These are critical questions from multiple angles. The ideal treatment for metastatic breast cancer would be effective, would have few side effects, and would not interfere with a patient’s day-to-day activities. Additionally, most patients prefer oral therapies to intravenous medications when there is a choice. This is why people have been so enamored with CDK4/6 inhibitors because they work for a prolonged period of time, and they improve progression-free and overall survival but with minimal effects on QOL. Thus, CDK4/6 inhibitors are precisely the type of drug that you want to develop for patients with metastatic cancer. 

In the second-line setting, a number of selective estrogen receptor degraders and selective estrogen receptor modulators are either approved, such as elacestrant, or are in development in ongoing phase 3 trials, including camizestrant, giredestrant, imlunestrant, and the selective estrogen receptor modulator lasofoxifene. These agents hold promise because they provide a new way to target the estrogen receptor and may be useful for patients who cannot tolerate current endocrine therapies due to side effects. As of right now, these drugs seem to exhibit the greatest antitumor activity in ESR1-mutant tumors that are typically resistant to other forms of antiestrogen therapy. These agents will hopefully provide us with several new options for our patients. The question is: How will patients tolerate these newer agents, as it is very likely that these drugs will have unique side effects? For example, some of these agents are associated with visual disturbances that manifest as photopsia or blinking lights, whereas others are associated with diarrhea. 

With the availability of multiple treatment options, QOL considerations are increasingly important, and trials for all major new therapeutics, including CDK4/6 inhibitors and endocrine-targeted agents, are assessing patient QOL. The days of using a new drug with slightly improved efficacy in all patients is likely behind us. What we want now are active drugs for biologically defined subsets, with minimal or tolerable side effects, that we can use to individualize treatment. 

The QOL in patients with advanced breast cancer is driven by symptoms of their disease (eg, pain with bone metastases) and toxicity that is associated with their cancer treatment. It is important to consider cancer therapy options to avoid exacerbating preexisting patient symptoms or comorbidities. For instance, if a patient already has irritable bowel syndrome, I would not select the CDK4/6 inhibitor abemaciclib, as one of the side effects with this cancer drug is diarrhea. When recommending a cancer therapy, it is important to look at both the efficacy and the toxicity of the drug in the context of each individual patient. 

It is also very important to remember that patients should be offered a number of lines of endocrine-based therapies to avoid the use of chemotherapy for as long as possible. Beyond the associated drug toxicities, intravenous chemotherapy is challenging for many patients, as it often requires the need to put in ports, has an increased risk of blood clots and infection, and requires time in an infusion center. One of the biggest changes that I have seen in the treatment of advanced HR+ breast cancer has been the movement away from "upfront" chemotherapy to endocrine-based treatment. A patient can be on endocrine-based therapy for, perhaps, 3, 4, or 5-plus years before their disease becomes resistant and they are started on chemotherapy. The avoidance of chemotherapy for longer periods of time, I feel, is associated with a better QOL.

Psychosocial stressors are also very important to address when considering treatment options for patients with advanced HR+ breast cancer. A number of self-report screening instruments have been developed over the years. Our center asks patients to complete such a tool at each clinic visit. This gives providers a general idea of how a patient is coping with their disease. This is particularly important when considering a patient’s adherence and compliance with oral cancer therapies. One of the challenges as a health care provider is finding adequate time to address patient stressors that can impact overall well-being. A multidisciplinary team including nurses, pharmacists, psychologists, social workers, and navigators are vital to help provide patients with the support they need to address both physical and psychological stressors. A multidisciplinary team can provide a more "person-centric" approach to patient care.

In addition to the impact that treatment can have on a patient’s QOL, particularly in causing fatigue, metastases can cause major complications. These complications include, but are not limited to, bone metastases that cause pain or result in fractures, pleural effusions that may require a thoracentesis or drainage catheters, and liver metastases that may cause fatigue and liver compromise.

To assess QOL, we evaluate how the patients look when they walk into the room, and then we run through a standard review of organ systems. We ask them, “How do you feel? Are you short of breath or coughing? Do you have pain anywhere or any fatigue? Are you nauseous? How are your bowel movements?” I also perform a physical examination to look for signs of disease progression and to monitor laboratory values and tumor markers to assess disease status and monitor for drug toxicity. The treatment-related toxicities that I monitor for depend on the drug that the patient is receiving. For example, if they are taking a CDK4/6 inhibitor, I order a complete blood count to assess bone marrow toxicity. I also monitor for interstitial lung disease, a toxicity that is associated with a variety of drugs, including trastuzumab deruxtecan, CDK4/6 inhibitors, and mTOR inhibitors. 

Altogether, a consistent theme is that people want to live longer and better. For patients with early-stage disease, I tell them that my job is to keep them cancer free and to minimize their risk for recurrence using adjuvant systemic therapy. For those with metastatic disease, I explain that the goal of therapy is to control their disease with as few symptoms from the disease and side effects from the treatment as possible.