In this issue of ONCOLOGY, Dr. Santa-Maria and colleagues have provided a comprehensive review of the current landscape of systemic therapy for patients with recurrent or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer, describing both current approaches and novel strategies for the future. They outline the impressive results of the CLEOPATRA study, where first-line treatment of patients with pertuzumab, trastuzumab, and docetaxel (THP) yielded a progression-free survival (PFS) advantage of 6 months and an overall survival (OS) advantage of nearly 16 months over combination treatment with placebo, trastuzumab, and docetaxel.[2,3] They also remind us that although in the phase III MARIANNE study trastuzumab emtansine (T-DM1) demonstrated noninferiority to treatment with trastuzumab and a taxane in the first-line setting, use of T-DM1 was not comparable to treatment with THP. Thus, Dr. Santa-Maria and coauthors conclude that while utilization of T-DM1 in the first-line setting can be considered for patients with rapid progression after adjuvant trastuzumab, or in patients who are taxane-intolerant, undoubtedly at least 6 cycles of THP remains the preferred first-line treatment for many patients with HER2-positive metastatic disease, followed by maintenance pertuzumab and trastuzumab.[4,5] In clinical practice, the combination of pertuzumab, trastuzumab, and paclitaxel is another commonly employed first-line regimen, based on a phase II trial showing a 1-year PFS rate of 71% (95% CI, 55%–82%) for patients who had not undergone prior therapy, and 66% (95% CI, 40%–83%) for those who received prior therapy.[5,6]
For patients with hormone receptor–positive disease, the National Comprehensive Cancer Network still recommends initial treatment with endocrine therapy, and it is a common approach to utilize trastuzumab in combination with endocrine therapy prior to chemotherapy in women with lower-volume hormone receptor–positive disease. The authors caution, however, that PFS gains are lower with this approach than with THP, due to the propensity for endocrine resistance in some patients with HER2-positive disease.[7,8] For instance, patients whose tumors exhibit phosphoinositide 3-kinase (PI3K) pathway activation can be resistant to anti-HER2 treatments, and upregulation of the estrogen receptor (ER) and ER-mediated signaling has also been correlated to lower pathologic complete response (pCR) rates in the neoadjuvant setting. Clearly, endocrine-resistant HER2-positive disease is a problem that we should bear in mind as we sequence therapies for our patients.
Treatment considerations in the second line include trastuzumab in combination with other chemotherapeutic agents, or T-DM1, based on the EMILIA study results of a 3.2-month PFS advantage and a 5.8-month OS advantage over combination treatment with capecitabine and lapatinib in patients previously treated with trastuzumab and a taxane. Initial results of the phase III TH3RESA study presented at the 2015 San Antonio Breast Cancer Symposium (SABCS) showed an improvement in OS with T-DM1 compared with treatment of physician’s choice (22.7 months vs 15.8 months) for patients who had been treated with at least two prior HER2-directed therapies, despite the fact that crossover was allowed at time of progression; these findings have further solidified T-DM1 as a highly effective treatment, even in later lines of therapy.
Despite the gains we have seen with dual HER2 blockade in CLEOPATRA, at year 3 two-thirds of patients receiving the combination had disease progression due to development of acquired resistance, and the OS rate was modest at 68%. Therefore, novel treatments are still greatly needed.
While neoadjuvant studies have provided valuable insight into the heterogeneity of response in patients with HER2-positive disease, we eagerly await biomarker analyses from ongoing trials, such as the neoadjuvant National Surgical Adjuvant Breast and Bowel Project (NSABP) B52 study examining chemotherapy plus dual inhibition of HER2, with and without estrogen deprivation. It is hoped that these trials will help elucidate mechanistic underpinnings of resistance in our HER2-positive patients.
Other current and future treatment options outlined by Dr. Santa-Maria and colleagues for patients with advanced disease include PI3K pathway inhibitors, small-molecule tyrosine kinase inhibitors (TKIs), nanoparticles, and immune approaches. To understand how to best sequence and tailor treatment for individual patients, it will be critical to identify biomarkers of response and resistance to these various therapies. For example, it will be important to find subgroups of patients who might benefit from treatment with small-molecule TKIs such as lapatinib and neratinib, possibly in combination with other agents. Ongoing trials of neratinib (ClinicalTrials.gov identifiers: NCT02236000 and NCT01808573) now incorporate regimented diarrhea prophylaxis in an attempt to achieve a more tolerable side effect profile. The question of whether neratinib and other HER2 TKIs may be helpful for women with brain metastases is of particular interest and the subject of ongoing research (ClinicalTrials.gov identifier: NCT01622868).
Ultimately, we understand that treatment with trastuzumab, as a monoclonal antibody, inhibits HER2 signaling. However, trastuzumab also exerts a variety of immunologic effects, including increasing antibody-dependent cell-mediated cytotoxicity as well as complement-dependent cytotoxicity, increasing interactions between immune cells, inducing immunomodulatory cytokines, and priming of the adaptive immune response via T-lymphocyte response to tumor-specific antigens. Strategies to extend this immunologic response are important, since preclinical studies have illustrated the potential for immunomodulating agents to potentiate the trastuzumab effect, such as an anti-CD137 agent increasing trastuzumab-mediated natural killer cell activity, TLR2 (toll-like receptor 2) agonists and lenalidomide activating both innate and adaptive immune response,[15,16] and an anti–programmed death 1 (PD-1) agent showing synergism with trastuzumab.
In the WSG-ADAPT trial, following 3 weeks of therapy with T-DM1, HER2-positive breast tumors showed a significant increase in the number of lymphocytes, and preclinical work has shown that treatment with T-DM1 transformed HER2-positive tumors that were resistant to cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)/PD-1 blockade into tumors that were highly sensitive to immune therapy. In this study, mice implanted with HER2-overexpressing breast tumors were treated with T-DM1, with subsequent increase in tumor expression of checkpoint proteins. Combination treatment of the mice with T-DM1 and checkpoint inhibitors was actually curative, because it led to both innate and adaptive immunity. The authors speculated that one underlying mechanism was that T-DM1 reduced the number of tumor cells, perhaps minimizing exposure of T cells to tumor antigens.
In the NeoSphere study, positive associations were seen with immune markers (interferon Y), certain metagenes, and pCR. Moreover, in a study presented at SABCS 2015, pretreatment stromal tumor-infiltrating lymphocytes (S-TILS) were shown to correlate with complete response to chemotherapy plus trastuzumab in the metastatic setting. PANACEA (ClinicalTrials.gov identifier: NCT02129556), currently accruing participants, is an important phase I/II trial of pembrolizumab and trastuzumab in women with trastuzumab-resistant HER2-positive metastatic breast cancer.
While we continue to be thankful for incremental gains in the treatment of our patients with metastatic HER2-positive breast cancer, much work remains in order to optimize and individualize care.
Financial Disclosure: The authors have no significant financial relationship with the manufacturer of any product or provider of any service mentioned in this article.
Acknowledgments: Dr. Jankowitz receives support from Susan G. Komen Career Catalyst Research Award CCR14300865 and Dr. Rastogi receives the following grant support from the National Cancer Institute: U10 CA-180868, U10 CA-180822, and UG-189867.
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