Recently, the US Food and Drug Administration (FDA) approved Lynparza (Olapali) for the treatment of metastatic breast cancer carrying the germline BRCA gene mutation (gBRCAm) and human epidermal growth factor receptor 2 (HER2) negative. Patient.
This is the third indication that Olapali was approved in the United States. In the United States, Olapali has been used to treat nearly 4,000 patients with advanced ovarian cancer, and the approval of this new indication has brought a new gospel to breast cancer patients with BRCA mutations, which will definitely redefine the late stage. The treatment path for breast cancer.
What is the germline BRCA mutation?
The occurrence and development of breast cancer are the results of multiple factors such as genetic factors, hormone levels, immune status, physiological conditions, living habits, and environment. These factors lead to gene mutations in normal cells, induction of oncogene activation or inhibition of tumor suppressor genes.
The most famous gene mutation associated with breast cancer is the germline BRCA mutation. The study found that BRCA germline mutations are derived from germ cell mutations and are inherited to the next generation, so ovarian cancer carrying BRCA germline mutations has a distinct family. Genetic predisposition.
Therefore, breast cancer patients and people with high-risk factors should recommend the detection of BRCA gene.
The NCCN guidelines recommend for BRCA mutation testing:
- The BRCA1/2 mutation has been identified in the family
- the age of onset of breast cancer is earlier (≤45 years)
- the triple-negative breast cancer is ≤60 years old
- the primary tumor of breast cancer is≥2
- breast cancer of any age is accompanied by ≥1 close relative of breast cancer diagnosed age ≤50 years old, or ≥1 close relative are diagnosed with ovarian cancer at any age, or ≥2 close relatives are diagnosed with breast cancer, pancreatic cancer or prostate cancer at any age, or from high-risk Family
- male breast cancer
The BRCA gene is divided into BRCA1 and BRCA2, which are two important tumor suppressor genes located on chromosomes 17 and 13 of a human nucleus. The proteins they produce are used to repair DNA damage and play an important role in maintaining the genetic stability of the cells. If any of these genes are mutated or altered, DNA damage may not be properly repaired, resulting in impaired cell stability and the possibility of additional genetic alterations leading to cancer.
The most famous carrier of the BRCA gene is the Hollywood actress Angelina Jolie. Because she was found to carry the BRCA gene inherited from her mother, her risk of breast and ovarian cancer was as high as 87% and 50%, so Julie chose to start with a strong first, at the age of 37, prophylactic resection of the bilateral breast, 39 Years old and preventive removal of the ovaries, shocked the world!
What is “HER2 negative breast cancer” and “three negative breast cancer”?
The three receptors that drive breast cancer growth are estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2). Breast cancer patients will be tested for these three receptors at the time of diagnosis. According to the receptor and gene mutation, breast cancer is divided into four types: lumen Luminal A, Luminal B, HER2 positive, and triple-negative breast cancer.
HER2-negative breast cancer refers to a type of breast cancer that does not have HER2 overexpression. Among them, some patients, not only have no overexpression of HER2, but also ER and PR are negative, which is the “three-negative breast cancer” that people smell. The famous singer Yao Beina was taken away by the Sanyin breast cancer for a young life.
Three-negative breast cancer accounts for about 15-20% of all breast cancers. It is more common in young patients, and the probability of recurrence and the probability of distant metastasis are higher than those of non-three-negative breast cancer. Moreover, due to the lack of effective treatment, chemoradiotherapy can only be performed at present, and the prognosis is very poor.
What is metastatic breast cancer?
Metastatic breast cancer is the most advanced stage of breast cancer. At this stage, cancer cells have spread to other parts of the breast, most commonly the lungs, brain, and bones.
In the past three decades, despite the increase in related treatment options, there are currently no drugs that can cure patients with metastatic breast cancer. After diagnosis, only 26.9% of patients survived for more than five years. Therefore, the main purpose of treatment is to delay the progression of the disease as much as possible and to improve or at least maintain the quality of life of the patient.
What is the efficacy of Olapali?
The FDA approved Olapa for the use of BRCA mutations, HER2-negative metastatic breast cancer, based on the drug’s OlympiAD Phase III trial data.
OlympiAD is a randomized, open-label, multicenter phase III trial designed to evaluate olaipril tablets (300 mg twice daily) against a “doctor’s choice” chemotherapy regimen (capecitabine, vinorelbine) Or Erebrin) for the efficacy and safety of patients with HER2-negative metastatic breast cancer with germline BRCA1 or BRCA2 mutations.
302 patients from 19 countries in Europe, Asia, North America and South America participated in the trial. About half of them (152) were estrogen or/and progesterone receptor positive, and the other half (150) were triple negative. 205 patients were assigned to the olalapril treatment group.
