Before the advent of HER2-targeted therapy, HER2-positive breast cancer was characterized as the breast cancer subtype with the worst prognosis.
The dual blockade of the HER2 receptor with pertuzumab (Perjeta) and trastuzumab (Herceptin), along with chemotherapy, represented highly relevant clinical progress in breast cancer patients, significantly enhancing the clear benefit Herceptin already offers. This combination was first approved for the treatment of the metastatic stage of HER2 positive breast cancer, thanks to the results seen in the CLEOPATRA study.
The metastatic stage of breast cancer is currently incurable. The goal of treatment is to extend survival and improve patients’ quality of life.
However, despite this circumstance, after more than 8 years of follow-up (final analysis of the CLEOPATRA study1published in 2020 in ‘Lancet Oncology’), a highly relevant clinical benefit is still observed with the anti-HER2 dual block in metastatic breast cancer. And it is that with the combination of trastuzumab (Herceptin) and pertuzumab (Perjeta), an increase in overall survival in these patients is statistically significant and clinically relevant of 16.3 months, with a median of 57.1 months. In addition, 37% of patients treated with this combination, despite metastatic and therefore incurable, are still alive after more than 8 years of follow-up and 16% have not progressed to first-line treatment.
Cleopatra Investigation1. Overall survival – final analysis of the study
Ana Lluch is coordinator of the Breast Cancer Research Department at Hospital Clínico Universitario de Valencia. The oncologist discusses the good results they get by treating their patients with the combination of trastuzumab and pertuzumab.
ASK. How is a patient diagnosed with HER2 positive breast cancer?
ANSWER. The way of diagnosing breast cancer has evolved in recent years and we are currently differentiating into subgroups of patients, based on their biological assessment (immunohistochemistry) or based on genomic platform (mammaprint). For example, we determine that a patient has luminal breast cancer when the growth of her cells depends on hormones. We call breast cancer HER2 when the cells of this tumor express receptors called HER2 on the surface. These patients are treated differently from other subgroups of patients. In this way, today we attach more importance to that biology of cancer cells than to other characteristics of it that have traditionally been taken into account.
Q. Is there a predisposition to this type of cancer?
R. There is no predisposition, nor can we predict which patient will be HER2 positive or not. The same does not happen if the patient was triple negative, since women with hereditary breast cancer are predictably triple negative.
Ana Lluch is coordinator of the Breast Cancer Research Department at Hospital Clínico Universitario de Valencia
Q. Could anti-HER2 therapy be said to have changed the natural history of metastatic disease? What has the use of Herceptin and Perjeta meant for the evolution of this disease?
R. The diagnosis of this type of breast cancer has changed the history of metastatic disease in these patients. In the past, we could only offer them chemotherapy. Since we have the anti-HER2 treatment (about 10 years), this natural course of breast cancer patients and this tumor subtype has radically changed. These patients survive much longer and these results have never been seen in patients with metastatic breast cancer. With the double combination treatment, trastuzumab (Herceptin) and pertuzumab (Perjeta), along with chemotherapy (docetaxel), they were found to survive an average of 5 years. It doesn’t matter what kind of metastasis they have (liver, lung, bone). There are currently no HER2 positive metastatic patients not treated with this combination.
P. In the Cleopatra study, after more than 8 years of follow-up, 37% of patients treated with Perjeta are still alive and 16% have not progressed, showing that these patients continue to benefit from clinical benefit many years later. What implications do these results have for patients and what do you think there is a high percentage of survivors after 8 years?
R. The Cleopatra study has shown that the combination of these two monoclonal antibodies along with chemotherapy prolongs patients’ lives. This in metastatic breast cancer is not easy to achieve because most medications tend to lengthen the time the patient is without disease progression but increase overall survival, that is, the total number of years the patient lives to enlarge is more difficult and with the combination it has been achieved. As for the implications for patients, they are many. While we don’t think a year or two matters, it is of great value to them, especially since they are drugs that have few side effects and are very well tolerated. They also don’t suffer from chemotherapy alopecia, and the treatment doesn’t cause nausea or vomiting. The most important thing to watch out for is possible cardiac toxicity. It is a treatment that can usually be carried out for a long time without side effects.
Q. Regarding the safety profile, especially the cardiac profile, what conclusions do the results of the final analysis of the Cleopatra study show?
R. Cardiac toxicity is not a major concern because it is not permanent, but reversible. If we determine that the patient has this toxicity, we stop its administration for two or three months and in this way the patient restores her heart function.
Q. What does it mean to you to have a therapeutic option in metastatic disease, such as the combination of Perjeta and Herceptin?
R. it was one before and one after. Today we couldn’t stop taking this drug because if a HER2 positive patient comes up with metastasis, we know we have drugs that can control and prolong her life. In addition to the benefits of these drugs in metastatic patients, it should be noted that they have very good results in women with non-metastatic breast cancer. If we give this treatment before surgery, there are 60-65% of patients who operate after a few months, the tumor is neither in the breast nor in the armpit, which is called complete pathological remission.
1. Pertuzumab, trastuzumab, and docetaxel for HER2 positive metastatic breast cancer (CLEOPATRA): end-of-trial results of a double-blind, randomized, placebo-controlled phase 3 study. Swain SM, et al. Lancet Oncol 2020; 21: 519-530.
2. Perjeta technical sheet and Herceptin technical sheet