Peritoneal mucinous carcinomatosis refers to a rare tumor of the peritoneum – the membrane that covers the abdominal cavity and the viscera it contains. This form of cancer starts in the appendix and is often resistant to standard chemotherapy. A clinical trial today brings new hope to patients. A drug already used to treat breast cancer has shown that it also has the potential to slow the progression of this tumor.
The ileocaecal appendix is a small outgrowth of the cecum (the first part of the colon). It measures 5 to 12 centimeters long and about 5 millimeters in diameter. His role within the organization is unclear. The latest research suggests that it serves as a reservoir of beneficial intestinal bacteria. It would also be an important element in the immune function of the mucous membranes. The sudden inflammation of this diverticulum, which we call “appendicitis”, is well known.
Appendix cancers are much rarer, accounting for less than 1% of all gastrointestinal cancers. L’American Cancer Society estimates that less than 2,000 cases are diagnosed each year in the United States. Most often, these cancers do not cause any symptoms. The diagnosis is usually made during an appendectomy or medical imaging of the abdomen. Therefore, the cancer may already be at an advanced stage, limiting treatment options. A subset of peritoneal mucinous carcinomatosis (PMC) proves particularly difficult to treat.
Mutations responsible for several cancers
There is a link between this subset and mutations in the GNAS oncogene. The latter encodes a protein which is involved in transmembrane signal transduction. Mutations in this gene appear in several other types of cancer (colon, bone, pituitary, testes). For CMP patients with this mutation, outcomes are generally poor. Conventional cytotoxic chemotherapy proves ineffective.
Experiences carried out on cultures of CMP type cancer cells and tumor tissues ex vivo however, suggested that one drug could be a game-changer: palbociclib. It is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4, CDK6) – proteins necessary for the cell cycle. Developed by the Pfizer laboratory, it is authorized by the Food and Drug Administration in the United States since February 2015 for the treatment of hormone-dependent (HR+), metastatic and advanced breast cancer. He is also authorized in France since 2017.
Researchers at the University of California San Diego School of Medicine conducted a study to evaluate the clinical effectiveness of palbociclib monotherapy in appendix cancer patients with the GNAS mutation. For this trial, they recruited 16 patients. They established for each, the genomic profile of the tumor tissue and/or circulating tumor DNA. They also assessed the expression of PD-L1 (a programmed cell death ligand, highly expressed on the surface of several cancer cells) and the mutational load of the tumor.
The disease had already progressed in 12 of the 16 patients after at least one prior line of chemotherapy. The primary tumor was located in the appendix in 13 patients, in the pancreas in another. Its location remained unknown in the last two patients. Eleven cases were low-grade tumors; the other five were of high rank. All participants took oral palbociclib daily.
Tumor markers reduced by more than 50%
The results of this clinical trialpublished in the Journal of Clinical Oncologyshowed that palbociclib stabilized tumor growth and reduced the levels of blood tumor markers in patients.
More specifically, the team observed a decrease in carcinoembryonic antigen (CEA) in 13 participants (80% of cases). In six of them, this rate even decreased by more than 50%! ACE is a protein produced by the fetus; it is involved in the cell adhesion mechanism. Normally, it is detected in very small amounts in the blood of adults. On the other hand, an increase in the blood level of CEA can indicate the presence of cancer.
Lab results also showed that the drug slowed or stopped the growth of cancer cells. Researchers report that 50% of evaluable patients had stable disease after 12 months of palbociclib treatment. This drug thus appears to be a well-tolerated alternative to intraperitoneal chemotherapy. This is good news knowing that it often causes serious side effects.
Inhibition of CDK4/6 by palbociclib therefore showed clinical activity in PMCs characterized by GNAS mutations superior to that previously reported with cytotoxic chemotherapy. “ CDK4/6 inhibition is a novel therapeutic strategy that merits further evaluation in this subgroup of gastrointestinal neoplasms », conclude the researchers.
Hope for other rare cancers
« The success of a breast cancer drug in treating a subset of appendix cancer – for which treatment options are currently limited – marks a significant advance in our fight against this disease. This advance constitutes the first targeted therapy for this rare cancer », said Dr. Andrew Lowychief of the division of surgical oncology at the UC San Diego School of Medicine and corresponding author of the study.
The advantage of palbociclib is that it is already on the market. Thus, this drug can be used immediately in CMP patients carrying the GNAS mutation. There is no point waiting for the development of a new drug or approval from health authorities, says Dr. Shumei Kato, an oncologist at UC San Diego and co-author of the study.
This trial once again highlights the potential of recently developed anticancer treatments. The results open a promising new era for the treatment of appendix cancer, but potentially also for other rare cancers with similar genetic mutations. “ NOur clinical researchers are leading trials that identify promising new treatments and provide hope to patients who previously had few options “, emphasizes Diane Simeone, director of the Moores Cancer Center at UC San Diego Health, which aims to discover new advanced treatment options.
The researchers now plan to determine how best to combine palbociclib with traditional chemotherapies and/or new targeted therapies to further improve its effectiveness.
