The receptors in the human epidermal growth factor receptor 2 (the HER2 ) gene are active participants in determining whether healthy breasts can repair themselves.
According to a recent article in TargetedOncology, between ten to forty percent of breast tumors are overexpressed (make excessive copies). Therefore, these tumors will not be as responsive to the most common therapies used in treating breast cancer.
There is widespread consensus that HER2 positivity has predictive value regarding patients’ response to chemotherapy. However, since patients’ response to chemotherapy depends on disease characteristics, the subject as a whole remains controversial.
About Trastuzumab (Herceptin)
Trastuzumab was FDA approved in 1998 as an addition to cytotoxic chemotherapy to treat HER2-positive breast cancer. The N99831 trial (NCT00005970) showed positive results in overall survival.
Trial results showed a ten-year disease-free survival rate when trastuzumab was added at 73.7%. This was compared to 62.2% for chemotherapy as a single agent. The overall survival rate (OS) during that same period was eighty-four percent versus seventy-two percent for chemotherapy used as a single agent.
(additional information on all clinical trials is available by accessing: www.clinicaltrials.gov)
About Individualized Treatment
Dr. Kari Wisinski, an oncologist at Wisconsin University’s Cancer Center, told Targeted Oncology that individualized treatment should be based on tumor size, hormone receptor status, and lymph node status.
Dr. Wisinski’s opinion was seconded by Dr. Sara Tolaney, a senior physician at Dana-Farber’s Cancer Institute. Dr. Tolaney agreed that individualizing treatment would decrease toxicity and improve outcomes.
Many of the newly-approved targeted therapies for HER2 include trastuzumab. Some of these therapies are slated to be used after the completion of trastuzumab treatment.
About the New Targeted Therapies
- pertuzumab (Perjeta) is an anti-HER2 monoclonal (single-cell line) antibody administered either before or after the primary cancer treatment
- neratinib (Nerlynx) is a tyrosine kinase inhibitor; tyrosine kinases are enzymes that are involved with many cell functions such as growth, signaling, and division. They can become too active and may be found in cancer cells; neratinib can block these cells. It has been approved for use following one year of treatment with trastuzumab
- KADCYLA® – (trastuzumab emtansine) the chemical name is T-DM1, and the drug was initially FDA-approved six years ago to treat metastatic HER2-positive breast cancer. Last year it received expanded approval to be used as a post-surgical treatment for less advanced breast cancer when trial results showed that T-DM1 reduced the risk of death or of cancer returning by fifty-percent when compared to trastuzumab.
I-SPY-2: A Revolutionary Trial
Over four thousand HER2-positive patients were included in the I-SPY-2 trial that involved a series of smaller studies. The trial compared novel drugs plus chemotherapy with trastuzumab plus paclitaxel. These two drugs were in turn followed by cyclophosphamide and doxorubicin.
The trial is one of the longest-running trials ever. I-SPY 2 involves the study of multiple combination therapy arms. In addition, the trial does not require resubmission or halting enrollment when new drugs enter or leave the study.
Additional Vaccine Therapies
Additionally, the following vaccine therapies are being investigated in phase 1/2 trials:
- NCT0338755 and NCT03384914 – dendritic cell vaccines
- NCT03894007 – Phase 2 involving trastuzumab plus chemotherapy administered before surgery
Immunotherapy Agents Under Investigation
A therapeutic treatment strategy that had shown efficacy in connection with other diseases is immune checkpoint inhibitor monotherapy. Another strategy is the combination of chemotherapy and immunotherapy.
The Phase 2 (NCT03747120) multicenter trial of paclitaxel and pembrolizumab versus single-agent pembrolizumab is a study of immunotherapy agents that are under investigation in the early stages of HER2-positive breast cancer.
NCT03742986 is a Phase 2 Opdivo clinical trial that is investigating inflammatory breast cancer as well as HER2- positive breast cancer.
NCT03620201 is evaluating patients with stage II or III HER2-positive breast cancer. Early in the study, the researchers will analyze M7824, which is a fusion protein that treats advanced cancers by inhibiting tumor growth.
Trastuzumab: Escalating vs Descalating Treatment
Dr. Wiscinski acknowledged that trastuzumab is now the standard chemotherapy backbone for HER2-positive breast cancer. With that in mind, Dr. Wiscinski discussed using the drug for purposes of de-escalation.
She envisions genomic markers that could identify which patients may need more or which patients need less chemotherapy. Dr. Wiscinski points out that although at times using the strategy of escalation treatment is required, other times de-escalation may be more appropriate.
Dr. Tolaney joined the discussion by saying that it is optimal to tailor preoperative therapy by escalating treatment for patients who have residual disease. If patients have exhibited a complete response, then de-escalation is appropriate.
Currently, the following studies are investigating trastuzumab in connection with de-escalation: NCT04266249, NCT02907918, and NCT03644186.
Dr. Wiscinski acknowledged the many challenges that currently exist but she trusts that this strategy will be explored in the future.