The availability of targeted therapy, antibody-drug conjugates, and immunotherapy necessitates greater discussions regarding second-line treatment for patients with metastatic hormone receptor–positive, HER2-negative breast cancer, third-line treatment for patients with metastatic HER2-positive breast cancer, and neoadjuvant therapy for patients with locally advanced triple-negative breast cancer.
The availability of targeted therapy, antibody-drug conjugates (ADCs), and immunotherapy necessitates greater discussions regarding second-line treatment for patients with metastatic hormone receptor (HR)–positive, HER2-negative breast cancer, third-line treatment for patients with metastatic HER2-positive breast cancer, and neoadjuvant therapy for patients with locally advanced triple-negative breast cancer (TNBC).
To shed some light on the considerations that should be made leading up to treatment selection in each clinical scenario, we spoke with Aditya Bardia, MD, MPH, director of Precision Medicine at the Center for Breast Cancer and founding director of the Molecular and Precision Medicine Metastatic Breast Cancer Clinic, Massachusetts General Hospital Cancer Center, and assistant professor of medicine, Harvard Medical School, during the 2020 Institutional Perspectives in Cancer webinar on breast cancer.
“The first case is a 55-year-old female who was diagnosed with HR-positive, HER2-negative localized breast cancer in 2005. She was premenopausal at that time and received 5 years of adjuvant tamoxifen and then 10 years later had disease recurrence in the bone. [At that time, she]received letrozole plus a CDK4/6 inhibitor. After 2 years, [the woman] had disease progression.
The question is: What therapy should one consider next?
This is a common problem in clinic where patients have disease progression in the metastatic setting. After first-line therapy, a number of treatment options can be considered. Sometimes it’s helpful to get tumor genotyping, particularly for HR-positive breast cancer, because there are genotype-directed therapies that are either FDA approved or in clinical trials that could be utilized.
This patient had tumor genotyping done, and the tumor genotyping revealed a PIK3CA mutation, a PTEN mutation, and a HER2 [ERBB2] mutation. We did a poll at the conference where we asked about fulvestrant alone vs fulvestrant plus neratinib [Nerlynx] vs fulvestrant plus alpelisib [Piqray] vs fulvestrant plus abemaciclib [Verzenio]. The vote was pretty much split between fulvestrant/neratinib, fulvestrant/alpelisib, and fulvestrant/abemaciclib.
All of these are reasonable treatment options to consider. With a PIK3CA mutation, one could consider alpelisib, which is FDA approved for PIK3CA-mutant, HR-positive breast cancer in the second-line and beyond settings. Neratinib is also attractive, because there’s evidence from preclinical and clinical studies that suggest that fulvestrant plus neratinib has activity in HER2-mutant, HR-positive metastatic breast cancer. At the  San Antonio Breast Cancer Symposium, the results of plasmaMATCH were presented. Patients in the HER2-mutant arm received neratinib and experienced a response rate close to 20%.
Outside of genotyping, there’s a question of continued CDK4/6 inhibition. Fulvestrant plus abemaciclib would be a reasonable option to consider. Fulvestrant changes the endocrine backbone, and abemaciclib [serves as] a different CDK4/6 inhibitor from what the patient had received previously. Some data, including retrospective series from our institution, demonstrate that in a subset of patients, fulvestrant plus abemaciclib has activity even after prior progression on palbociclib [Ibrance] or ribociclib [Kisqali].
[The decision comes down to] a discussion with the patient. Many times, in the metastatic setting, the therapies are used sequentially. Therefore, one could start with one therapy, get the maximum mileage out of the therapy and then move on to the next one.
In terms of scientific rationale, given that this patient has a PIK3CA and PTEN mutation, specifically a loss of function PTEN mutation, which would decrease the activity of a PI3 kinase inhibitor, in the presence of a HER2 mutation, which might be a driver mutation, one could make the case for using neratinib first, which would impact the HER2 mutation. However, all of these are reasonable options. It’s a matter of starting with one therapy and monitoring closely at the time of disease progression, then switching to the other therapy.
It’s nice that this patient has multiple options. The recommendation was that the patient should start fulvestrant plus another targeted therapy, be it alpelisib or neratinib, or even abemaciclib.”
“The second case is a 55-year-old female with metastatic HER2-positive breast cancer who had T2N1 localized invasive breast cancer. She underwent lumpectomy with radiation therapy then received standard anti–HER2-directed therapy plus AC-THP [doxorubicin, cyclophosphamide, paclitaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta)], which was the standard chemotherapy backbone at that time. She completed 1 year of anti–HER2-directed therapy and was seen in active surveillance. In 2018 she developed abdominal pain, which prompted CT scans, leading to the discovery of hepatic metastases. [These metastases] were biopsied and confirmed to be HER2 positive, HR negative.
She started THP, which is the standard first-line therapy for HER2-positive breast cancer. Because it had been many years since her adjuvant therapy, the physician felt comfortable using THP per the CLEOPATRA trial. It worked for close to 2 years. Then the patient had disease progression and received second-line therapy with ado-trastuzumab emtansine [TDM-1; Kadcyla]. After about 6 months, the patient had disease progression.
The question is: What therapy should one consider next?
The poll options consisted of fam-trastuzumab deruxtecan-nxki [Enhertu], tucatinib [Tukysa], capecitabine [Xeloda], and trastuzumab [Herceptin], capecitabine/neratinib, and trastuzumab/lapatinib [Tykerb]. The poll was pretty much split between trastuzumab deruxtecan and tucatinib with trastuzumab and capecitabine.
