER2-positive early-stage breast cancer were included. A total of 513 patients with HER2-positive metastatic breast cancer were evaluated during the time period. Of the 513 patients identified, 160 patients had presented with de novo stage IV HER2-positive breast cancer and were analyzed separately. A total of 353 patients had a history of stage I to III HER2-positive breast cancer and were included in the primary analysis. These 353 eligible patients were stratified based on whether they did or did not receive prior (ie, adjuvant or neoadjuvant) trastuzumab-based therapy, and clinical outcomes were evaluated accordingly.
The Institutional Review Board at The University of Texas MD Anderson Cancer Center approved the retrospective review of medical records for the current study. The primary tumors were staged according to the 6th edition of the American Joint Committee on Cancer criteria. The HER2 status of primary tumors was determined using immunohistochemistry and/or fluorescence in situ hybridization. Tumors were classified as HER2 positive if the protein was overexpressed on immunohistochemistry (score of 3+) or if the HER2 gene was amplified on fluorescence in situ hybridization (HER2/chromosome 17 centromere [CEP17] ratio of ≥ 2). The nuclear grade and estrogen receptor and progesterone receptor expression were recorded from each patient's pathology reports. A tumor was considered to be positive for estrogen receptor or progesterone receptor if the respective immunostaining showed expression in at least 10% of cells. The grading and histologic classification of tumors were based on the modified Black and Speer nuclear grading system and World Health Organization criteria, respectively.
Patients were followed according to the practice guidelines in place at the time. We reviewed the medical records to determine the patients' response to first-line therapy using Response Evaluation Criteria in Solid Tumors, dates of first-line treatment, and survival status. The United States Social Security Death Index was also used to identify deceased patients. If a patient had died, the date of last follow-up was considered as the date of death. Overall survival was calculated from the date of the initiation of first-line trastuzumab-based therapy for metastatic disease until the time of death or last follow-up. Objective response was defined as a complete or partial response. Clinical benefit was defined as complete response, partial response, or stable disease for at least 6 months. For patients with metastasis in > 1 organ, the first site of distant metastasis was defined by prespecified importance in the following order: brain, liver, lung, pleura, bone, and other. The “other” category included lymph node and soft tissue metastasis.
Logistic regression was used to assess the association between prior trastuzumab use and response to trastuzumab in the metastatic setting. The Kaplan-Meier method was used to estimate survival curves from the initiation of trastuzumab treatment in the metastatic setting. The Cox proportional hazards regression model was used to assess the association between prior trastuzumab use and overall survival. Univariate and multivariate analyses were performed to compare response rates, clinical benefit rates, and median overall survival durations between the group of patients who had received prior trastuzumab and the group who had not. The sample sizes for the multivariate analyses were slightly smaller than those of the corresponding univariate analyses due to missing data for some of the covariates included in the statistical models. Analyses were conducted using the SAS software (SAS Institute Inc, Cary, NC); statistical significance was defined as P < .05.
Of the 353 patients eligible for analysis, 75 had received trastuzumab in the adjuvant or neoadjuvant setting and 278 had not. Table 1 shows the baseline patient characteristics stratified by prior trastuzumab exposure. The median interval from the time of diagnosis of first metastasis to the initiation of treatment with trastuzumab in the metastatic setting was 20.5 days (range, 0.0 days-210.0 days) in patients without prior trastuzumab exposure and 23.0 days (range, 0.0 days-435.0 days) in patients with prior exposure. The number of deaths was 190 among patients without prior trastuzumab exposure (68%) and 50 in the group with prior exposure (67%). The median age at diagnosis with metastatic disease was 50 years (range, 25 years-93 years) in patients without prior trastuzumab exposure and 49 years (range, 26 years-81 years) in patients with prior exposure. The median disease-free interval was 2.4 years (range, 0.0 years-22 years) in patients without prior trastuzumab exposure and 1.5 years (range years, 0.4-9.6 years) in patients with prior exposure. The median follow-up time was 28.6 months for all patients. Among the 113 patients still alive at the date of last follow-up, the median follow-up time was 36 months.
