History, initial treatments and response
A 39-year-old woman presented in February 2023 with lower-back pain that had persisted since November 2022. She also noted a palpable and painful right breast mass since 2021, but did not seek consultation earlier due to the COVID-19 pandemic.
Physical examination found a large fungating tumour occupying the entire right breast without ulceration or bleeding, palpable right axillary lymph node (LN), and lumbar spine tenderness. PET-CT scan confirmed these findings, revealing diffuse bone metastases throughout the spine with right pleural involvement.
Biopsy of the right breast mass confirmed grade 2, hormone receptor (HR)–positive (ER8/PR8), HER2-low (HER2 2+ on immunohistochemical [IHC] analysis/FISH negative), invasive ductal carcinoma with a Ki-67 proliferation index of 30 percent. She was assessed to have stage cT4N3M1 breast cancer involving the lungs, bones and LNs.
The patient received four cycles of fluorouracil, epirubicin hydrochloride and cyclophosphamide between February and April 2023. At the same time, subcutaneous denosumab was given every 3 months to manage bone metastases and protect against skeletal-related events.1
A follow-up PET-CT scan in April 2023 showed significant regression of the right breast tumour, LNs, and bone metastases. The patient’s lung lesions had also resolved, and the pleural effusion had cleared. At this time, the LNs, bone, and lung lesions were non–fluorodeoxyglucose (FDG)-avid.
Following good response to chemotherapy and to avoid further toxicity, the patient was switched to maintenance hormonal therapy (ie, letrozole and leuprolide) and a CDK4/6 inhibitor (ribociclib) in May 2023, and remained disease-free for 11 months.1
Subsequent treatments and response
In April 2024, a PET-CT scan revealed recurrence in the right breast, bone, and liver. No PIK3CA mutation was identified. Treatment was changed to another CDK4/6 inhibitor, abemaciclib, and another hormonal therapy, fulvestrant, in May 2024.1 However, the patient did not respond to this regimen.
In July 2024, she experienced shortness of breath and was admitted to hospital. Imaging studies showed multiple stable liver metastases and a massive right pleural effusion with a mediastinal shift to the left. The disease had relapsed and the patient was in visceral crisis. At this time, her CA15-3 level was elevated at 642 U/mL. (Figure)
The patient underwent pleurodesis and was immediately started on the antibody-drug conjugate (ADC), trastuzumab deruxtecan (T-DXd), at 5.4 mg/kg (300 mg) Q3W.1 She received five cycles of T-DXd and had excellent response, with respiratory symptoms rapidly resolving and CA15-3 level decreasing to 65 U/L on 8 October 2024. (Figure) Except for mild nausea and fatigue, which resolved spontaneously, the patient tolerated T-DXd well and did not develop interstitial lung disease (ILD).
However, in November 2024, the patient complained of pelvic pain. Her CA15-3 level had increased to 112 U/mL. (Figure) A repeat PET-CT scan showed mixed response to ongoing treatment – largely quiescent disease (previous lung metastases remained resolved with minimal pleural effusion, and no new active distant metastasis) with evidence of metastasis to the pelvic bones and left femur, as well as multiple new active pleural lesions and nodal metastases. Palliative radiotherapy was initiated to treat the bone metastases.
Mixed response in multiple bilobed liver metastases prompted a repeat liver biopsy, which confirmed that the patient’s HER2 status had become negative (ie, from HER2 IHC score of 2+ to 0, and FISH negative). T-DXd was discontinued and capecitabine was started in December 2024, with plans to reassess treatment options pending results of next-generation sequencing (NGS) to identify potentially targetable mutations.1,2 Last seen in December 2024, the patient’s pelvic pain had improved with radiotherapy.
Discussion
Visceral crisis in patients with metastatic breast cancer (mBC) is defined as severe organ dysfunction as assessed by symptoms and signs such as dyspnoea, pleural effusion and, in our patient’s case, bone pain, as well as rapid disease progression. Treatment guidelines recognize this scenario as a clear clinical indication for the most rapidly efficacious therapy.1,3
Consistent with treatment guidelines, upon disease relapse with visceral crisis, our patient was promptly started on HER2-targeted ADC treatment with T-DXd, which is recommended in adults with unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy or experienced recurrence within 6 months of adjuvant chemotherapy.1,2
T-DXd’s approval for HER2-low mBC was based on the DESTINY-Breast04 trial results, which demonstrated improved survival vs physician-chosen chemotherapy. The study involved 557 patients with HER2-low mBC who had received prior chemotherapy or experienced recurrence within 6 months of adjuvant chemotherapy. In the overall population (regardless of HR status), progression-free survival (PFS) was 9.9 vs 5.1 months for T-DXd vs chemotherapy (hazard ratio, 0.50; 95 percent confidence interval [CI], 0.40–0.63; p<0.001), while median OS was 23.4 vs 16.8 months (hazard ratio, 0.64; 95 percent CI, 0.49–0.84; p=0.001). Confirmed objective response rates were also higher with T-DXd vs chemotherapy in all patients (52.3 vs 16.3 percent), and median time to response was rapid (2.73 vs 2.22 months).4 These results aligned with our patient’s experience, where T-DXd at the recommended dose of 5.4 mg/kg Q3W provided significant early response with marked symptom improvement (ie, rapid decrease in tumour marker and resolution of shortness of breath) during visceral crisis.
Of note, the present case highlights the need for ongoing biomarker assessment and molecular profiling to guide treatment decisions in mBC.5 In our patient’s case, the change in HER2 expression from low to negative during treatment, coupled with mixed response after initial symptomatic improvement and CA15-3 decrease, warranted a change in treatment from HER2-targeted therapy to chemotherapy.1,5
T-DXd is generally well tolerated, with self-limiting nausea and fatigue being the most common AEs in the author’s practice. While the author has not encountered ILD in clinical practice, it affected 12.1 percent of patients who received T-DXd in DESTINY-Breast04, underscoring the need for vigilance and continuous monitoring.2,4 ILD can be managed with corticosteroids. In patients with asymptomatic ILD or pneumonitis (ie, grade 1 severity), T-DXd may be temporarily withheld then resumed after appropriate ILD management. T-DXd should be discontinued in those who experience grade ≥2 ILD/pneumonitis.2,4,6,7
The present case provides an example of rapid, notable clinical response and meaningful control of relapsed disease with T-DXd in a patient in visceral crisis, who had a mixed response to prior therapies. While T-DXd can be administered any time after previous chemotherapy, early use in patients with relapsed HR-positive, HER2-low mBC could maximize benefits before further disease progression, while avoiding toxicities associated with prolonged chemotherapy, thus optimizing outcomes.
