Managing Hormone Dysfunction-Related Adverse Events of Immunotherapy for Breast Cancer Treatment

Immune checkpoint inhibitors (ICIs) have improved short and long-term survival for many previously difficult-to-treat triple negative breast cancers (TNBCs). Recently, the combination has yielded significant response to neoadjuvant treatment. Yet the unique mechanism of ICIs result in unique adverse events, often long after treatment is initiated.

Immunotherapy vs. chemotherapy

Chemotherapy and immunotherapy are two current options to systemically treat breast cancer. Traditional cytotoxic chemotherapy works by killing rapidly dividing cancer cells using various mechanisms of DNA damage, cell death and prevention of cell replication. while ICIs exert their anti-tumor effect by targeting inhibitory immune checkpoints such as programmed death cell PD1.

Understanding endocrine ICE-related adverse events

The exact mechanism of ICI-related toxicity or immune-related adverse events (IRAEs) remains unclear, but it is believed that that by inhibiting immune checkpoints, ICIs dysregulate immune homeostasis. Endocrine toxicity is a well-recognized class of IRAEs and unlike other IRAEs which may be temporary with resolution of symptoms on therapy discontinuation, endocrine IRAEs are often permanent and require lifelong hormone replacement. It should be noted that endocrine dysfunctions can be “primary,” involving the primary endocrine organ, or “central” or “secondary,” involving the pituitary hormone in the brain that is responsible for regulating hormone secretion from the adrenal, thyroid, or sex hormones, among others.

Thyroid dysfunction: Primary thyroid dysfunction can present as hypothyroidism or hyperthyroidism. The mechanism is not well understood but it is thought to involve T-cell regulation. Hypothyroidism can often be asymptomatic or present with symptoms of cold intolerance, constipation and fatigue. Primary hypothyroidism is characterized by low free thryoxine (FT4) and elevated thyroid stimulating hormone (TSH). In mild cases, immunotherapy can be continued with levothyroxine replacement and close follow up of thyroid hormone levels to ensure improvement in thyroid hormone levels with supplementation.

Hyperthyroidism (thyrotoxicosis) often presents with symptoms of palpitations, insomnia and anxiety. Labs would show a high FT4 and low TSH level. This is typically managed with control of symptoms with a beta-blocker. “For both hypo- or hyper-thyroid scenarios, we recommend involving our endocrinology colleagues early for close follow up symptoms, laboratory levels and guidance on medication dose adjustments, which often is needed,” says Azka Ali, MD, a hematologist/oncologist at Cleveland Clinic Cancer Center. “Interestingly, immunotherapy-related hyperthyroidism often ‘burns out’ to hypothyroidism and in those situations, patients would need eventual thyroid replacement similar to hypothyroidism.

Secondary or central hypothyroidism presents with low TSH and low resultant FT4, and would often need levothyroxine supplementation similar to primary hypothyroidism. When secondary or central hypothyroidism is suspected, patients must be worked up for hypophysitis or pituitary dysfunction to evaluate further hormonal imbalances. “In line with recommendations of the National Comprehensive Cancer Network (NCCN), we recommend baseline testing of TSH and free T4, follow up testing every 4-6 weeks during immunotherapy every 12 weeks afterwards as clinically indicated,” says Dr. Ali.

Adrenal insufficiency. Symptoms of adrenal insufficiency would include hypotension, orthostasis and low levels of electrolytes. Because of hypotension, primary adrenal insufficiency can often masquerade as sepsis or infection. In primary adrenal insufficiency, labs would show a low morning cortisol level and a high adrenocorticotropic hormone (ACTH) level. Primary adrenal insufficiency from immunotherapy is rare.

As the adrenal gland is responsible for producing the body’s natural glucocorticoids and minerolcorticoids, both of those should be supplemented as treatment.

Secondary adrenal insufficiency would result from hypophysitis ICI therapy. Labs would indicate a low ACTH and a resultant low morning cortisol. When suspecting secondary adrenal insufficiency, one should be looking for additional symptoms of hypophysitis, such as headache, dizziness, nausea/vomiting, visual defects or fatigue in addition to hypotension. Clinicians must also check levels for thyroid (TSH, FT4) and sex hormones (follicle-stimulating hormone, leutenizing hormone, in addition to estradiol in women and testosterone in men.