These patients received anthracyclines (unless contraindications) and taxane chemotherapy in neoadjuvant, adjuvant, or metastatic settings prior to enrollment in clinical trials, and chemotherapy regimens previously used to treat metastatic disease did not More than two. Hormone receptor-positive patients require at least one endocrine therapy and disease progression during endocrine therapy or have been shown to be unsuitable for endocrine therapy. Previous treatment regimens using endocrine drugs were not considered a previously used chemotherapy regimen.
Figure 2 Comparison of PFS between Olapali group and chemotherapy group in OlympiAD trial
Figure 3 Cover of the article published in NEJM magazine
The results of the trial showed that olalapril significantly prolonged the progression-free survival of 2.8 months (median 7.0 months vs 4.2 months) and reduced the risk of disease progression or death by 42% compared with the chemotherapy group; 167 patients who could measure the lesions took olipalic, and the objective response rate reached 59.9%, while the objective response rate of 66 patients in the chemotherapy group was only 28.8%. Among them, the complete response rate of patients in the olalapril group was as high as 9 %, while the chemotherapy group was only 1.5%.
In terms of safety, the proportion of side effects of grade 3 or higher was 36.6% in the olaapali group and 50.5% in the chemotherapy group. Considering that patients who participated in the trial were relapsed or resistant, and lacked effective treatment, the prognosis was poor. This improvement is very meaningful.
Data on the OlympiAD trial was published in the June 2017 issue of the New England Journal of Medicine.
What kind of medicine is Olapali?
Olapali has been the “magic drug” in the minds of patients with ovarian cancer. This AstraZeneca star drug was approved for marketing in the United States at the end of 2014, becoming the world’s first listed PARP inhibitor.
The FDA-approved indication is for the treatment of patients with advanced ovarian cancer with BRCA germline mutations that have failed at least 3 chemotherapy treatments. In August 2017, the FDA expanded the indications for olaparibis and approved for the treatment of adult ovarian epithelial cancer, fallopian tube cancer, and primary peritoneal cancer in response to platinum-based chemotherapy (whether or not there is a BRCA detection mutation). Second line maintenance treatment.
The most common adverse events (≥20%) in patients receiving olapaci include nausea (58%), anemia (40%), fatigue (including weakness) (37%), vomiting (30%), neutrophil Agranulocytopenia (27%), respiratory infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).
In the olapali treatment group of the OlympiAD Phase III trial, the proportion of patients who discontinued treatment was 5%, compared with 8% in the chemotherapy group.
Why is Olapali effective?
Olapali is a PARP inhibitor, which, as its name suggests, acts to inhibit the function of the PARP protein. PARP and BRCA are the two main types of proteins responsible for repairing DNA mutations in cells, and they are the “left and right protection methods” that protect our cells.
The BRCA1/2 gene and PARP are responsible for a DNA repair pathway, respectively. If the cancer cells have BRCA1/2 gene mutation (in principle, both blast mutation and somatic mutation can be used), and then another PARP inhibitor such as olalapril will be used. When the DNA repair pathway is blocked, both DNA repair pathways are blocked, DNA cannot be repaired in time, and cancer cells are apoptotic. However, even if the normal cells encounter the PARP inhibitor, because the BRCA protein is still present, the DNA can be repaired normally and survived.
Olapali tears open the crack of “refractory metastatic breast cancer”
Metastatic breast cancer is the most advanced stage of breast cancer. The limitation of treatment means that the 5-year survival rate of patients is only 26.9%, especially for triple-negative breast cancer which is considered to be extremely dangerous and prone to metastasis. The treatment of curative effect is mainly based on chemotherapy, endocrine therapy and molecular targeted therapy. The survival time of patients is often short, and the approval of the new indication for the targeted oral drug olalapril means triple negative metastatic mammary gland. The patient has new hopes.
In addition, this is also good news for patients who are HER2-negative, ER- and PR-positive, because if such patients have a positive BRCA gene test, they may also be suitable for treatment with olapali.
Breast and ovarian cancer are the main arenas of this type of PARP inhibitor, but its value goes far beyond that.
On the one hand, BRCA mutant tumors are widespread, including prostate cancer, fallopian tube cancer, lung cancer, and pancreatic cancer.On the other hand, even patients without BRCA mutations can benefit. PARP inhibitors may be effective against tumors with “homologous recombination defects”, and BRCA mutant tumors are only a part of them. Scientists have discovered a number of “like BRCA mutant tumors”, which do not have BRCA mutations themselves, but the molecular mechanisms of the disease are similar, and PARP inhibitors are also applicable.
In addition, BRCA gene mutation detection will become a key step in the treatment of tumors. The detection of BRCA mutations in cancer patients can help to better judge the prognosis, the selection of targeted drugs, the choice of chemotherapy regimens, and the risk assessment of family members of family genetic history, helping doctors to select more precise based on the patient’s genetic characteristics. Treatment plan.
Currently, olalapril is being used in the treatment of a series of “homologous recombination-deficient” tumors. There is no doubt that more and more patients will benefit from new drugs such as PARP inhibitors.