Duration of trastuzumab in patients with HER2-positive metastatic breast cancer in prolonged remission

Background Outcomes in metastatic breast cancer (m bc ) positive for her2 (human epidermal growth factor receptor 2) are generally unfavourable. Trastuzumab has revolutionized the prognosis of her2 -positive m bc . Some her2 -positive m bc patients go into prolonged remission, and a few patients remain in remission even after discontinuation of trastuzumab, suggesting the possibility of a cure. In our practice, 4 her2 -positive m bc patients treated with chemotherapy and trastuzumab have remained in remission on maintenance therapy for 5 years or more. Of those 4 patients, 2 have continued in remission after discontinuation of trastuzumab for more than 1 year. The objective of the present paper was therefore to address the duration of trastuzumab therapy in her2 -positive m bc patients in prolonged remission. We conducted a literature review of the duration of trastuzumab in her2 -positive m bc patients in remission. We also conducted an online survey of oncologists in Ontario to determine their treatment practices in her2 -positive m bc patients. The literature search found no specific evidence about the optimal duration of trastuzumab maintenance therapy in her2 -positive m bc in prolonged remission. However, retrospective studies suggest predictive markers of good prognosis in patients in complete remission taking maintenance trastuzumab. Identifying those markers could lead to more personalized treatment. Our survey of oncologists about their treatment practices in her2 -positive m bc patients revealed that 82.93% of respondents ( n = 34) follow the currently available guidelines. this topic.


INTRODUCTION
Approximately 15%-25% of breast cancers show amplification or overexpression of her2 (human epidermal growth factor receptor 2) 1 . Each year, at least 276,000 women worldwide are newly diagnosed with her2-positive breast cancer (1.38 million × 20%), a number that is estimated to rise to 540,000 in the year 2030 (2.7 million × 20%) 2 . Patients with her2-positive breast cancer have more aggressive disease and significantly shortened disease-free survival and overall survival than do their counterparts without her2 overexpression 3,4 .
Trastuzumab (Herceptin: Genentech, San Francisco, CA, U.S.A.), a humanized monoclonal antibody against her2, has revolutionized the treatment of her2-positive breast cancer 5 . It was approved in Canada for metastatic breast cancer (mbc) in 1999 and for early breast cancer in 2006. Per current guidelines, the standard therapy for patients with her2-positive mbc is chemotherapy combined with trastuzumab, followed by maintenance trastuzumab.
Use of trastuzumab has significantly altered the natural history of her2-positive mbc, converting it from an historically aggressive subtype to a subtype with improved prognostic outcome and prolonged survival 6  Unfortunately, a large proportion of patients with her2positive mbc treated with trastuzumab relapse after 12-24 months 7 . Nevertheless, a small proportion of her2-positive mbc patients remain in prolonged complete remission on trastuzumab maintenance therapy. The frequency of durable remission in this patient population is not known.
In our practice, 4 patients with her2-positive mbc (biopsy proven) experienced a complete response after chemotherapy and trastuzumab, and remained in remission on maintenance trastuzumab for more than 5 years. Of those 4 patients, 2 continue in remission even after discontinuation of maintenance trastuzumab for more than 1 year. Their long-term outcome is unknown.
With the emergence of prolonged remissions in her2-positive mbc patients, the optimal duration of maintenance trastuzumab has become an important and relevant clinical question worldwide, whose answer remains unknown. Thus, we conducted a literature review and a survey of oncologists about the duration of trastuzumab in her2-positive mbc patients in prolonged remission.

Literature Search
We searched the literature in the medline, embase, and PubMed clinical databases from January 1985 to March 2015. The search included randomized controlled trials, retrospective studies, guidelines, systematic reviews, meta-analyses, and case reports. In addition, abstracts from major conferences, including the annual meetings of the American Society of Clinical Oncology, the European Society for Medical Oncology, and the San Antonio Breast Cancer Symposium were examined. The Cancer Care Ontario Web site was also searched for current relevant guidelines. The reference lists of identified articles were further searched to locate publications not captured in the database search. The search used a combination of these key words: "her2-positive," "metastatic breast cancer," "trastuzumab," "complete or prolonged remission," "optimal duration of treatment," and "maintenance or monotherapy." Only English-language publications were searched and reviewed.

