ABSTRACT
Background
Taxanes combined with trastuzumab plus either pertuzumab (THP) or pyrotinib (THPy) are standard first‐line treatments for HER2‐positive metastatic breast cancer (HER2+ MBC). Nevertheless, direct comparative evidence remains insufficient. This study compared the efficacy and safety of THP vs. THPy for HER2+ MBC.
Methods
The multicenter retrospective study comprised patients treated in first‐line with either THP or THPy from January 2018 to March 2025. Confounding factors were adjusted using 1:1 propensity score matching (PSM) and multivariable Cox regression. Progression‐free survival (PFS) was the primary endpoint, with clinical benefit rate (CBR), objective response rate (ORR), and safety as secondary endpoints.
Results
A total of 411 patients were enrolled (THP: 148; THPy: 263). After matching, 139 pairs formed. Before PSM, patients in the THPy group experienced a longer median PFS than those in the THP group (23.6 vs. 19.3 months, HR = 0.72, 95% CI: 0.53–0.97, p = 0.031). After PSM, THPy still provided a PFS benefit (23.6 vs. 17.3 months, HR = 0.68, 95% CI: 0.48–0.97, p = 0.033), with an adjusted HR of 0.44 (95% CI 0.30–0.66, p < 0.001). Before PSM, the THPy group had a lower ORR than the THP group (69.2% vs. 81.1%, p = 0.009), but after PSM, this disparity in ORR was no longer significant (74.1% vs. 79.9%, p = 0.254), and CBR remained comparable between the two groups throughout. THPy showed potential PFS benefit in the subgroup with de novo stage IV disease and liver metastasis. Gastrointestinal toxicities were more common in the THPy group, with diarrhea being the most prominent (any grade: 76.1%; grade ≥ 3: 22.7%).
Conclusions
THPy may provide PFS benefit over THP in HER2+ MBC, with suggestive advantages in patients with de novo stage IV disease and liver metastasis. A higher frequency of diarrhea and other gastrointestinal toxicities was observed in the THPy regimen.
Keywords: first‐line treatment, HER2‐positive, metastatic breast cancer, Pertuzumab, Pyrotinib
1. Introduction
Breast cancer is a leading malignancy among women worldwide. Epidemiological data from 2022 revealed that over 2 million women received a new breast cancer diagnosis, with over 665,000 succumbing to the illness [1]. An aggressive subtype characterized by Human epidermal growth factor receptor 2 (HER2) protein overexpression or gene amplification [2, 3], HER2‐positive breast cancer accounts for 15%–20% of all breast cancer cases. Compared with other subtypes, it is marked by high recurrence and metastasis rates, rapid progression in advanced stages, and poor prognosis [4].
The regimen of docetaxel, trastuzumab, and pertuzumab (THP) has been internationally established as the first‐line standard of care for HER2‐positive metastatic breast cancer (HER2+ MBC), firmly supported by the landmark CLEOPATRA study [5]. Pyrotinib, an oral, Chinese‐developed small‐molecule tyrosine kinase inhibitor (TKI), has emerged as a prominent therapeutic option in recent years. According to the PHILA research, docetaxel with trastuzumab and pyrotinib (THPy) significantly extended PFS in comparison to the placebo group, offering a novel first‐line treatment option [6]. Currently, the THP regimen has strong international recognition supported by extensive clinical experience, while the THPy regimen is growing in popularity domestically due to the convenience of oral dosing with pyrotinib and its inclusion in medical insurance schemes. As a result, both the THP and THPy regimens have been accorded Level I recommendations as first‐line therapeutic options for HER2+ MBC in the most recent Chinese Society of Clinical Oncology (CSCO) breast cancer guideline [7].
