Can Targeted Biologic Treatments Be Used Without Chemotherapy In Her2+ Cancers? Well, Yes And No.
Dual blockade with the targeted biologic therapies, trastuzumab and pertuzumab, has improved the prognosis of HER2-positive breast cancer. When first discovered, the presence of HER2 in a cancer gene was associated with a very poor prognosis. Since then, much has happened, as monoclonal antibodies have been developed to fight these very genetic defects. The treatments have been incredibly effective when used with chemotherapy, particularly paclitaxel (Taxol). Patients with a complete pathological response after neoadjuvant therapy have a significantly better prognosis. Furthermore, ER-negative (ER-) patients fare better than ER-positive ones.
German Professor/MD Nitz et al. (Lancet Oncology 23:2022) recruited patients for a trial comparing the complete pathological response (ypN0) in patients receiving dual anti-HER2 therapy vs. patients receiving the same biologic blockade plus paclitaxel, which is a standard chemotherapy treatment regimen. The WSG-ADAPT-HER2+/HR- trial fell under the larger ADAPT trial and took place at 40 breast cancer centers in Germany.
De-escalation (a reduction in the amount or duration of treatment) aims to reduce or eliminate the chemotherapy part of the treatment, which is generally responsible for the toxic effects of treatment. Randomization was stratified by center and clinical node status (N1, N2, and N3). Surgery was performed within three weeks after treatment, and a core needle biopsy was done if there was no evidence of no response by three weeks. A core needle biopsy was required within three weeks after the trial conclusion if further chemotherapy was planned, i.e., ado-trastuzumab (a combination of trastuzumab and chemotherapy on a single molecule). The researchers subtyped each cancer by using PAM50 testing.
Now is a good time to digress and discuss the treatment of HER2-positive breast cancer before these clinical trials. For most patients with HER2 amplification, chemotherapy is typically given before surgery and lasts between 12 and 20 weeks, depending on the regimen. Trastuzumab and pertuzumab, two of the available and most studied targeted therapies against the HER-2 gene, are given concomitantly with the chemotherapy and then continued for 12 months. The targeted therapies are usually given intravenously every three weeks.
The end-point compared the number of patients who had an early response (low cellularity or Ki67 decrease ≥30%) after three courses of therapy to those who had a complete histologic response.
In this study, the researchers investigated whether they could spare chemotherapy in a significant proportion of women with HER2 breast cancer that responded early and effectively to treatment with anti-HER2 therapies without compromising survival. The purpose of this study was to prove or disprove this hypothesis.
Those patients who had a complete pathological response (no tumor present after anti-HER2 or chemotherapy or both before surgery) had an excellent outcome even without chemotherapy. Over one-third of the patients had a complete pathological response with chemotherapy-free regimens containing trastuzumab plus pertuzumab alone. However, when the authors looked at the entire cohort of patients, not just those having targeted therapy, they saw that adding a single chemotherapy agent (paclitaxel) to trastuzumab plus pertuzumab dramatically increased the response of cancer to therapy. These excellent responses to chemotherapy occurred with only 12 weeks of treatment which is usually less than commonly given. Patients who received only targeted HER2 therapy had excellent survival rates even when nearly one-third did not receive chemotherapy (a far less toxic brew). Moreover, the standard course of these anti-Her2 therapies is approximately a year, yet these excellent results required only 12 weeks of treatment! The authors concluded “that polychemotherapy (multiple chemotherapy drugs) might not be required for most patients with HER-2 positive early breast cancer in the context of a highly effective HER-2 blockade, particularly in HER-2 positive and hormone receptor-negative disease”.
Dr. Alan Stolier, MD, FACS, clinical breast oncologist, shares his expert medical perspective with a series of educational and scientific articles.