Real-World Study Sheds Light on Treatment Sequences and Second-Line Outcomes in HER2+ Breast Cancer


A real-world study dives into treatment sequencing data and indicates most patients with HER2-positive metastatic breast cancer discontinued second-line treatment in the US.

HER2+ Breast Cancer | Image Credit: © Sebastian Kaulitzki -

HER2+ Breast Cancer | Image Credit:

© Sebastian Kaulitzki -

A real-world study published in the International Journal of Clinical Oncology demonstrated that most patients with HER2-positive metastatic breast cancer discontinued second-line treatment in US community practices, which study authors noted underscores the need for timely second-line treatment.

Findings from the retrospective cohort revealed that at a median follow-up of 22 months (IQR, 13-37) from the index date, patients (n = 312) had received first vs second vs third-line treatment with HER2-targeted monotherapy (16% vs 33% vs 20%), HER2-targeted combination therapy (71% vs 56% vs 34%), chemotherapy alone (3% vs 4% vs 4%), a chemotherapy combination (7% vs 2% vs 2%), another regimen (3% vs 4% vs 3%), or no treatment (0% vs 0% vs 37%).

Additionally, 78% of patients received a trastuzumab (Herceptin)-based regimen with the most common regimens in the frontline including trastuzumab plus pertuzumab (Perjeta) and a taxane (40%); trastuzumab plus pertuzumab, a taxane, and carboplatin (11%); and trastuzumab monotherapy (10%).

“This observational study of [patients with] HER2-[positive] metastatic breast cancer routinely treated in clinical practice across the US shows that [the] majority of patients—88%—discontinued their second-line [treatment],” the study authors wrote. “Disease progression and intolerance/toxicity to current treatments were amongst the most common reasons noted for treatment discontinuation suggesting second-line effectiveness and tolerability continues to remain a challenge.”

In a sub-cohort of patients who received a trastuzumab-based second-line regimen (n = 116), patients had received first-line treatment with HER2-targeted monotherapy (22%), HER2-targeted combination therapy (59%), chemotherapy alone (1%), a chemotherapy combination (12%), or another regimen (5%). In the second line, patients received either HER2-targeted monotherapy (5%) or HER2-targeted combination therapy (95%). Finally, in the third line, patients received HER2-targeted monotherapy (24%), HER2-targeted combination therapy (32%), chemotherapy alone (2%), a chemotherapy combination (3%), another regimen (4%), or no therapy (35%).

“Also key to note was that of the 274 patients who discontinued second-line therapy 20% died during or just after second-line therapy,” study authors said. “Additionally, two-thirds of the patients [in the second line] also went on to receive a subsequent therapy. The results of this study highlight the patient attrition seen in the metastatic setting and further emphasize the need for effective treatments being used at the earliest opportunity in the metastatic setting.”

The retrospective cohort was comprised of patients included in the Syapse Learning Health Network database and additional data were captured from electronic health records (EHRs) by Certified Tumor Registrars with a February 28, 2022, data cutoff. Patients with HER2-positive metastatic breast cancer who were 18 years or older at metastatic diagnosis and received 2 or more prior lines of therapy in this setting were included in the study. Second-line therapy was initiated between January 2014 and the February 2021 index date, and patients had 2 or more clinical encounters in the EHR with at least 1 occurring after the index date.

Patients included were a median age of 59 years (IQR, 50-66) at the index date and almost all were female (99%); most were White (69%), were postmenopausal (56%), and had hormone receptor–positive disease (54%). Patients had de novo (62%) or recurrent disease (37%) at metastatic diagnosis with sites of distant metastases at the index date of bone (58%), distant lymph node (42%), lung (38%), liver (38%), brain (27%), and other (18%). Further, patients were from the Midwest (89%) or South/East (11%) in the US and had a Charlson Comorbidity Index score at metastatic diagnosis of 0 (17%), 1 (2%), 2 or higher (50%), or unknown (31%).

Study authors noted that as contemporary real-world data on treatment sequencing as well as clinical outcomes beyond the first line of therapy for patients with HER2-positive metastatic breast cancer are limited, the real-world study was of interest; they added this was especially so as second-line therapy shifted in 2022 following the approval of fam-trastuzumab deruxtecan-nxki (Enhertu) which showed improved efficacy vs ado-trastuzumab emtansine (Kadcyla).

The second line–associated clinical outcomes in the study revealed that the median time to treatment discontinuation (TTD) was 7.2 months (95% CI, 6.5-8.9) in the overall cohort. Patients achieved a median real-world progression-free survival (rwPFS) of 7.9 months (95% CI, 7.0-9.9) and the median time to next treatment (TTNT) was 10.6 months (95% CI, 8.8-13.3). In the sub-cohort, patients experienced a median TTD of 10.6 months (95% CI, 7.4-14.0), rwPFS of 13.6 months (95% CI, 8.3-20.2), and TTNT of 14.9 months (95% CI, 9.9-22.0).

“This real-world US study showed that approximately two-thirds of patients [in the second line] received subsequent therapy and disease progression was the most common reason for second-line discontinuation. [This highlights] the need for timely second-line treatment with the most efficacious drug to allow patients to achieve longer treatment duration and delayed progression,” study authors concluded.


Varghese D, Cruz GI, Johanson C, et al. A real-world study of treatment sequences and second-line clinical outcomes in patients with HER2-positive metastatic breast cancer in US community practice. Int J Clin Oncol. Published online March 25, 2024. doi:10.1007/s10147-024-02492-5

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