Discussing HER2-Positive Breast Cancer With a Patient Advocate

At an Around the Practice presentation hosted by CancerNetwork^®, multidisciplinary oncology clinicians and a patient advocate discussed treatment options for managing HER2-positive breast cancer and explored the treatment journey from the perspective of a patient. The panel was led by Sara Hurvitz, MD, medical director of the University of California Los Angeles (UCLA) Jonsson Comprehensive Cancer Center Clinical Research Unit, co-director of the Santa Monica-UCLA Outpatient Oncology Practices, and director of UCLA’s Breast Cancer Clinical Trials Program.

Other experts were Kamran Ahmed, MD, chief of radiation oncology at Moffitt Cancer Center in Tampa, Florida, and Julia LaBarbera, NP, a nurse practitioner of oncology at UCLA in Santa Monica, California. They were joined by Erika Rich of Pittsburgh, Pennsylvania, a patient advocate and survivor of HER2-positive breast cancer.

Advancements in HER2-Positive Breast Cancer

Hurvitz: The field has evolved [significantly] in terms of the management of metastatic HER2-positive breast cancer. We now have 8 different HER2-targeted therapies available for metastatic HER2-positive disease, which is a lot more than when I started practicing back in 2006, when we only had 1 HER2-targeted therapy available. In many ways, it [has become] challenging for us to understand how to best sequence these agents and choose among these different therapies, especially as we get in the second-line setting and beyond.

Some patients will present with metastatic disease having had a history of early-stage disease, and some patients will present with a mass in their breast and then be found to have what we call de novo metastatic disease, which is stage IV breast cancer at the initial presentation. As our therapies for HER2-positive, early-stage disease have accelerated and improved the chances of not having cancer return, the rates of de novo metastatic disease, or the proportion of de novo metastatic disease, have gone up for the HER2-positive subtype.

Case

• Panel member Erika Rich was diagnosed in March 2019, aged 25 years, with a 3.2-cm right breast mass.
• Biopsy showed invasive ductal carcinoma of estrogen receptor/progesterone receptor–negative, HER2-positive disease with an immunohistochemistry score of 3+.
• Lesions were present on the lymph nodes, liver, and bones; the largest was a 1.3-cm round, lytic lesion of the subtrochanteric region.
• She was treated with docetaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta; THP) for 6 months and had 6 rounds of hip radiation.
• Scans in August 2019 showed no evidence of disease.
  Trastuzumab was continued for 3 weeks.

Hurvitz: You were so young when you were diagnosed and still are very young. It’s not on the top of someone’s mind when you’re in your 20s that when you notice a breast symptom, the first thing you [would] think of is cancer. I imagine that [meant you did not] seek medical attention as soon as you would have if you were 50 with this new symptom. Is that right?

Rich: Yes, that is correct. I was doing yoga. I was gaining a little bit of weight at the time and there were things that [made me seek a] doctor. But outside of that, I never typically went to the doctor, so it did take me a little bit longer [to make an appointment].

Hurvitz: The THP—trastuzumab, pertuzumab, docetaxel—regimen is the standard-of-care first-line regimen. That’s what you received initially. How did you do with that?

Rich: I did well because I was so young and I had no family history. [I didn’t know what to expect] and I thought I was [going to] be in the hospital, bedridden, but I took that time to go visit my friends and I was very active. They did give me some medicine to help with adverse effects [AEs] like nausea, and that allowed me a bit more freedom and I spent a lot of time traveling and felt well.

Hurvitz: Were you having pain in your hip? You had mentioned some back pain. Were you also having pain in the area where they saw lesions in the bones?

Rich: Yes, I was having significant pain in that area. My entire life, until I graduated from college, I played soccer, so I just thought it was from that; I’d always gone into my seasons injured so I didn’t second-guess whenever my back was hurting. [However], I did go to Disney World the month before I got diagnosed, and I started noticing [aches and pains]. [In fact], it was excruciating pain, to [the point] where I was having to miss out on a lot of the activities that my family was partaking in because I couldn’t keep up with them. [But] I just wrote it off as back pain.

