My first-line therapy for an asymptomatic or symptomatic 60-year-old patient would be a combination of endocrine therapy, trastuzumab and lapatinib. Letrozole and lapatinib is an approved combination that does not require prior trastuzumab. The EGF104900 study demonstrated an overall survival benefit with the combination of lapatinib and trastuzumab compared to lapatinib alone for patients with HER2-positive metastatic breast cancer.

For an asymptomatic patient, I would administer endocrine therapy and trastuzumab. I would also consider endocrine therapy if the patient had a problem with infusional therapy. Data from clinical studies suggest poor progression-free survival with endocrine therapy alone in triple-positive disease. Also, preclinical data suggest cross talk between the hormone receptor and HER2 pathways. Therefore, I believe a biologic rationale exists for cotargeting the estrogen receptor and HER2 pathways.

For a symptomatic patient in the same scenario, I would again opt for endocrine therapy in combination with trastuzumab. If the patient found infusional therapy difficult, I would opt for hormone therapy.

I would choose endocrine therapy and trastuzumab for this asymptomatic 60-year-old patient who has metastases to the bone. I would hold off on chemotherapy and pertuzumab because they can always be added later.

For a symptomatic 60-year-old patient, I would administer trastuzumab in combination with pertuzumab and weekly paclitaxel. I would follow this initial treatment with endocrine therapy. I would also consider endocrine therapy and trastuzumab with close monitoring after discussion with the patient.

I believe that endocrine treatment alone would be the least toxic approach for a 60-year-old patient who was either symptomatic or asymptomatic and had metastases to the bone. If it is not effective, I would become aware of that shortly and switch to trastuzumab with pertuzumab and weekly paclitaxel.

For a patient without symptoms or visceral disease, I would consider endocrine therapy alone or with trastuzumab. The alternative would be a taxane in combination with trastuzumab and pertuzumab, but the use of chemotherapy would likely negatively affect her quality of life in the short term. The rationale for considering endocrine therapy without trastuzumab is that the improvement in progression-free survival associated with trastuzumab in this setting is relatively small. In addition, trastuzumab requires more frequent trips to the oncologist and may compromise the patient’s ability to receive pertuzumab when I want to start chemotherapy.

For a symptomatic patient in the same scenario, I would administer trastuzumab and pertuzumab in combination with a taxane, which is highly likely to provide tumor reduction and reduce symptoms. It is also associated with an overall survival benefit. After the response plateaued, I would discontinue the chemotherapy and continue trastuzumab and pertuzumab.

I would administer endocrine therapy and trastuzumab in the asymptomatic scenario. The goal of therapy is to help patients live as long as possible and as well as possible. Because the patient is asymptomatic I can’t administer any therapy that would make her feel better. It would be tempting to add pertuzumab, but insurance approval would be difficult and that would add some toxicity, albeit minor.

I would offer the symptomatic 60-year-old patient with bone metastases trastuzumab and pertuzumab in combination with endocrine therapy. Because this patient is symptomatic, the increased toxicity is outweighed by greater benefit. Depending on how symptomatic the patient is and how quickly she became symptomatic I might consider trastuzumab and pertuzumab with weekly paclitaxel followed by continued biologic therapy and endocrine therapy after stopping the taxane.

For the asymptomatic patient, I would choose to administer trastuzumab and pertuzumab in combination with nab paclitaxel to avoid the toxicity of steroids. HER2-positive metastatic breast cancer to the bone is almost always symptomatic at presentation. However, if I were to see such a patient, my treatment would depend on whether she had locally advanced primary breast cancer that needed to be cytoreduced prior to surgery to achieve local control, which is usually the case, how strongly ER-positive the disease was, whether the disease was PR-positive and the grade of the cancer. In my experience, patients presenting with de novo HER2-positive metastatic breast cancer are pre- or perimenopausal with locally advanced disease and symptomatic bone metastases. I would choose the trastuzumab and pertuzumab combination along with nab paclitaxel to achieve good cytoreduction to allow for primary breast surgery. I would continue the 2 antibodies along with an aromatase inhibitor after surgery.

For a symptomatic 60-year-old patient, I would have the same recommendation. The factors that would influence my decision would be the grade of the tumor, whether tumor reduction prior to surgery was necessary and the level of hormone receptor expression. The combination of trastuzumab, pertuzumab and nab paclitaxel allows for good cytoreduction prior to surgery. I would opt to continue trastuzumab, pertuzumab and an aromatase inhibitor after surgery.

For this asymptomatic 60-year-old patient, I would administer trastuzumab and pertuzumab in combination with a taxane. A survival benefit was observed with this approach in the CLEOPATRA trial, and it is well tolerated. I prefer to use paclitaxel, but the sequencing is complex because pertuzumab is only administered every 3 weeks. I have administered paclitaxel for 2 weeks on and 1 week off to facilitate sequencing. I would follow her initial treatment with pertuzumab and trastuzumab with endocrine therapy. If the patient is interested in delaying chemotherapy I would consider trastuzumab with endocrine therapy alone. If allowed, I would also consider T-DM1 for this patient.

I would choose the same treatment approach for a symptomatic 60-year-old patient in this situation but would not follow it with endocrine and HER2-directed therapy. I would also consider T-DM1 if it were feasible. The results of the MARIANNE trial evaluating T-DM1 versus T-DM1 in combination with pertuzumab versus trastuzumab and a taxane will be critical to these discussions in the future.