Keytruda (pembrolizumab) may not be effective in Lynch syndrome patients — those with inherited mutations in certain DNA repair genes — who develop Cushing’s syndrome due to cortisol-secreting metastatic adrenal cancer, a case report suggests.
The report, “Rapid disease progression in a patient with mismatch repair-deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab,” appeared in Seminars in Oncology. The work was led by the Cambridge University NHS Foundation Trust in the United Kingdom.
DNA mismatch repair (MMR) genes provide instruction for the making of the proteins responsible for repairing errors that occur during the normal production of a newly synthetized DNA strand, playing a key role in the upkeep of genetic information.
Last year, the U.S. Food and Drug Administration approved Keytruda (pembrolizumab) for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors with specific genetic features, including MMR deficiencies.
MMR-deficient cells lack proper DNA repair mechanisms and frequently have many DNA mutations, which can turn a healthy cell into a cancerous one, and therefore lead to cancer. This also means that cancer cells will have a lot of mutated proteins, which facilitates the job for the immune system.
Keytruda is an anti-PD-1 cancer immunotherapy meant to unleash the full power of the immune system onto cancer cells. PD-1, a protein found on T-cells, helps control the body’s immune responses. When PD-1 is bound to another protein, known as PD-L1, at the surface of cancer cells, T-cells fail to recognize and eliminate the abnormal cells.
By blocking PD-1 so that PD-L1 doesn’t have the chance to bind to it, the body’s natural immune response is not blocked, and T-cells are able to destroy cancer cells.
“Recent landmark studies have now demonstrated that MMR-deficient tumors are more responsive to PD-1 blockade with the anti-PD-1 antibody pembrolizumab than MMR-proficient tumors, with response rates exceeding 50%,” the researchers wrote.
In this case report, investigators described a 58-year-old woman with Lynch syndrome — an inherited cancer predisposition condition caused by mutations of MMR genes, in this case the MSH2 gene — who complained of progressive weight gain and reduced mobility for the past two years.
The woman’s reproductive organs (uterus, fallopian tubes, and ovaries) were previously removed due to a precancerous condition of the cervix, also known as cervical cell dysplasia.
She was obese and had high blood pressure (165/130 mmHg), excessive body hair, a swollen red appearance with bruising, and noticeable proximal muscle weakness.
Biochemical assessment showed elevated concentrations of androgens (male sex hormones), high amounts of circulating cortisol and normal levels of adrenocorticotrophic hormone (ACTH) — which usually drives cortisol production — suggesting an independent source for the excess cortisol.
A computed tomography (CT) scan revealed an 11×7 cm tumor in the left adrenal gland without evidence of metastasis. As a result, the patient had her left adrenal gland and kidney surgically removed.
Researchers reported that “examination of the resected tumor confirmed a stage III [adrenocortical carcinoma],” meaning it was a large mass that could have started to spread to surrounding tissue or nearby lymph nodes. Further analysis showed that besides MSH2, the MSH6 gene was also mutated and its expression compromised.
The patient was started on mitotane — a chemotherapy most often used for people with adrenal cancer — accompanied by hydrocortisone replacement therapy to avoid symptoms of adrenal insufficiency.
“Three months following surgery, the patient developed worsening abdominal pain,” the researchers wrote. A CT scan showed tumor recurrence in the same anatomical region plus liver metastasis.
Given the patient’s MMR-deficient tumor history, she was started on Keytruda treatment in combination with mitotane.
After the first cycle of Keytruda, she had a mild elevation of serum alanine aminotransferase (ALT), an enzyme mainly found in the liver, which was suggestive of liver damage.
Because mitotane can be toxic to the liver and cause elevated serum ALT levels, the clinical team stopped treatment with the chemotherapy and delayed the second cycle of Keytruda.
Her liver function had improved, meaning the ALT levels had decreased, after 14 days, and continued to do so until the next examination nine days later.
She received a second round of Keytruda and experienced significant side effects including nausea, vomiting, and fatigue, which led to poor treatment tolerance but did not further disturb her liver function.
At 12 weeks into the treatment regimen, a new CT scan showed “significant disease progression, with both rapidly increased size of the relapsed disease at the primary site and multiple new liver metastases,” according to the researchers.
Treatment with Keytruda was discontinued, and doctors focused on providing the best supportive care for her.
Almost two months later, the patient developed jaundice, a yellowing of the skin and whites of the eyes, and significant liver damage with a limited increase in the size of liver metastases.
“The possibility of pembrolizumab-induced autoimmune hepatitis could not be excluded,” according to the researchers, so they started a new treatment protocol accordingly.
Three days later, the woman died from fulminant (acute) liver failure. An autopsy was not performed.
Investigators concluded that “treatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to [high] levels of circulating corticosteroids, which may in turn mask severe drug-induced organ damage.”
But they also caution that “no single case should be used to argue against recommendations based on comprehensive scientific and clinical investigation,” but some “cases can serve as a salutary reminder that there can be exceptions to the rule.”