If visual symptoms are present, a pituitary MRI should be considered to evaluate for pituitary gland swelling. Endocrinology should be promptly involved, and patients would require interruption of therapy with initiation of high-dose steroids and replacement of hormones as appropriate. Typically, patients can resume immunotherapy once symptoms are resolved. “We agree with NCCN recommendations and recommend baseline cortisol check, and that clinicians should consider repeating cortisol level checks every four to six weeks as clinically indicated,” says Dr. Ali. Symptoms as noted above should always prompt detailed testing as highlighted above.

Type 1 diabetes mellitus: Patients on ICI therapy should get their glucose checked as part of their routine blood work. New onset hyperglycemia defined as fasting blood glucose > 200mg/dL, or random glucose > 250mg/dL should prompt evaluation of IRAE of type 1 diabetes (T1DM). While this is rare, it can be a serious and life-threatening side effect if appropriate insulin-based therapy is not timely initiated. Patients should be evaluated for diabetic ketoacidosis, and additional testing should include checking of c-peptide level, which would be lower than normal in T1DM. Endocrinology should be involved for prompt and emergent glycemic control and any associated complications.

Essential monitoring for patients receiving ICI treatment

Careful monitoring of patient symptoms and lab work is necessary to astutely identify IRAEs while patients are on ICI therapy. For Dr. Ali, she performs a head-to-toe review of systems during her visits with patients on ICI therapy. She asks questions about fatigue, abdominal pain, diarrhea, shortness of breath, chest pain, vision changes, heat or cold intolerance, significant weight changes, palpitations, anxiety, polyuria and watches for laboratory changes suggesting hormonal abnormalities. She and her nursing team also do extensive patient counseling to educate patients on all possible side effects and encourage patients to take notes during the education visits.

The importance of screening pre-surgery

Adrenal insufficiency, which is decreased production of the body’s “fight or flight” hormone cortisol, is one side effect that can occur with ICIs. “Roughly 63% of patients with TNBC who receive this combination therapy achieve a complete response to therapy, but still require surgery,” says Director of Cleveland Clinic’s Western Region Breast and Fairview Hospital Breast Programs Stephanie Valente, DO. “However, patients may experience symptomatic or asymptomatic hormonal imbalances as a consequent of ICI treatment, and the stress of undergoing surgery might put them at risk for significant complications including shock during or after surgery.”

For this reason, for ICIs like pembrolizumab, the drug manufacturer recommends monitoring of blood cortisol at baseline, prior to surgery and as clinically indicated for patients treated for TNBC in the neoadjuvant setting. However, not all providers are aware of this or have adopted this practice routinely.

“In some cases, a patient may be on chemo-immunotherapy for six months or more before surgery,” says Dr. Valente. “The patient could be maintaining her symptoms of decreased hormones at baseline, but the stress of surgery can exacerbate these changes and can be life threatening. Routine lab work as well as monitoring for symptoms such as fatigue, diarrhea and change in heart rate can be clues that something is off. Obtaining blood work prior to surgery to check for decreased immune function is a must. This is the role of the surgeon, to make sure the patient, functionally and hormonally, can tolerate the stress that surgery and recovery will add to the body.”

One week prior to any surgery, Dr. Valente checks these labs, and has identified a few patients with low hormone levels requiring steroid or thyroid replacement medications prior to and after the procedure. “This time frame prior to surgery gives us enough time to consult with the medical oncologist and endocrinologist and develop a peri-operative plan,” she adds.

“As ICI therapy is more commonly used in breast cancer, particularly in patients on neoadjuvant therapy, oncologists and surgeons should get increasingly familiar with both the more common and rare side effects. The threshold to involve the right specialist should be low when patients are on ICI therapy, as side effects can range from mild to serious,” says Dr. Ali. “Having a good understanding of side effects – and having colleagues you can rely on for support – is crucial in an effective multi-disciplinary team.”

For more information, download the NCCN Guidelines on Management of Immunotherapy-related Toxicities.