Hurvtiz: You did ultimately present to a radiation oncologist. Before you tell us about your therapy there and how you tolerated it, I [want to] ask Dr Ahmed to talk to us about the indications for radiation in somebody with de novo metastatic breast cancer. Could you speak to the features of this case and how you might approach it in somebody who is starting systemic therapy for widespread metastatic disease, but who also has painful bone metastases?

Ahmed: It’s quite common for us to deliver radiation therapy in the stage IV setting when areas of pain are being caused by sites of bone metastasis. That’s what we’ve traditionally thought of as palliative radiation therapy, but more and more now, as systemic agents are improving, we’re noticing the greater importance of improving local control with radiation therapy as well. In addition to the palliative effects of improvement in pain control, local control is becoming an increasing reason to deliver radiation therapy. A couple of important trials [have been done, especially] the SABR-COMET study [NCT01446744], which was published by David Palma in Toronto, which basically showed that there was improvement in terms of overall survival [OS] and progression-free survival [PFS] in patients who received stereotactic body radiation therapy [SBRT] or focal radiation therapy to 1 to 5 sites of metastasis.¹ This study didn’t specifically enroll patients with breast cancer, [but] about 20% of patients in that study had breast cancer. Another study ongoing now through NRG Oncology, the BR002 study [NCT02364557], is specifically looking at patients with breast cancer. More and more, now, we’re delivering radiation therapy for the purposes of improved local control.

Hurvitz: The SABR-COMET study is notable to me because I’ve noticed that few trials have randomized patients to SBRT or radiation vs systemic therapy alone. I really congratulate the trial investigators for that design, [because] they indeed found a benefit. As you mentioned, the downside is [that it included] only a handful of patients with breast cancer. I’m so excited to see the NRG study data come out because I think this remains an open question. We don’t [want to] radiate a patient too much if it’s not for palliative reasons, but I think it’s so critical for us to gather these data to help us decide how to move forward. Erika, can you talk to us about the radiation you received and how you responded to it?

Rich: I responded well. I received 6 rounds of direct radiation to my right hip, and I was also diagnosed with arthritis at the same time that I was diagnosed with my metastasis, so I had to also be wary of that. [I would receive treatment for] 5 days in a row and then have off on the weekend. I didn’t notice any AEs; [there wasn’t] any redness on my skin, and the pain went away quickly. I am not a fan of pain medications and I think I only had to use it once during that sixth course of treatment.

Hurvitz: It sounds like you [received] very good care at your facility. Julia, can you talk to us about the treatment that Erika received from a systemic perspective? Is this in line with what we typically do? Also, how do you think things have changed in the COVID-19 era with frequent infusion visits and the recent availability of subcutaneous HER2-targeted therapies?

LaBarbera: [THP] is our front-line treatment [regimen] for metastatic HER2-positive breast cancer. That was exactly as indicated for Erika. Subcutaneous trastuzumab and pertuzumab have been developed, which patients are excited about because it will avoid the need, in some instances, for them to have to come to the infusion center for treatment. Docetaxel is not yet available in any other form besides intravenously. For at least the beginning portion, patients will still have to come to the infusion area to get those 3 treatments. Once that component is done, they may have the option of continuing treatment with the subcutaneous at home or at their infusion center, depending on what the availability is for that person and their insurance coverage. That’s exciting for some people who, particularly during this pandemic, want to avoid contact with people as much as possible.

Hurvitz: It’s really been interesting to have that available now. I think the pandemic has certainly changed a lot of our practices in the clinic. We’ve allowed patients to do video visits and, in some cases, they’ve even received at-home subcutaneous injections rather than coming to the infusion room, provided that insurance covers it. It’s an interesting time, as we see this crisis move forward, [to see] our ability to treat patients outside of the clinic setting.

Pivoting a bit, and discuss patients who struggle with a lot of information; clinicians struggle with the change in data and information available to help guide treatment decisions. More and more, we’re learning how to integrate shared decision-making with patients and it’s a fine balance. You don’t [want to] overwhelm patients with too much data, but you also want share in the decision[-making] with patients regarding what treatment you’re going to ultimately pursue. How do you manage that in your own practice?