Table 1. Baseline Patient Characteristics According to Prior Trastuzumab Exposure
No Prior Trastuzumab (n = 278)
Prior Trastuzumab (n = 75)
Abbreviations: AJCC, American Joint Committee on Cancer; ER, estrogen receptor; PR, progesterone receptor.
Trastuzumab was approved by the US Food and Drug Administration for adjuvant use on November 16, 2006.
Eleven patients were also found to have liver metastases at the time of presentation (2 with prior trastuzumab exposure and 9 with no prior trastuzumab exposure).
As the first-line therapy for metastatic disease, all patients received trastuzumab in conjunction with various chemotherapies, including capecitabine, vinorelbine, paclitaxel, docetaxel, gemcitabine, and carboplatin. In the adjuvant or neoadjuvant setting, the majority of patients had received anthracycline/taxane-based chemotherapy regimens: docetaxel, doxorubicin, and cyclophosphamide; 5-fluorouracil, doxorubicin or epirubicin, and cyclophosphamide; or doxorubicin and cyclophosphamide. Seventy-five patients had received adjuvant or neoadjuvant trastuzumab in combination with paclitaxel or docetaxel, with continuous weekly administration of trastuzumab for 52 weeks. The majority of patients in both groups had initial tumors with a high nuclear grade at the time of presentation. The percentages of premenopausal and postmenopausal patients were roughly equal in both groups. The percentages of hormone receptor-negative breast cancer were slightly different: 46% in the group without prior trastuzumab exposure and 57% in the group with prior exposure.
Of the 353 patients, 57 (16%) were excluded from the response analysis due to nonmeasurable disease (39 patients) or lack of response data (18 patients). Patients were considered not evaluable for response if they had received radiotherapy before or concurrently with chemotherapy; undergone surgical resection of the metastatic site of disease before receiving chemotherapy; or had isolated metastasis to bone, pleura, ascitic fluid, or skin only (22 patients). In addition, patients with brain metastases who had received whole-brain radiotherapy or surgery before systemic chemotherapy were excluded from the response analysis (17 patients). Of the 296 patients included in the response analysis, a higher objective response rate (51% vs 29%) and clinical benefit rate (71% vs 39%) were observed in the group of patients without prior trastuzumab exposure compared with the group with prior exposure. After controlling for age, disease-free interval, postmenopausal status, stage of disease, hormone receptor status, and nuclear grade using multiple logistic regression, the adjusted odds ratios were 0.39 (95% confidence interval [95% CI], 0.18-0.82; P = .038) for the objective response rate and 0.28 (95% CI, 0.13-0.59; P = .0009) for the clinical benefit rate.
The median overall survival was 36 months in the group without prior exposure to trastuzumab (278 patients) and 28 months in the group with prior exposure (75 patients) (hazards ratio [HR], 1.47; 95% CI, 1.07-2.01 [P = .022]) (Fig. 1). No significant difference was noted when the HR was adjusted for age, disease-free interval, menopausal status, stage of disease, hormone receptor status, and nuclear grade (HR, 1.22; 95% CI, 0.86-1.73 [P = .27]). The median overall survival from the time of the original diagnosis of stage I to III disease in the 353 patients was 73 months (range, 65 months-81 months).
The analyses were repeated to include patients who presented with de novo stage IV HER2-positive breast cancer (160 patients). As expected, the overall response and clinical benefit rates followed similar trends when the analysis included this group of trastuzumab-naive patients. Higher rates of objective response (57% vs 29%) and clinical benefit (76% vs 39%) were observed in the group without prior trastuzumab exposure compared with the group with prior exposure. The adjusted odds ratios were 0.37 (95% CI, 0.17-0.79; P = .010) for the objective response rate and 0.28 (95% CI, 0.13-0.58; P < .0001) for the clinical benefit rate. When overall survival was analyzed to include the patients with de novo stage IV disease, the median overall survival was 39 months in the group with no prior trastuzumab exposure and 28 months in the group with prior exposure (HR, 1.65; 95% CI, 1.21-2.23 [P = .0024]) (Fig. 2). After adjustments for age, disease-free interval, menopausal status, stage of disease, hormone receptor status, and nuclear grade, the HR for overall survival was 1.23 (95% CI, 0.87-1.75; P = .24).
