It is well recognized that the treatment of HER2-positive metastatic breast cancer has been revolutionized in the last 15 years—first by the introduction of trastuzumab; followed nine years later by lapatinib; and in the last two years, by the approval of two additional HER2-targeted therapies, pertuzumab and trastuzumab emtansine (T-DM1). The availability of these treatments has literally altered the natural history of HER2-driven disease, allowing many patients to live years, and in some cases beyond a decade, after diagnosis with metastases.
In my own practice, I now routinely utilize trastuzumab, pertuzumab, and a taxane in the first-line HER2+ metastatic setting based on the improved overall survival and progression-free survival as well as relatively similar tolerability of this regimen compared with standard trastuzumab plus docetaxel in the Phase III CLEOPATRA study.
I discuss with the patient the differences between docetaxel and paclitaxel in terms of the side effects profile and dosing frequency (q3 weekly vs. q weekly respectively), and based on this discussion will select which taxane to use. In keeping with the design of CLEOPATRA, my goal is to have the patient complete at least six cycles of chemotherapy, and at that time, if the disease is responding, we may discontinue the chemotherapy and continue pertuzumab and trastuzumab until the time of disease progression.
If a patient's tumor co-expresses estrogen and/or progesterone receptors, I will often add an anti-hormonal therapy upon discontinuation of the chemotherapy. While the CLEOPATRA study design did not include hormonal blockade in its design, my opinion is that using endocrine therapy in combination with dual HER2-blockade after the initial chemotherapy cycles may be beneficial to patients with ER+/HER2+ disease.
At the time of progression on trastuzumab and pertuzumab, I will consider resuming the taxane (and continuing the dual HER2-targeted therapy). Again, whether this practice is as effective as immediately switching therapy to another drug such as T-DM1 is an unanswered question at this time.
My theory is, if the patient's disease responded well to the taxane previously and the patient has no significant neuropathy, then reintroducing the taxane and continuing the pertuzumab/trastuzumab may regain control of the disease. Patient preference regarding taxane-related side effects, including hair loss, certainly plays a role in this decision process, however.
In the second-line setting (or in the case of a patient whose disease relapsed quickly—i.e., within six months of adjuvant trastuzumab), I recommend initiating T-DM1 based on the results of the EMILIA study. Patients with HER2-positive metastatic breast cancer resistant to trastuzumab and taxane had a better progression free survival-treated with T-DM1 compared with use of capecitabine and lapatinib. Patients tend to tolerate this therapy extremely well, although it is important to monitor platelets and liver transaminases as dose delay or reductions are occasionally warranted.
While the CLEOPATRA and EMILIA studies have nicely defined optimal treatment in the first- and second/third-line settings respectively, the most effective sequencing and therapeutic combinations beyond the first two or three lines of therapy have not been defined. In addition, management of brain metastases remains a significant challenge in clinical practice. These questions will hopefully be addressed in the coming years with ongoing studies.
In the absence of this data, however, clinicians are faced with making treatment decisions based on a combination of factors including the hormone-receptor status of the tumor, response (or resistance) to prior therapies received, disease burden, and the patient's performance status, comorbidities, and residual toxicities as well as her goals of treatment.
It is not uncommon for patients with HER2+ metastatic breast cancer to have more than five lines of therapy. In my own practice, I will continue to treat a patient with subsequent lines of therapy as long as she has a good performance status (ECOG 0–2) and she desires to continue therapy. Data is mounting that strongly supports continued use of HER2-blockade even in the face of disease progression while on HER2-targeted therapy.
Thus, in subsequent lines of therapy I will always continue either trastuzumab or lapatinib. I find the combination of trastuzumab with vinorelbine to be especially well tolerated and active. Other trastuzumab and/or lapatinib-based regimens include combinations with capecitabine, gemcitabine, or eribulin, and in the case of hormone receptor-positive disease, fulvestrant or an aromatase inhibitor.
I will also use T-DM1 if a patient has received multiple lines of therapy but has not yet received T-DM1. The Phase III TH3RESA study, reported in late 2013, suggests that T-DM1 is better tolerated and is associated with an improved progression-free survival rate compared with treatment of physician's choice in patients who are beyond the third-line treatment setting.
I have also found lapatinib plus trastuzumab to be generally well tolerated and active; however, patients must be prepared for the possibility of diarrhea and should be monitored closely in the first few cycles.
Needless to say, patients are strongly encouraged to participate in clinical trials of newer therapeutic combinations and novel targeted therapies especially in the later-line disease setting.
One problem that remains vexing in clinical practice is the most appropriate management of central nervous system metastases. Local regional therapy with stereotactic radiosurgery, surgical resection, and/or whole-brain radiation are used as an initial approach in the absence of a suitable clinical trial. I will often utilize lapatinib in these situations, given its potential for better penetration of the blood-brain barrier compared with trastuzumab.
It will be interesting to see the results of ongoing studies evaluating drugs that are able to penetrate the blood-brain barrier, including the mTOR inhibitor everolimus. Hopefully in the next several years we will see an improvement in our ability to treat, and ultimately prevent, CNS disease.
While there are multiple treatment options available for patients with HER2+ metastatic breast cancer, treatment resistance remains the rule. An increasing number of treatment options will no doubt continue to emerge as clinical trials evaluate new biologically targeted therapies aimed to prevent or circumvent treatment resistance. The use of tumor genetic profiling will in the future, it is hoped, improve our ability to select therapeutic choices and sequencing in an era where so many options for therapy exist.