Case Presentation: Treating Patients With HER2-Positive Breast Cancer Case Presentation

Betsy is a healthy 30 year female who developed right ear pain and right jaw pain around 2 weeks after a dental exam. She returned to the dentist who found no issues with her teeth. Due to progressive numbness over the next month with extension into the right cheek and top right lip, she saw her primary care physician who ordered a brain MRI which showed a 3cm brain metastasis near the right pterogopalatine fossa. Additional imaging confirmed a right breast mass as well as three enlarged right axillary lymph nodes. Biopsies of both the breast mass and the brain metastasis confirmed Estrogen Receptor Positive (ER+) 100%, Progesterone Receptor Positive (PR+) 95% and HER2+ by immunohistochemistry (IHC 3+) breast cancer.

While HER2+ breast cancer makes up 15 to 20% of all breast cancer cases, a higher proportion of HER2+ breast cancer patients develop brain metastases than other breast cancer subtypes with some studies indicating that up to 50% of patients with HER2+ breast cancer will develop brain metastases over the course of their disease. Most metastases within the central nervous system (CNS) are intraparenchymal with a small percentage (5 to 14%) of patients have leptomeningeal metastases – although these metastatic sites are not mutually exclusive. Patients with brain metastases have worse outcomes than those without brain metastases (30.2 months vs 38.3 months) and patients with leptomeningeal metastases have the worst outcomes with medial survival at 3.5 to 4 months.

Betsy underwent stereotactic radiosurgery (SRS) of the brain metastasis and following radiation started on first line systemic therapy with Docetaxel/Herceptin/Pertuzumab (THP) from the CLEOPATRA trial. After 8 cycles of THP, all disease except the breast mass had resolved and she was transitioned to maintenance Herceptin/Pertuzumab.  

Dual treatment of brain metastases is recommended with the involvement of local therapies including radiation (like stereotactic radiosurgery, whole brain radiation) and/or surgical resection as well as systemic therapy. Historically, there has been a limited role for systemic therapy in brain metastases; however, studies like the CLEOPATRA trial, demonstrate that better systemic control of breast cancer leads to delayed development of CNS metastases. In the CLEOPATRA trial, patients who received THP had improved progression free survival (PFS; 18.7 months THP vs 12.4 months docetaxel/Herceptin (TH)) as well as improved overall survival (OS; 57.1 months THP vs. 40.8 months TH). While patients with brain metastases were excluded from the initial trial, a subsequent analysis showed that patients who received THP and developed brain metastases had improved progression free survival and overall survival than those patients who only received TH.

21 months after starting THP, Betsy developed multiple new 1-2cm liver hypodensities concerning for metastases. A biopsy of the largest liver metastasis confirmed metastatic cancer that was consistent with a breast primary and was ER+, PR+, HER2+.  Betsy was transitioned to second line therapy with T-DM1 with a significant decrease in her liver metastasis at 5 months. However, approximately 7 months into therapy, she developed a new frontal headache. Repeat brain MRI demonstrated a new 1.5cm lesion in the left parietal lobe as well as two smaller lesions that were concerning for additional metastatic sites. Repeat CT scan showed two additional small liver lesions but no other new sites of disease.  

T-DM1 was approved for second line therapy based on the EMILIA trial, of which patients had prior treatment with trastuzumab plus a taxane (but no Pertuzumab). The ongoing KAMILLA trial is evaluating the effect of T-DM1 in patients who have progressed on THP and investigators are including an exploratory CNS subgroup of which approximately 400 patients of the 2000 patient trial have active brain metastases. Recently published data suggests that T-DM1 does have activity in CNS disease with a brain metastasis overall response rate (ORR) of 21%, clinical benefit rate (CBR) of 43% and PFS of 5.5 months.

Betsy underwent SRS to the metastatic lesion in the left parietal lobe and subsequently was started on therapy with tucatinib/herceptin/capecitabine. Due to grade 3 fatigue, Tucatinib was dose reduced at the end of cycle 1 but capecitabine was kept at the same dose due to no sign of hand-foot syndrome and no laboratory abnormalities. At her next restaging scan in 3 months, she had no new brain metastases and her liver disease had decreased. She remained on Tucatinib/Herceptin/capecitabine for the next 18 months until staging scans showed explosive new disease in her liver and bones.

Tucatinib/Herceptin/capecitabine (THX) was evaluated in the HER2CLIMB trial, in which patients with active brain metastases were included. Patients with brain metastases who received THX had a longer 1 year CNS-PFS (40.2% vs 0% in the Herceptin/capecitabine (HX) arm) and a longer 1 year CNS-OS (70.1% THX vs 46.7% HX). Even more exciting was that patients with active brain metastases, which was defined as untreated brain metastases or treated and progressing with brain metastases also had an improved 1 year CNS-PFS (35.0% THX vs 0% HX) and a longer 1 year CNS-OS (71.7% THX vs 41.1% HX). 

Besty grew increasingly concerned about her disease progression. She has a young family and wanted to continue therapy. She was fatigued and was losing weight. Her oncologist discussed a clinical trial, but since she would have to travel away from home, she opted for the next line of standard care, trastuzumab deruxtecan. Within two months of starting trastuzumab deruxtecan, Betsy felt better. Her first restaging scans after starting trastuzumab deruxtecan showed a marked reduction in her tumor burden.

The DESTINY trial reported an impressive ORR of 60.9% in heavily pretreated patients (median 6 prior therapies), a PFS of 16.4 months and the median OS is yet to be reached. In the trial, median time to response is 1.6 months so if patients are going to respond, they respond quickly. The DESTINY trial included patients with treated, stable of asymptomatic brain metastases. While the CNS subgroup analysis was small (24 patients in total, 17 patients with measurable brain metastases at baseline), similar ORR and PFS to the general population suggesting trastuzumab deruxtecan has activity in the CNS.

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