Understanding HER2-Positive Metastatic Breast Cancer Treatments

HER2-positive metastatic breast cancer Alireza Nikanfar M.D. Medical Oncologist & Hematologist

Approximately 20 percent of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), a transmembrane glycoprotein epidermal growth factor receptor (EGFR) with tyrosine kinase activity. Historically, overexpression of this receptor was associated with an increased risk of disease recurrence and an overall worse prognosis.

A high level of HER2 overexpression, as determined by either 3+ staining by immunohistochemistry for the HER2 protein or evidence of HER2 gene amplification by fluorescence in situ hybridization (FISH ratio 2.0 or HER2 copy number 6.0), is a strong predictive factor for sensitivity to HER2- targeted agents. The use of HER2-directed therapy improves survival for patients with HER2-positive metastatic breast cancer.

HER2-directed agents Trastuzumab Trastuzumab is a monoclonal antibody that binds the extracellular domain of HER2. Formulations Subcutaneous forms of trastuzumab have received approval by the US FDA. Either formulation may be used in the metastatic setting.

Pertuzumab Pertuzumab is a monoclonal antibody that binds the extracellular dimerization domain of HER2 and prevents it from binding to itself or to other members of the EGFR family. It is administered in combination with trastuzumab rather than as a single agent in the treatment of HER2-positive breast cancer.

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of trastuzumab, a thioether linker, and the antimicrotubule agent DM1. The HER2-directed antibody-drug conjugates incorporate a cytotoxic agent, and therefore chemotherapy is not added.

Fam-trastuzumab deruxtecan (trastuzumab deruxtecan, or DS- 8201) Fam-trastuzumab deruxtecan is an antibody-drug conjugate composed of an anti- HER2 antibody , a cleavable tetrapeptide- based linker, and a cytotoxic topoisomerase I inhibitor. As with T-DM1, this conjugate incorporates a cytotoxic agent, and chemotherapy is not added.

Tucatinib Tucatinib is an oral tyrosine kinase inhibitor that is selective for the kinase domain of HER2, with minimal inhibition of EGFR. It is used in combination with capecitabine and trastuzumab.

Lapatinib Lapatinib is a tyrosine kinase inhibitor against EGFR1 and HER2 that results in inhibition of signaling pathways downstream of HER2, used in combinations with trastuzumab or capecitabine.

Neratinib Neratinib is an irreversible pan- HER inhibitor, used in combination with capecitabine. Margetuximab Margetuximab is an Fc- engineered anti-HER2-receptor monoclonal antibody used in combination with chemotherapy.

PREVIOUSLY UNTREATED PATIENTS Preferred option trastuzumab, pertuzumab, and a taxane (docetaxel or paclitaxel). The evidence to support the three-agent combination of trastuzumab plus pertuzumab and a taxane comes from the phase III CLEOPATRA trial.

Alternatives Ado-trastuzumab emtansine (T-DM1) The role of T-DM1 as a first-line treatment of advanced or metastatic HER2-positive breast cancer was evaluated in the phase III MARIANNE trial. Single-agent trastuzumab, or trastuzumab plus pertuzumab For patients who want to avoid cytotoxic chemotherapy, in particular if they do not have visceral disease .

hormone receptor-positive disease While most patients are treated in the first line with a HER2-directed agent plus chemotherapy, HER2-directed therapy in combination with endocrine therapy is an acceptable alternative for those whose disease is not rapidly progressive or symptomatic, or is not characterized by significant visceral involvement (ie, multiorgan metastases).

For premenopausal women ovarian suppression or ablation in combination with endocrine therapy and HER2-directed (an aromatase inhibitor (AI) over therapy). For postmenopausal women administration of HER2-directed therapy plus an AI tamoxifen.

PATIENTS WHO RECEIVED (NEO)ADJUVANT HER2-DIRECTED THERAPIES

Treatment-free interval of six months or longer Taxane plus trastuzumab and pertuzumab T-DM1 is now used as adjuvant therapy if there is not a complete pathologic response to neoadjuvant taxane, trastuzumab, and pertuzumab. For such patients as well, it is appropriate to return to taxane, trastuzumab, and pertuzumab for treatment.

Treatment-free interval of less than six months T-DM1 if it has not already been given in the adjuvant setting . For those patients with progression on or within six months of adjuvant T-DM1, multiple options exist.

DURATION OF TREATMENT Optimal treatment duration of chemotherapy After achievement of best response to treatment (usually after 6 to 12 months of combined therapy), discontinue cytotoxic chemotherapy and continue trastuzumab.In HR+ patients add ET. Optimal treatment duration of a HER2-directed agent should be individualized. Anti-HER2- directed therapy can be continued for years .

SECOND- OR LATER-LINE TREATMENT Preferred option: T-DM1. This recommendation is based on two phase III trials, the TH3RESA trial(Comparison with clinician's choice of treatment) and the EMILIA trial (Comparison with lapatinib plus capecitabine).

After progression on ado-trastuzumab emtansine Fam-trastuzumab deruxtecan risk of pulmonary toxicity Fam-trastuzumab deruxtecan should be permanently discontinued if grade 2 or higher interstitial lung disease/pneumonitis develops.

Tucatinib, capecitabine, and trastuzumab Margetuximab is a relatively newer agent with only modest benefits over trastuzumab. Trastuzumab with cytotoxic agents As an alternative to options described above, a reasonable strategy after progression on trastuzumab/pertuzumab chemotherapy regimens and T-DM1 is to resume trastuzumab with a different cytotoxic agent.

Lapatinib plus trastuzumab is an option for patients whose disease has progressed on trastuzumab, and is particularly attractive for patients who wish to avoid, or are not candidates for, chemotherapy.

Tyrosine kinase inhibitor plus capecitabine Both lapatinib and neratinib have been studied in combination capecitabine, and these combinations are appropriate later-line options . A benefit is they allow avoidance of infusional therapy. Another advantage is the theoretic diffusion across the blood-brain barrier. A prospective randomized clinical trial has demonstrated that neratinib is more effective than lapatinib when combined with capecitabine. (NALA trial)

Lapatinib plus capecitabine is an option for patients who experience disease progression on trastuzumab, particularly if they prefer an orally administered regimen and do not tolerate neratinib.

Cardiotoxicity Trastuzumab-related cardiotoxicity is most often manifested by an asymptomatic decrease in LVEF and less often by clinical heart failure. Cardiotoxicity does not appear to be related to cumulative dose. It is often reversible with treatment discontinuation, and rechallenge is often tolerated after recovery.

Risk factors associated with a higher likelihood of developing trastuzumab-related cardiotoxicity include age greater than 50 years and previous or concurrent anthracycline use, particularly among obese or overweight patients. By contrast, concurrent treatment with trastuzumab and adjuvant radiation therapy does not increase the risk.

In contrast to trastuzumab, the risk of cardiotoxicity seems to be less with other (HER2)-targeted agents, such as lapatinib, ado-trastuzumab emtansine (T- DM1), and pertuzumab. There is a potential risk of cardiotoxicity with all agents.

In the adjuvant setting, a baseline assessment prior to starting trastuzumab and serial LVEF monitoring (at 3, 6, and 12 months after initiating trastuzumab ) are appropriate to screen for cardiac dysfunction. In the metastatic setting, after a baseline assessment, LVEF is infrequently monitored in the absence of symptoms.