Ahmed: It’s very patient-dependent, and every patient is a bit different. Some patients [want to] see specifics in terms of clinical trial data. In those instances, I’ll certainly [show them] clinical trials and rates and give specific numbers. In other instances, patients just want to know what my opinion is and what I would recommend for a member of my own family. In those instances, I’ll specifically state what I would recommend. One of the easiest things to do, also, is get NCCN [National Comprehensive Cancer Center] guidelines. The Moffitt Cancer Center is an NCCN institution, so we follow those guidelines very closely. If patients want to know exactly what the standard of care is right now, the NCCN guidelines are something that I like to use. Above all, I try to tell patients that this is a team approach, and although I’m here to provide guidance, treatment decisions are ultimately in their hands.

Hurvitz: Some patients want the nitty-gritty details and have already done their own research; they’ll surprise you by asking specific questions about clinical trials. Others just want your gut instinct based on your experience.
The patient is not just a single person isolated on an island, but has a group of people who care about them, so it’s important to include [those other people] in decision-making. Second opinions are always the right answer. I encourage my own patients to get second opinions so that they’re comfortable with the treatment they’re pursuing.

I [want to] talk a bit about the AEs of therapy. Erika, you indicated that you tolerated [treatment] well. I would have to say that’s not everybody’s experience. Dr LaBarbera, can you take us through some of the more typical AEs of frontline [THP]: what we expect, and how you prepare patients and see them through those first 6 cycles where the chemotherapy is the component of the regimen?

LaBarbera: Many of the AEs are mostly related to the chemotherapy itself. With docetaxel, the white blood cell count can be lowered, so we do need to monitor that prior to each cycle. There can be hair loss, unfortunately, so patients are encouraged to pursue cold capping if that’s an option for them. There could be peripheral neuropathy, which you tend to see in the later cycles, and some nausea, bowel changes, constipation, or diarrhea. We do have an extensive teaching visit prior to when the patient starts [therapy], where we go through each of these AEs individually and how to manage them—just to prepare the patients and their families to be more proactive at home. Once they get to the trastuzumab and pertuzumab maintenance therapy, that’s well tolerated. Diarrhea and skin rash are the more common AEs. There’s always the risk of cardiotoxicity, too, so we do have to educate patients to report any new cough or shortness of breath, swelling, or weight changes. Generally, that portion is much better tolerated when you’re doing the 3 drugs combined.

Hurvitz: Erika, how did your team prepare you for your treatment? What do you feel they did effectively, or maybe not as effectively? Can you also talk about mental wellbeing and whether you were given resources to help you through such a difficult and scary diagnosis?

Rich: Getting ready for the AEs was one of the most anticipated and scary parts of it. During those first few rounds, I did lose my hair and had some trouble with my bowels being very inconsistent, which was something that I was not prepared for and didn’t know how to handle at first. Now, on year 3 of this cancer journey, I have that down pat, so I [have forgotten] about it when it came to preparing for what to expect whenever I did start taking my medicine. This was prior to the COVID-19 pandemic. I had my dad, my mom, my aunt, and some sisters at [my appointments], so we all had our notepads out. Everyone had different [thoughts] to contribute, but one of the big things that I made sure to do was to stay hydrated. That was a tip that another patient had given me beforehand. I was drinking a minimum of 2 liters of water and an entire Pedialyte every time I had treatment, and for 3 days afterward to flush out my system. I will say that helps quite a lot.

Luckily, I found a cancer therapist from the time that I started my treatment, and it was one of the biggest blessings. I was able to meet with her in person at first, and bring my family in to come meet with her and talk with her, too, because, like you mentioned before, this was a big change for me, but it also was a big change for my family.

I’m a big advocate for medical marijuana and that was something that I relied on during this time. It helped a lot with my nausea and made me feel so much better. It also helped with my appetite and things of that nature. My weight fluctuated a little bit, but that helped keep it
consistent, among other things.