Survey
Our survey was intended to gather information from medical oncologists in Ontario about current treatment trends in her2-positive mbc. The multiple-choice questionnaire included an initial screening question that identified oncologists who treat breast cancer. The remaining 4 questions identified years of practice, number of her2-positive mbc patients seen annually, number of her2-positive mbc patients on trastuzumab maintenance therapy in complete remission, and duration of continued trastuzumab maintenance therapy.
In December 2014, an e-mail invitation containing a link to the survey questionnaire was sent to a purposive sample of 201 oncologists. The sample included oncologists from the Community Oncologists of Metropolitan Toronto and several well-known breast oncologists in the province of Ontario, which in our opinion constituted a good representation of oncology practice across the province.
Participation was voluntary, with no incentives provided to encourage responses.

Literature Review
After removal of duplicate citations, the search located 395 publications. Of the clinical trials, prospective studies, guidelines, systematic reviews, meta-analyses, and case reports located, twenty-three articles were deemed to be directly related to the study question and are discussed here.

Currently Available Guidelines
Current guidelines for her2-positive mbc from the European Society for Medical Oncology recommend indefinite uninterrupted continuation of her2-targeted therapy in the absence of any toxicity 8 . Guidelines from the American Society of Clinical Oncology also recommend the continuation of her2-targeted therapy in patients with her2-positive advanced breast cancer until the time of disease progression or unacceptable toxicity 9 (with the exception of patients having congestive heart failure or significantly compromised left ventricular ejection fraction) 9 . Guidelines from Cancer Care Ontario accord with the foregoing guidelines and recommend continuation of trastuzumab in her2-positive mbc till disease progression or unacceptable toxicity 10 .

Optimal Duration of Trastuzumab in HER2-Positive mBC Patients in Complete Remission
A few published studies and case reports in the literature have, because of late relapses, cautioned oncologists about discontinuing maintenance trastuzumab even after 2-3 years in remission 7,11 . In 2007, Beda et al. 11 published a case report describing a patient with her2-positive mbc in complete remission for 2 years who relapsed soon after discontinuation of trastuzumab maintenance therapy. Similarly, some retrospective studies have shown that, because of the possibility of late progression, trastuzumab should not be stopped after 3 years of durable response 12 . Although some institutional guidelines 13 advocate 5 years of maintenance trastuzumab therapy, the effectiveness of that approach is still unknown. In 2014, Witzel et al. 7 used results from the her-os registry to describe a cohort of patients who benefited from a longer duration of trastuzumab maintenance therapy. Yet, to date, no clear consensus on the duration of trastuzumab maintenance therapy in this patient population has emerged 6,14 .

Evidence of Prolonged Remission in HER2-Positive mBC Patients
Gullo et al. 13 reported long-term follow-up of patients with her2-positive mbc in complete remission after chemotherapy and trastuzumab, suggesting that a small proportion of those patients achieve prolonged complete remission. Since 2006, several published studies and case reports have described patients who received long-term trastuzumab and experienced prolonged survival 5,15 . In 2014, two published case reports described patients in prolonged remission on trastuzumab maintenance therapy for more than 8 16 and 9 years 17 . According to those authors, their patients are the longest survivors on trastuzumab maintenance therapy in complete remission. A group of patients are also emerging who continue to be disease-free even after discontinuation of trastuzumab therapy 18 , indicating a potential for curable disease in a subset of her2-positive mbc patients 13,19 . That hypothesis was further highlighted in recent case reports of 2 patients in continued remission at 30 and 42 months after withdrawal of trastuzumab maintenance therapy 18 . To our knowledge, those durations are the longest reported for persistent complete response after trastuzumab discontinuation. Do those observations 13,19 suggest the probability of a cure in those patients? Discontinuation of trastuzumab by patient choice led to the discovery of both cases. Understandably, additional similar cases might not have been identified because of adherence to current guidelines. Our review found no substantial data to suggest that trastuzumab maintenance therapy can be safely interrupted after a specific time period.

Current and Future Directions
Reviews have shown that her2-positive breast cancer is a heterogeneous disease; it can have different behaviour patterns in different patient subsets. Predicting the subset of patients achieving a complete response who could do well after trastuzumab withdrawal remains a challenge 18 . Data characterizing her2-positive mbc patients with favourable long-term outcomes are limited, and definitive characteristics remain to be reported [19][20][21][22] , but retrospective studies have suggested favourable prognostic factors, which include younger age at diagnosis, good performance status, best response to trastuzumab treatment, estrogen and progesterone receptor-positive disease, metastases to nodes or local sites rather than to distant sites, and response to first-line taxane and trastuzumab 16,21 .
In patients with favourable factors, comprehensive molecular and cytogenetic studies of tumour samples are being conducted to identify a subset of patients with her2-positive mbc who are more likely to achieve a durable complete response after treatment with chemotherapy and trastuzumab 13 . The data come essentially from retrospective studies with low patient enrolment. Prospective randomized trials are still lacking 23 .