We have a number of treatment options [in the third-line setting]. The NALA trial demonstrated that capecitabine plus neratinib is superior to capecitabine/lapatinib, resulting in FDA approval of neratinib. Earlier this year, the FDA approved tucatinib in combination with capecitabine and trastuzumab based on the HER2CLIMB trial, which demonstrated superior activity compared with the control group. Finally, trastuzumab deruxtecan, an ADC that targets HER2 is also FDA approved for the treatment of metastatic HER2-positive breast cancer.
These drugs have different flavors. All of them are active. They have different adverse effects [AEs], and also some difference in activity in patients who have brain metastases. All of those factors help with decision making.
The HER2CLIMB trial with tucatinib allowed patients who had progressive brain metastases to enroll in the trial, which is something that’s usually not done in clinical trials. Kudos to the investigative team and the FDA for allowing that. The study showed that tucatinib compared with the control group was more effective in controlling brain metastases. It’s clearly an agent that has activity in patients who have progressive brain metastases. In the clinical setting, if a patient has progressive brain metastases, tucatinib with trastuzumab and capecitabine is an attractive option.
Neratinib also has activity in that setting with capecitabine but tends to have more AEs in terms of diarrhea. Tucatinib in general is better tolerated compared with neratinib, but there are no head-to-head trials. But that’s the general perception, and looking at the data from clinical trials, it appears that tucatinib is better tolerated.
In terms of trastuzumab deruxtecan, very impressive activity was seen in the DESTINY-Breast01 study. The waterfall plot was something we’ve not seen in breast oncology; it was very impressive, with more than a 60% response rate. The median progression-free survival overall survival look very impressive if you look at the number of patients who are still on treatment. Therefore, it is a very active agent and something that should be considered for patients who have metastatic HER2-positive disease.
It’s a matter of sequencing. Do you start with tucatinib plus capecitabine and trastuzumab first and then switch to trastuzumab deruxtecan or vice versa? The factors of IV [intravenous] vs oral, AE profile, and the site of metastatic disease and whether a patient has brain metastases or not can help with these decisions. When asked if the [panelists] had a strong preference, they essentially said if the patient has progressive brain metastases, they would lean towards tucatinib. Otherwise, both of these [regimens] are reasonable to consider.”
“The third case is a 44-year-old premenopausal patient with TNBC who noticed a lump in her right breast. An exam revealed a big mass. The mammogram showed ill-defined borders in the right upper quadrant with associated calcifications. Ultrasound confirmed the hypoechoic mass, which was 4 cm in size. The biopsy confirmed poorly differentiated triple negative carcinoma, which was estrogen receptor, progesterone receptor, and HER2 negative.
The question is: What therapy should one consider next?
First, should we do neoadjuvant therapy followed by surgery or surgery followed by adjuvant therapy? In general, in TNBC, if a patient is a candidate for systemic therapy, the inclination is to consider neoadjuvant therapy. The consensus was to consider neoadjuvant therapy for this young patient with TNBC.
It gets more controversial in terms of the regimen to choose. We polled the audience, the options being neoadjuvant ACT, neoadjuvant ACT with carboplatin, neoadjuvant ACT, carboplatin plus pembrolizumab [Keytruda], or a clinical trial. The 2 options that were strongly considered were neoadjuvant ACT and neoadjuvant ACT with carboplatin. Those in favor of neoadjuvant ACT said that that’s the standard regimen. We feel very comfortable with this regimen, and it is something that is utilized widely. The argument for carboplatin is that it is associated with a higher response rate. If we talk about pathological complete response [pCR] rate, the CALGB 4603 trial demonstrated that the addition of carboplatin was associated with superior pCR compared with an anthracycline and taxane backbone, but it is also associated with higher toxicity, and that could be limiting to the point that you’re not able to give the chemotherapy that you want. It’s a balance and it’s a discussion with the patient.
In this patient who does not have lymph node–positive disease, the group felt that ACT would be a reasonable option to consider. But if the patient does not have a good response to the AC, that after completion of AC, when you’re using the paclitaxel, you could consider the addition of carboplatin at that time.
In terms of immunotherapy, the jury’s still out. The KEYNOTE-522 trial demonstrated the addition of pembrolizumab to an ACT plus carboplatin backbone was associated with higher pCR. The IMpassion031 trial also demonstrated that AC with nab-paclitaxel [Abraxane] and atezolizumab [Tecentriq] was associated with higher pCR. But these drugs are not FDA approved at this time, so any use of these agents would be off label. If there’s a young patient with lymph node–positive disease, sometimes there is an inclination to use immunotherapy with the consideration that it would result in higher cure rates potentially, and also the patient would be able to tolerate it better. However, we don’t have any evidence [of that] and it’s not FDA approved at this time, so it should be [given] in the setting of a clinical trial.
Finally, we reviewed clinical trials at our institution. We have a clinical trial with a novel agent called sacituzumab govitecan [Trodelvy], which got accelerated approval by the FDA for patients with metastatic TNBC. This trial is investigating this agent for patients with localized TNBC. After completing 4 cycles of sacituzumab govitecan, patients have the option of choosing additional therapy per investigator’s discretion. This has been a popular trial at our institution, and it’s something that would be considered if the patient is interested. It’s good to have options for patients with TNBC.”