Case (continued)

• October 2019: tender firmness and erythema in right breast
• Palpable masses found in breast and patchy thickened areas around the nipple
• Masses in posterior fossa seen in CT scan
• 20 spura and infratentorial metastatic lesions in the brain seen via MRI
• Dominant infratentorial lesion was 19 mm in the right hemisphere
• Trastuzumab emtansine given for 10 rounds of brain radiation
  

Hurvitz: So much happened to you quickly after having your disease so well controlled. Can you tell us if you were having symptoms in the brain at the time: headaches, vision changes, nausea, anything that would indicate this was going on? Or was the brain scan done as a part of reevaluating you when you had these new breast lesions show up?

Rich: My doctor suggested it. [I had received a CT from the neck down and] he saw something at the bottom of my neck and asked to do an MRI. I hadn’t noticed any symptoms when it came to nausea, but when it came to my mental state of being, from the time that I was told that I had no evidence of disease until I was rebiopsied, I was more depressed than I had ever been. I was very confused about what to do now that the cancer was suddenly gone. I had just gone through this crazy journey.

Whenever they initially called, they asked if I was having any symptoms; I [told them no]. They [told me] this is how you presented in your scans. A few days later, they called to reschedule me because someone had scheduled me for targeted therapy, [and they said] we need to reschedule you for [whole]-brain radiation. At that point, they told me that I had about 18 to 20 lesions all over my brain. I had never heard of anyone experiencing that kind of brain metastasis, so I thought that that was the end for me.

Hurvitz: Can you talk to us about what questions patients have about brain metastases? What things do they typically ask and what do they forget to ask?

LaBarbera: It’s important for patients to understand that this is still the same disease. When patients hear that there’s cancer in the brain, they think they have brain cancer, but it’s important just to reiterate that this is breast cancer that’s spread to the brain. Their first question is, ‘What does this mean for my overall prognosis? Am I going to die sooner? Is this treatable? What does the treatment look like?’ There’s a sense of bewilderment in terms of how these changes affect where they go from here. I’m not present for the discussion with the radiation oncologist. From the discussions that I have with the patients, [I think] what they forget to ask about are the AEs related to this type of treatment, the long-term AEs that they need to be aware of, and—particularly when you’re dealing with metastatic cancer—what to do next. They’re not necessarily thinking that they could still live for several years with cancer in the brain and how will this impact them long term. We need to do a better job as clinicians to address that over time as well.

Hurvitz: While our statistics give us an idea of median survival after brain metastases, those are statistics that are based on patients from multiple years ago who had different treatment options available. I always remind patients that the median OS of a patient diagnosed with brain metastases today is very different, and probably better, based on the advances that we have for local therapy and now even systemic therapy.

Can you take us through how you address brain metastases? When do you feel that radiosurgery is appropriate vs whole-brain radiation therapy?

Ahmed: Typically, we like to consider SBRT or focal radiation therapy [in the case of] more isolated or limited brain metastasis. We have very good prospective data for treating up to 10 brain metastases, and another ongoing trial is looking at patients who have up to 15 brain metastases. Now, for patients who have more brain metastases that can be detected on MRI, we’re also concerned about microscopic deposits that we’re potentially missing. In those instances, like Erika’s, we recommend whole-brain radiation therapy.
There are different ways of approaching whole-brain radiation therapy to mitigate some of the long-term AEs, like short-term memory loss, which have been well detailed prospectively. Those techniques include hippocampal sparing. Another tool in our arsenal is the use of systemic therapy. Particularly for HER2-positive brain metastasis, we’ve seen good responses from tucatinib [Tukysa] from the HER2CLIMB study [NCT02614694], which showed that there was an improvement in CNS [central nervous system] PFS within the treatment arm of tucatinib.² In our practice, what we look at [first] is whether patients are symptomatic at initial presentation. If patients are symptomatic, potentially surgery and/or radiation therapy should be considered upfront. If patients are asymptomatic and haven’t yet been exposed to systemic therapy, we can consider tools such as tucatinib. I work closely with our medical oncologists and recommend we start systemic therapy first; then, we do a quick interval MRI and see if there’s a response. If we don’t see a response, we can quickly add radiation therapy.