Survey Results
Of the 201 oncologists contacted, 47 responded to the online questionnaire by February 2015 (overall response rate of 23.4%). Of the 47 responders, 44 identified themselves as medical oncologists treating breast cancer (93.6%); 3 did not. Table i presents the results of the survey.
The question about duration of trastuzumab therapy in her2-positive mbc patients in prolonged remission was answered by 41 respondents; 3 respondents skipped the question. In terms of the duration of trastuzumab maintenance therapy in the mbc setting, 78% of respondents (n = 32) reported continuing trastuzumab until disease progression; 4.9% (n = 2) continue trastuzumab until the development of side effects. Another 4.9% of respondents (n = 2) reported continuing trastuzumab for 2 years, and 12.2% (n = 5) reported continuing it indefinitely. None of the respondents reported continuing trastuzumab maintenance therapy for 5 years. Overall, 82.9% of respondents (n = 34) reported continuing trastuzumab till disease progression or development of side effects in accordance with current Cancer Care Ontario guidelines.

DISCUSSION
Given the improvements achieved in the outcomes for her2-positive mbc with trastuzumab and other anti-her2 agents, the group of patients in complete remission should continue to grow. The current guidelines recommend trastuzumab maintenance therapy until disease progression or development of side effects, but the real benefits of prolonged therapy and the related potential for longterm toxicities, especially cardiovascular toxicity, are unknown 11 . Additionally, the huge costs associated with prolonged trastuzumab administration should be weighed against the paucity of demonstrated efficacy 11 . Currently, the optimal duration of trastuzumab therapy in patients with her2-positive mbc in complete remission remains an unanswered question. That uncertainty should be an important consideration in current and future studies in the her2-positive mbc patient group.
The discovery of favourable patient characteristics, specific molecular predictors of response to emerging therapies and combination therapies, and a better understanding of the molecular mechanisms beyond trastuzumab sensitivity and resistance will allow for a more personalized approach to the treatment of her2-positive breast cancer 1 and, potentially, for tailoring of the duration of treatment regimens to suit individual patient characteristics so as to move beyond the "one size fits all" approach.
As we await the results of such studies, the plausibility of using trastuzumab maintenance therapy for a limited time (such as for 5 years) in patients in prolonged remission should be cautiously explored. Randomized trials of patients with favourable outcome characteristics in complete remission are needed to test the efficacy of this observation approach in her2-positive mbc. However, the patient population eligible for a randomized trial would be a very small proportion of the total mbc population. A large global collaboration might therefore be required to confirm the impact of maintenance trastuzumab discontinuation on long-term survival or cure and to ensure the adequate statistical power and strength of the results 23 .

CONCLUSIONS
Prolonged remission with chemotherapy and trastuzumab for her2-positive mbc can be observed in a small group of patients in clinical practice. And yet the optimal duration of maintenance trastuzumab in prolonged remission is not clear from a literature review, and studies in this patient group are limited. The currently available guidelines advocate continuing trastuzumab until disease progression or development of side effects. Our survey of Ontario-based breast oncologists revealed that most respondents follow those guidelines in their practice.
The discovery of favourable patient characteristics and specific molecular predictors will be crucial for providing personalized treatment to her2-positive mbc patients in prolonged remission. Discontinuation of maintenance trastuzumab in this patient population after a limited time should be explored cautiously while a global collaborative effort for a randomized trial is awaited.

CONFLICT OF INTEREST DISCLOSURES
We have read and understood Current Oncology's policy on disclosing conflicts of interest, and we declare the following interests: RH has received honoraria for advisory committee meetings from Amgen, Novartis, Astra Zeneca, Ingelheim Boehringer, Leo Pharma, and Pfizer, and support for education and survivorship research projects from Astra Zeneca, Roche, and Bristol-Myers Squibb. RH has also received support for the ambassador program to international conferences on thrombosis in cancer. PG has no conflicts of interest to declare.