AJMC®: What are some of the most notable obstacles to effective management of metastatic breast cancer (mBC) with currently approved therapeutic agents?
RUGO: The first and most obvious is the development of resistance to endocrine and chemotherapy approaches, including both acquired and de novo resistance. This is our biggest challenge in the treatment of breast cancer, both in the early- and late-stage setting. Specific sites of disease that are difficult to access or treat can be a significant obstacle. For example, for a patient who is responding systemically to a specific therapy but then develops new or progressing brain metastases or leptomeningeal disease, now that we have more effective systemic therapies, this escape in the brain and leptomeninges can be quite difficult to manage. Discordant response to therapy may also complicate treatment decisions, where the disease responds in one or more organs but progresses in another.
Understanding the biology of the tumor is an important factor, and we are learning more about incorporating knowledge of biology into treatment decisions. Disease-free interval, response, or recurrence to prior therapy all play a role in treatment sequencing in the metastatic setting. Toxicity can be a major barrier to treatment and limit effective therapy. The most common limiting factors are peripheral neuropathy, cytopenias, GI toxicities, and fatigue, although we are seeing new toxicities with novel therapeutics such as immunotherapy.
An example is a patient who was on the IMpassion 130 trial [NCT02425891] [who] received nab-paclitaxel and atezolizumab [and] developed severe neuropathy from 5 cycles of nab-paclitaxel. When she would come in, she would wear only pink fluffy slippers because her feet hurt so much. It took 3 years for it to be possible for her to wear shoes, although she is remarkably still living on therapy. She was unable to continue the nab-paclitaxel after the 5 cycles, so this particular toxicity very much limited her treatment [as well as] her ongoing options.
For an individual patient, IV access, frequency of administration, hair loss, and the specific toxicity of that agent are the 4 main things we think about. But the very first thing [clinicians] think about is how rapidly do we need treatment to impact the disease? If somebody has immediate life-threatening disease, we make a different choice [from what we choose for] somebody who has disease which is not immediately life-threatening.
AJMC®: What are some of the most common concerns from the patient’s perspective when it comes to treatment?
RUGO: The need for IV [intravenous] access can be a big issue for patients if they have had problems with port sites from the past. Breast cancer patients have poor IV access in general due to prior surgery in the axilla.
Much of the chemotherapy that we give in the metastatic setting is administered on a weekly schedule. Being able to give drugs less frequently with no increase in toxicity while maintaining efficacy is really important for patients.
There’s been a movement on the patient side about giving lower doses, which helps to modify toxicity to some degree. But that likely means that patients have to come in more frequently to receive those lower doses. This is a combination of different issues that can be problems from the patient perspective. Coming in frequently and needing to spend hours in the center is quite challenging.
Toxicity is a major issue for our patients with metastatic breast cancer that can significantly impact quality of life and limit therapy as well. Other than hair loss up front, fatigue and neuropathy are 2 of the biggest issues for patients receiving treatment for metastatic disease. Neuropathy can be very disruptive in terms of being able to just manage daily activities. An example would be a patient who works part time at a store, and as her neuropathy [becomes] worse, she [needs] narcotics just to get through a day at work. This can be a really big issue for patients, with implications for work, family, and quality of life. Worsening fatigue could mean that patients are unable to get much done during the day, and many patients find that fatigue limits many aspects of their daily life. Sometimes people find that their speed of thinking is not as rapid [while] on treatment.
Some of my patients find the injections for the selective estrogen receptor [downregulators] quite painful. Particularly if they’re having bone pain, it can be difficult to differentiate bone pain from the pain from the injection, which can be an issue for patients and providers.
There are multiple other challenges of having mBC, such as sexual dysfunction, issues associated with menopause, the unknown, [and] the fear and challenges of having repeated scans and what those scans will show. Cost of therapy is an increasing issue as well, particularly for supportive care medications.
Additionally, we have to think about the fact that patients need to come to the medical center and park, and in the era of COVID-19 [coronavirus disease 2019], for example, [if] they have their companion coming with them, that companion has to sit in the parking lot or come in and be masked all day, and they don’t have a way of caring for their family, including small children or elderly parents. These are huge challenges for patients.
AJMC®: What other factors deserve consideration when it comes to selecting a treatment regimen for patients with mBC?
RUGO: Pharmacogenomics play a big role, but, unfortunately, we still do not have the tools to incorporate this into our clinical practice or drug dosing. We give the treatment to the patient, and then we wait and see what happens. For example, you might give 1 drug that 9 out of 10 of your patients tolerate well, and [then] the tenth patient has grade 3 diarrhea or throws up for 3 days… or 5 days. A big challenge on both the clinician and the patient side is the unknown aspect of metabolism and individual toxicity.
This has played a role with immunotherapy as well. For the very common toxicities, you give a drug that your last patients all tolerated well, and 1 patient ends up in the [emergency department] with severe diarrhea. I recently had a couple of older women who started capecitabine, and both of them developed whole-body rashes. They’re both very light skinned and have had a lot of sun exposure, but you can’t see these premalignant lesions before you give the drug, and then it’s just a unique toxicity that you couldn’t even have educated them well about beforehand.
The unknown of toxicity, the unique aspects of toxicity, and the fact that we can’t individualize our drug doses for patients because we don’t actually understand this in detail, is so important.
AJMC®: Given the limitation of IV-based chemotherapy, how can we devise goals for the treatment of mBC?
RUGO: There are 2 aspects of treatment that we think about. The first is trying to provide a therapy that is most effective, and the second is to provide a therapy [that] has the least impact on the quality of life of our patient and their lifestyle. I tell patients that the goal of treatment is to help them live as long as possible with the best quality of life and that we need to take both of those issues into account. Decisions about treatment need to balance the chance of benefit, duration of benefit, and potential toxicities.
When feasible, we prefer to limit the number of visits to the cancer center, as well as blood draws and infusion visits, as this is quite time-consuming. Unfortunately, as cancer progresses, this becomes less feasible. IV access can be very important to patients, as is alopecia and, of course, other toxicities such as neuropathy.
Oral therapy can help with a number of these issues. In general, oral therapy reduces the time spent at the cancer or infusion center, eliminates the need for indwelling IV access, and, in some cases, may have minimal risk for alopecia. Newer oral taxanes will be an extremely welcome addition for many patients who are disappointed that we have only 1 current oral chemotherapy option. As we devise goals, this balance of efficacy, toxicity, and quality of life is critical. Agents that can maintain efficacy and reduce toxicity that cannot be easily managed, such as neuropathy, are important options. And, as mentioned above, alopecia remains a potential barrier to therapy in the metastatic setting; hair loss is such an important external view of what’s going on [with] your health. Perhaps with COVID-19 and the stay-at-home orders, this is a little less important.
Oral therapy has the potential to make a big difference for our patients. We can eliminate the need to wait for and sit through infusions and monitoring. Patients don’t need IV access, and if there are some advantages in terms of toxicity, that’s a further advantage. Even with an agent that is equally efficacious and toxic compared to IV therapy, there might still be advantages in terms of having oral administration where patients can be treated at home.