For the majority of patients, the liver was the first site of metastatic disease; there was a lower rate of liver-first metastasis in the group previously exposed to trastuzumab compared with the group without prior exposure (44% vs 25%) (Table 1). Of the patients categorized as having brain-first metastasis (30 patients), 11 patients also had liver metastases (2 patients in the group with prior exposure and 9 patients in the group without prior exposure). A log-rank test was performed to determine whether the site of distant metastatic disease influenced overall survival (Fig. 3). Patients with brain metastases had the shortest median survival (17 months), followed by patients with metastases to the lung or pleura (31 months) and those with metastases to the liver (32 months). Next, this analysis was performed with patients stratified according to whether they had received prior trastuzumab. Patients with liver metastases (122 patients) without prior trastuzumab exposure had a significantly longer median survival (33 months) than patients with liver metastases who had received trastuzumab in the adjuvant or neoadjuvant setting for early-stage breast cancer (19 patients) (19 months) (HR, 2.1; 95% CI, 1.2-3.6 [P = .011]) (Fig. 4). Patients with brain metastases who had not received prior trastuzumab also had a longer median overall survival; however, 30 patients were included in the analysis (17 without and 13 with prior trastuzumab exposure). This sample was not large enough for a valid analysis.
In the current retrospective analysis of patients with HER2-positive breast cancer who received front-line trastuzumab-based therapy for metastatic disease, we observed that trastuzumab-naive patients had higher overall response and clinical benefit rates compared with patients who had received trastuzumab in the adjuvant or neoadjuvant setting.
To the best of our knowledge, the topic of whether prior trastuzumab exposure affects clinical outcomes when patients develop disease recurrence and are treated with trastuzumab-based therapy in the first-line metastatic setting has been largely unexplored. The findings of the current study indicate that patients previously exposed to trastuzumab derive less clinical benefit from trastuzumab in the metastatic setting compared with trastuzumab-naive patients. This supports other observations that disease recurrence after the use of adjuvant trastuzumab is associated with a lower likelihood of prolonged trastuzumab use in the advanced/metastatic setting.
Novel therapies targeting HER2 are moving rapidly to the clinic, and the selection and sequencing of these therapies has become more challenging. Several recent clinical trials for the treatment of patients with advanced HER2-positive breast cancer highlight the evolving treatment options for women with this disease. In the Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) trial, which established docetaxel, trastuzumab, and pertuzumab as the first-line regimen in patients with metastatic HER2-positive breast cancer, only 10% of the population had prior trastuzumab exposure, and a disease-free interval of ≥ 12 months was required for eligibility. Nevertheless, it is important to note that the patients with prior trastuzumab exposure derived benefits similar to those who were trastuzumab-naive. In contrast, all patients enrolled in the EGF104900 study were heavily pretreated; these patients had received a median of 4 prior regimens, the majority of which were trastuzumab-based (perhaps reflecting a higher rate of HER2-positive disease). Both a progression-free survival and overall survival benefit were demonstrated when patients with heavily pretreated metastatic HER2-positive breast cancer were treated with a combination of lapatinib and trastuzumab compared with lapatinib monotherapy.[29, 30] Finally, in the EMILIA (NCT00829166) study, which established ado-trastuzumab emtansine as the optimal treatment in the second-line setting, all patients had been previously exposed to and had retained potential sensitivity to trastuzumab. In the current treatment algorithm for metastatic HER2-positive breast cancer, patients who present with de novo metastatic disease (previously untreated) or those with prior trastuzumab exposure who have a treatment-free interval of ≥ 6 months are offered the CLEOPATRA regimen (docetaxel, trastuzumab, and pertuzumab) upfront. For patients with a treatment-free interval of < 6 months, the preference is to initiate therapy in the metastatic setting with ado-trastuzumab emtansine. For patients with metastatic breast cancer who progress while receiving HER2-directed therapy, we continue targeted agents beyond disease progression with subsequent regimens at the current time.
