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Just as in all types of cancer, the use of targeted therapies to treat breast cancer has increased in recent years. , women with breast cancer can be treated with monoclonal antibodies, antibody-drug conjugates, kinase inhibitors, cyclin-dependent kinase (CDK)4/6 inhibitors, mammalian target of rapamycin inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, poly ADP ribose polymerase (PARP) inhibitors, or immunotherapies.

With these new options and potential for enhanced efficacy, patients and their clinicians are also faced with the challenge of managing a variety of new adverse events, including dermatologic toxicities.

"Broadly speaking the use of these agents is really increasing in the field of breast cancer," said Alexandra Thomas, MD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina. "In the metastatic space, a lot of women are being treated with these because they are proven [there], and we will be seeing more and more women treated with them as these drugs move into the earlier, adjuvant space, which is much larger."

Types of Toxicities

Skin toxicities are less frequent with certain targeted therapies such as PARP inhibitors or CDK4/6 inhibitors, and more commonly are associated with other classes such as PI3K inhibitors. For example, in the of alpelisib (Piqray) in women with hormone receptor (HR)-positive, HER2-negative disease, 35.6% of patients had rash of any grade with almost 10% experiencing grade 3 or 4 rash.

"These rashes with alpelisib tend to be very non-specific, with itchy pink papules and patches," explained Nicole LeBoeuf, MD, MPH, of Dana-Farber Cancer Institute in Boston. "Thankfully, most tend to be responsive to topical steroids and antihistamines. Most patients do not need to interrupt therapy, but occasionally [the rashes] can be more severe and may require dose interruption or discontinuation."

While patients may rarely experience some specific dermatologic adverse events from antibody drug conjugates, the more common toxicities from these tend to mirror the side effects of the cytotoxic component of the drug, she said.

However, as many as half or more of patients treated with immunotherapy will experience toxicities related to their skin or hair. "Immunotherapy drugs that target immune checkpoints can cause new skin problems to occur or cause existing ones to flare," LeBoeuf continued. "For example, patients may develop new or worsening psoriasis, eczema, or even blistering disease. Up to two-thirds may develop itch related to immunotherapy even if no rash occurs."

Pruritus occurs in . Although this type of toxicity is not life-threatening, it can be very detrimental to quality of life. "While itch itself won't shorten your life, patients may have a hard time getting itch under control, and are uncomfortable and miserable," LeBoeuf said. "We must also make sure that our treatments for itch don't decrease efficacy of immunotherapy – which could indirectly shorten life, but continued research is needed."

Patients treated with cytotoxic T-lymphocyte-associated protein-4 inhibitors may experience morbilliform or classic maculopapular eruptions -- a rash that looks like measles -- which can often be managed with topical steroids, emollients, or antipruritic agents.

Lichenoid eruptions, which can resemble lichen planus, psoriasis, and autoimmune blistering diseases, all occur in patients receiving anti-PD-1/PD-L1 inhibitors. These can present early or late in the treatment course.

In breast cancer, it is still too early to know if the appearance of these skin toxicities correlates to response, LeBoeuf said, noting, though, that there are data in other cancer types that show an association between dermatologic adverse events and progression-free and overall survival.

, however, that these effects can be detrimental to quality of life. "Any time a cancer treatment causes something to appear that is visible to the outside world, it can affect a patient's sense of privacy," LeBoeuf noted. "Understandably, things like psoriasis or eczema that suddenly are visible on the arms or face -- like losing hair -- may feel like a privacy invasion. Others know something is going on with the patient."

Partnership

Managing the list of possible dermatologic toxicities requires close cooperation with dermatology colleagues, Thomas emphasized. "Many of these treatments are newer to breast cancer, and outside of clinical trials we haven't seen patients on them for long periods of time. Like with so many things, once we gain more experience with these toxicities we will likely be able to manage mild grade 1 or 2 events on our own."

LeBoeuf agreed that a close partnership between medical oncology and dermatology is important in handling these challenging new toxicities. One of the unique benefits of involving a dermatologist is the ability to make a specific dermatologic diagnosis that can help to guide treatment.

"If a patient has pink patches, without a specific diagnosis, a medical oncologist may feel they need to prescribe systemic steroids for the patient's safety. There are data to suggest that giving systemic steroids may decrease immunotherapy response in other cancers," LeBoeuf noted.

"A dermatologist may look at that same rash and give a specific diagnosis of eczema or psoriasis. For psoriasis, for example, I could prescribe light therapy or an oral psoriasis-specific medication. By working collaboratively, we can best target the toxicities and save the globally immunosuppressive agents for severe cases," she said.

Everyone who treats patients affected by these dermatologic toxicities could benefit from more specific national level guidelines and definitions in the Common Terminology Criteria for Adverse Events used in clinical trials, LeBoeuf added.

"There is currently a limitation in the available data that puts us all at a disadvantage. When we see patients on newly approved drugs, often all there is available in the literature is data on 'rash.' These limitations create a knowledge and management gap for dermatologists and medical oncologists alike," she said.

She noted that as more medical oncologists and breast oncologists encounter patients being treated with targeted therapy who are experiencing dermatologic toxicities, she encourages them to find a go-to dermatologist colleague -- and she encourages and trains dermatologists to be aware and available.

"That way, anytime you are thinking about the possibility of treatment interruption or discontinuation, or if a rash were to be life-threatening, you have someone to ask for help who will see your patient urgently," LeBoeuf said. "The hope is that together we can treat toxicities in a way that doesn't eliminate or decrease therapeutic response, while maintaining patient quality of life."

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