Hurvitz: Tucatinib was practice-changing in the HER2CLIMB trial looking at tucatinib plus capecitabine and trastuzumab vs capecitabine/trastuzumab. It
demonstrated an improvement in PFS and OS in the overall population of patients, but also specifically in those patients with active, progressing, previously untreated brain metastases [TABLE].² That study was so uniquely designed to allow patients with progressive brain metastases [to participate]. Owing to its CNS penetration, we did see a remarkable improvement in outcomes for patients with tucatinib added to therapy. That trial did allow patients who had previously untreated disease, and not only large, bulky symptomatic metastases where an urgent intervention was required, but smaller ones as well. That now has [earned] a place as a regimen in the second-line setting for those with brain metastases, according to our NCCN guidelines and FDA approval, if we feel the patient is appropriate.^3,4 Something we think about as clinicians when we’re changing systemic therapy is if progression is occurring outside the brain as well as inside the brain.

TABLE. Outcomes With Tucatinib vs Placebo Plus SOC in HER2CLIMB

Ahmed: I recommend using memantine in patients who are receiving whole-brain radiation therapy. A prospective study has shown that cognitive function can improve in patients who receive memantine during radiation therapy and then continue that for at least 6 months afterward. I find that it’s well tolerated in patients. We increase the doses over about a 1-month period, increasing to about 10 mg [twice daily].

Hurvitz: T-DM1 [trastuzumab emtansine; Kadcyla] had been the gold standard for second-line therapy based on the EMILIA trial [NCT00829166].5 Erika received this therapy in the second-line setting. However, we just saw data from the phase 3 DESTINY-Breast03 trial [NCT03529110], which looks at T-DXd [trastuzumab deruxtecan], another antibody-drug conjugate, compared with T-DM1. [The results] showed that T-DXd was associated with a substantially improved PFS, with a hazard ratio of 0.28 [95% CI, 0.22-0.37; P = 7.8 10^–22]. This makes T-DXd the standard second-line option now and places T-DM1 in a later position.⁶ We also have tucatinib plus capecitabine and trastuzumab in the third-line setting and beyond, but [that regimen is] also appropriate now in the second-line setting for those patients who have brain metastases. Then we have a bunch of other agents as well: lapatinib [Tykerb]-based therapy, neratinib [Nerlynx]-based therapy, trastuzumab combined with other chemotherapy, and now margetuximab [Margenza]. It is not entirely clear how to optimally sequence these agents because we don’t have enough clinical trial data to address that, but the NCCN guidelines are an appropriate resource for us to turn to when we’re making decisions about systemic therapy. Dr LaBarbera, could you take us through high-level AEs that we watch for with these newer agents, such as tucatinib and T-DXd?

LaBarbera: T-DXd can cause nausea, neutropenia, and diarrhea. One of the more serious AEs we need to look out for is interstitial lung disease [ILD] or pneumonitis. This could be asymptomatic, so it is something that we need to monitor for on scans. [We also have to] educate patients to report any new cough or shortness of breath. Tucatinib is well tolerated, but patients can experience significant diarrhea and hepatotoxicity with it, so we do need to keep monitoring liver enzymes and stay on top of the patient’s symptoms, encouraging them to report diarrhea that’s not well controlled.

Hurvitz: With T-DXd, pneumonitis—inflammation of the lungs—is a serious AE that occurs in about 10% of patients. Any patient on T-DXd who develops shortness of breath or cough needs to bring it to the clinician’s attention. If any ground-glass opacities are seen on imaging, therapy needs to be held. It’s rare now to have death. They didn’t have any deaths in the DESTINY-Breast03 trial with T-DXd due to ILD, [showing us that] with careful attention, this can be mitigated.6 With tucatinib, as you mentioned, diarrhea is the biggest challenge we’re seeing with our own patients, but it’s easy to manage given the HER2 selectivity of this agent. Erika, I [want to] turn to you for a moment and talk to you about the decision to go on T-DM1 as your second-line therapy. When you were making this decision with your clinician, what sort of things did you express as being important to you?