Results from the MARIANNE study (ClinicalTrials.gov identifier: NCT01120184), a randomized trial comparing trastuzumab emtansine alone, trastuzumab plus a taxane, and trastuzumab emtansine plus pertuzumab for the first-line treatment of patients with metastatic breast cancer) are eagerly anticipated to further expand the options available to women with metastatic HER2-positive breast cancer. Until more advances are made in biomarker-driven research, clinicians are charged with the task of selecting the most appropriate drug for each patient in the best order using their best clinical judgment, and prior trastuzumab exposure should be an important consideration in current and future treatment algorithms.
Resistance to targeted therapy is a significant problem in patients with advanced HER2-positive breast cancer, and potential mechanisms have been postulated and continue to be explored.[17, 32] The phosphatidylinositol 3-kinase pathway plays a central role in the mechanism of resistance to trastuzumab; it can be activated by genetic alterations or by increased upstream signaling via growth factor receptors and is associated with poor outcomes.[33-35] Furthermore, mammalian target of rapamycin is a key intracellular point of convergence for multiple cellular signaling pathways and has emerged as the most advanced therapeutic target in treatment-resistant HER2-positive breast cancer.[36, 37] The incorporation of tissue-based correlative studies into prospective trial designs will help to expand the current knowledge base of trastuzumab resistance mechanisms in patients with HER2-positive breast cancer and potentially inform the development of improved therapeutic strategies and predictive markers. Resistance mechanisms to trastuzumab may in part explain the worse outcomes of patients who were previously exposed to prior targeted therapy; however, it is important to consider that there may also be underlying resistance to chemotherapy itself.
We acknowledge the limitations of the current study. This was a retrospective study performed at a single institution. Although to the best of our knowledge, the current study is the largest series of its kind, the patient population was small considering that trastuzumab has been a well-accepted adjuvant therapy since 2005. The majority of patients in the group who did not receive prior trastuzumab were originally diagnosed with stage I to III HER2-positive breast cancer in the late 1990s or early 2000s, when adjuvant trastuzumab was not yet established as the standard of care. In addition, the eligibility criteria for this retrospective review did not require measurable disease, and 16% of the patients had to be excluded from the response analysis because of nonmeasurable disease or a lack of response data. The data regarding the first site of distant metastasis were difficult to interpret because patients who presented with multiple sites of disease were classified into 1 group based on a prespecified order of importance. Finally, it is important to recognize that patients previously exposed to trastuzumab were more likely to have received anthracycline-/taxane-based chemotherapy, to have had aggressive disease at the time of presentation, to have had hormone receptor-negative disease, and to have had a shorter disease-free interval. Because of these limitations, definitive conclusions should not be drawn from the results of the current study. The value of the current study lies in recognizing prior trastuzumab exposure as we sequence available therapies in the clinic and design intelligent clinical trials. The current study also provides a point estimate for expected benefit from HER2-targeted therapies tested in the metastatic disease setting.
The results of the current study demonstrate the need for further research and emphasize the importance of recognizing pretreated populations in selecting currently available therapies and in future trial enrollment. The discovery of more reliable tools will enhance clinical judgment and allow for better patient selection and the optimization of current and future therapeutics.
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
Dr. Hortobagyi has received a grant and personal fees from Novartis as well as personal fees from Pfizer, Antigen Express, Galena Pharmaceuticals, Genentech, Amgen, AstraZeneca, and Sanofi-Aventis for work performed outside of the current study. Dr. Esteva has received personal fees from Genentech, Novartis, and GlaxoSmithKline for work performed outside of the current study.