Highlighting the clinical scenario of a 29-year-old woman with breast cancer, Tiffany Traina, MD, leads a discussion on challenges associated with accurate biomarker testing, tumor heterogeneity, and repeat biopsies.
Tiffany Traina, MD: My patient is a young woman. She was 29 back in 2017, [when she] palpated a mass in her left breast. This was outside of the United States at the time. She had quite a large mass, [which was stage] T3N1 on presentation. Biopsy locally showed a strongly estrogen receptor [ER]-positive cancer, ER 90%, PR [progesterone receptor] 50%, [and] HER2 [human epidermal growth factor receptor 2] negative, [and very low Q67]. [We] didn’t have more details than that. She had germline genetic testing, [which was] totally appropriate for a young woman developing breast cancer without any known hereditary alterations. As you’d imagine, she had no other comorbidities. [She had an] excellent [Karnofsky Performance Status] and was a healthy, young, 29-year-old woman.
She was given neoadjuvant anthracycline taxane–based regimen followed by docetaxel. [She] went on to breast conservation surgery and had an axillary dissection. She still had a great amount of residual disease—1.9 cm in the primary tumor [and] 1 positive node. We don’t know what the ER/PR/HER2 [status] was on that residual disease. She received radiation, then was started on tamoxifen as a premenopausal woman with an ER-positive breast cancer. No ovarian suppression at the time.
As I said, this was outside of the United States in 2017. She came to the United States for a job and presented with persistent, escalating sternal chest pain in 2020. Ultimately, [she] was working in a hospital setting, mentioned it to a colleague, got imaging performed, and the [positron emission tomography-computed tomography scan] showed multiple pulmonary nodules and a sternal bone lesion. The bone was biopsied and showed metastatic triple-negative breast cancer, ER 0, PR 0, HER2 low, [and] immunohistochemistry [IHC]1+. She came to see me and things just weren’t adding up, given her ER-positive primary, and this was a bone lesion. It just seemed a little suspicious. We biopsied 1 of the lung nodules, [which] confirmed metastatic ER-positive breast cancer 95%, but also strongly HER2 positive at [IHC]3+. [There was] real opportunity here.
In the first-line setting, I recommended paclitaxel/trastuzumab/pertuzumab. She agreed [and] went through 12 weeks of that, then we were able to drop the taxane for quality of life. She had a beautiful response. At that point, we tried to maximize endocrine therapy with ovarian suppression and an [aromatase inhibitor] and continued the trastuzumab/pertuzumab as a maintenance [therapy]. She did well for about a year, but then on subsequent imaging, developed progression of disease. At this point, [there was] progression in the bones pleural, hilar adenopathy, and progression of the pulmonary nodules.
Here we are in fall 2021, about less than a year ago but prior to Destiny-Breast03 [NCT03529110]. We started [trastuzumab emtansine] for her in that setting. She did really well at the first set of scans about 3 months later but started to develop limiting neuropathy in a significant way in her feet bilaterally. [She] was still working but [couldn’t] exercise [and] wasn’t running anymore because it was really bothersome to her. Follow-up imaging in February of this year unfortunately showed progression of disease more rapidly than I would’ve expected and anticipated—new lung lesions, more adenopathy, more bone lesions, [and] more pulmonary metastases. [The] neurology [specialist] was helping to manage the neuropathy, and they ordered a [magnetic resonance imaging scan] of the brain, which incidentally found these tiny subcentimeter parenchymal lesions. [There was] no other clear attribution of her symptoms to these lesions in the brain—no edema, no shift, [and] nothing else concerning. At that point, on the heels of all the other progression she had, she started capecitabine/tucatinib/trastuzumab and had been on denosumab because of the bone lesions. She has had a short-interval imaging already, having just started on that regimen, and is doing just fine. [She] is tolerating it well, thank goodness. [The] neuropathy has stabilized, so that’s fortunate. [She isn’t] having issues with hand-foot syndrome and is doing well so far.
Erika Hamilton, MD: Well, if there was an award for who had the most interesting case, I think you win that one. How often do you think cancer changes its stripes like this? Or is it tumor heterogeneity? Did you kill off 1 clone and she ended up with HER2? What do you make of that?
Tiffany Traina, MD: I think those are great hypotheses. I just wonder [whether] it had to do with the testing, not so much the biology. I don’t know that her biology changed so much. I think we were looking at a false negative on the bone biopsy in terms of her hormone receptors. As we know, HER2 testing is notoriously challenging and is sometimes difficult to reproduce. I was just thrilled to find a target that we have great drugs to be able to address.
Erika Hamilton, MD: Rita, what do you make of this case? When do you decide to rebiopsy a patient?
Rita Nanda, MD: I think that’s great. I do think this case is very puzzling, and like Tiffany said, I just wonder about the receptors up front initially. Receptors can change [approximately] 20% of the time, but I don’t generally see a HER2-negative tumor become HER2 positive. I’ve definitely seen heterogeneity. I’ve had a patient who had 2 very distinct populations within her breast. One was triple negative, and 1 was HER2 positive. It’s certainly possible that what remained behind was the HER2-positive clone. You’ve raised [great] points about the issues with bone biopsies and the reliability of doing receptors on the bone. It’s fabulous that you did that lung biopsy and found a great therapy for this patient. She’s so young. We don’t want to miss the opportunity to treat her very well. I suspect it was more of a testing issue than a heterogeneity issue, potentially.
Erika Hamilton, MD: I might share a [fascinating case] I had. I had a young [woman who] was [in] one of the first-line CDK4/6 trials. She had bulky disease, long mediastinal nodes, etc. She was on for over 3 years with a [gonadotropin-releasing hormone]. She developed 2 tiny lesions in the liver and everything else was stable. It was just these spots in the liver. I biopsied them, and they were HER2 positive. Now she’s subsequently been on HER2 therapy, [and] she’s been alive for [approximately] 7 years. I always think that’s what makes me pull the trigger on [performing a] biopsy—when something is happening that just doesn’t make sense, doesn’t feel right, [isn’t] behaving like I anticipate.
Rita Nanda, MD: One-hundred percent.
Erika Hamilton, MD: One of the other interesting things in this case was the capecitabine/trastuzumab/tucatinib and the fact that her brain metastases were small and you didn’t radiate them. Tell us a little about the evidence behind that.
Tiffany Traina, MD: I will say this is a multidisciplinary decision.
Erika Hamilton, MD: It wasn’t all you?
Tiffany Traina, MD: [The] patient, radiation oncologist, [and] everybody involved altogether made these decisions. She was asymptomatic. They were teeny tiny [lesions]. This was on the heels of seeing data from HER2CLIMB [NCT02614794], where a significant proportion of patients not only had brain metastases but untreated brain metastases. We saw beautiful benefit from drugs. I thought she was incredibly reliable. I had no doubt she would be following up to communicate any symptoms. We’d be keeping a close eye on her and had a bit of comfort in giving her this opportunity before we needed to move on to radiation, hopefully. We haven’t had to yet.
Transcript has been edited for clarity.