Rich: When it came to any kind of treatment, my No. 1 concern was hair loss. [The most surprising thing] about cancer was not only losing your hair, but your eyebrows, too. Since I had recently been on a medicine where my counts weren’t affected, I had the freedom to travel and got a good taste of that. My big focus with my oncologist right now is what I am [going to] do in order to be able to be gone for an entire month [traveling]. By the time I’m done with this medicine, and everything gets back [to normal], there might be something new.

When I had my brain metastases, tucatinib didn’t even exist. It was interesting that it came out a few months later, and then I was able to give that a try. I’m so grateful for all these new [treatments]. In the past year, I’ve done 3 or 4 different treatments and each time [I think] this is my last option. We’ve started looking into clinical trials and then if something else happens, [investigating] a new medicine.

Hurvitz: For this subtype of breast cancer, we’re now seeing data from real-world registries. A study published from France included 18 comprehensive cancer centers that participated in something called ESME [Epidemiological Strategy and Medical Economics] that reported the median OS for a patient diagnosed with HER2-positive breast cancer in 2008 or 2009 all the way through 2015 or 2016.⁷ The median survival has gone up every year by many months. Now instead of the expected OS being about 3 years, we’re going beyond 4 or 5 years, and it’s just [going to] continue to rise given the changes in the way we approach this disease, and the fact that the driver of the cancer has been identified.

We continue to look at whether a patient has active brain metastases or stable brain metastases. That helps us guide our recommendations, but always it's a partnership with our patients. We struggle with the issue of radiation necrosis in patients who’ve received radiation for brain metastases. Give us a picture of what this is and how we treat it, and approaches that are being developed to help us distinguish necrosis from progression in the brain.

Ahmed: Radiation necrosis is one of the most worrisome AEs that, as radiation oncologists, we follow patients for and counsel patients on, in terms of its risk of happening post stereotactic treatment. The rates of that vary in series, but it can occur in up to about 10% to 15% of patients who receive stereotactic radiation treatment. Some data show that immunotherapies might potentially increase the risks of radiation necrosis when [they are] combined with stereotactic radiation treatment. That’s something that we must watch for and obviously counsel patients about.

In terms of our diagnosis, the gold standard has been surgical pathology for a long period of time. For patients who develop radiation necrosis, often what is needed is surgical resection of that [area] because it’s difficult to tell whether it’s [metastasis or] local progression vs radiation necrosis. MRI perfusion and PET/CT imaging are available, that we can use to help differentiate [among them]. Steroids are commonly given to help manage the AEs of radiation necrosis as well, and sometimes bevacizumab [Avastin].

LaBarbera: I’m hopeful for this subtype of breast cancer—hopeful that it becomes more of a chronic illness for these women (and some men) who are diagnosed with this type of cancer. Instead of receiving grave news, patients in Erika’s situation, who are young when they’re diagnosed, can have plenty of life ahead of them—and that’s encouraging.

Ahmed: We’ve seen many studies combining radiation therapy with immunotherapies, potentially improving the effects of immunotherapy acting as an immune stimulator, and then also for the potential of combining systemic agents in the brain with stereotactic radiosurgery. Study results have also shown that radiation therapy can help improve opening of the blood-brain barrier, and appropriately sequencing systemic agents with radiation therapy can help improve the efficacy of systemic agents in the brain as well.

References

1. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial. J Clin Oncol. 2020;38(25):2830-2838. doi:10.1200/JCO.20.00818
2. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609
3. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 2.2022. Accessed February 9, 2022. https://bit.ly/3rCPdQn
4. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. FDA. April 17, 2020. Updated April 20, 2020. Accessed February 9, 2022. https://bit.ly/34N3CAn
5. Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-1791. doi:10.1056/NEJMoa1209124
6. Cortés J, Kim S, Chung W, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): results of the randomized phase III DESTINY-Breast03 study. Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741
7. Pérol D, Robain M, Arveux P, et al. The ongoing French metastatic breast cancer (MBC) cohort: the example-based methodology of the Epidemiological Strategy and Medical Economics (ESME). BMJ Open. 2019;9(2):e023568. doi:10.1136/bmjopen-2018-023568