However, there is currently insufficient evidence in quality comparison data to distinguish between these two first‐line strategies in terms of efficacy. Although a recent real‐world study by Liu et al. [8]. provided preliminary insights, it was limited by a small sample size, did not reach statistical significance for the primary endpoint, and failed to provide an in‐depth analysis of the characteristics of beneficiary subgroups. Therefore, leveraging the real‐world cohort, the present study aimed to assess and compare the safety and efficacy outcomes of THPy to THP when given as first‐line therapy, focusing on identifying which patient subgroups benefit the most based on distinct clinical characteristics. The findings may provide valuable comparative insights from real‐world settings to inform individualized treatment strategies.
2. Materials and Methods
2.1. Study Setup and Patient Selection
Under a provincial regional responsibility framework, this multicenter, retrospective, real‐world study was carried out across medical facilities in 13 Chinese provinces (Table S1). The primary center (the Fifth Medical Center of Chinese PLA General Hospital) led the study design and established unified inclusion criteria, data collection procedures, and quality control standards. These standards were implemented by one designated medical center in each of the remaining 12 provinces (e.g., Hunan Provincial Cancer Hospital for Hunan Province) to conduct data collection within their respective provinces. Together, these participating institutions formed the other centers in this study. Within this framework, we recruited patients with HER2+ MBC who had started first‐line treatment from January 2018 to March 2025.
This study included female patients with histologically confirmed HER2+ MBC who were at least 18 years old. An immunohistochemistry (IHC) score of 3+ or an IHC score of 2+ combined with a positive fluorescence in situ hybridization (FISH) result was considered HER2 positivity [9]. According to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) [10], each participant had at least one measurable lesion and had started first‐line treatment with either the THP or THPy regimen. Patients were excluded if they had a concomitant diagnosis of another cancer, if crucial clinical or treatment information was missing, or if the disease‐free interval (DFI) from the end of neoadjuvant or adjuvant therapy to the first recurrence or metastasis was shorter than 12 months.
Ethical approval (Approval No. KY‐2025‐7‐145‐1) was obtained from the Ethics Committee of the Fifth Medical Center of Chinese PLA General Hospital. Given the retrospective design, informed consent from participants was waived.
2.2. Treatment
First‐line THP or THPy regimens (taxane regimens include paclitaxel, nab‐paclitaxel, and docetaxel) were administered to all included patients. Treatment assignment was not randomized, reflecting the real‐world design of the study. Following an individualized assessment of clinical data, health status, and preference, the treating physician made the final regimen decision. Initial dosing and subsequent modifications of these agents were overseen by the physician, tailored to each patient's distinct response and treatment tolerance. Upon discontinuation of taxane therapy because of toxicity, patients continued to receive dual anti‐HER2 therapy until disease progression, emergence of intolerable adverse effects, or patient‐initiated withdrawal.
2.3. Data Collection and Follow‐Up
The retrospective data collection was performed from electronic medical records and laboratory databases across all participating centers. IHC and FISH were utilized to evaluate hormone receptors, HER2, and Ki‐67. Priority was given to the most recent histopathological specimen obtained before or at the initiation of first‐line therapy. Specifically, if available, a biopsy from a metastatic lesion was selected; otherwise, the most recent pre‐treatment primary tumor specimen was used. Nuclear staining ≥ 1% for either the progesterone receptor (PgR) or the estrogen receptor (ER) was considered hormone receptor positive. Visceral metastasis was characterized radiologically as involvement of visceral organs (lung, liver, pleura, or central nervous system). Taxane cycles referred to the total number of taxane‐based chemotherapy cycles actually completed during first‐line treatment. Concomitant endocrine therapy included agents administered either concurrently with taxanes or as maintenance combined with anti‐HER2 therapy after taxane discontinuation. Treating physicians evaluated tumor response based on RECIST 1.1 criteria [10] through imaging studies such as chest CT and abdominal MRI. At baseline and every two treatment cycles, imaging evaluations were conducted to assess response, continuing until radiographically confirmed progression was documented. Adverse events were categorized per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and all patients were followed up through July 1, 2025.
2.4. Endpoints
Progression‐free survival (PFS) served as the primary endpoint, calculated as the time from first‐line treatment initiation to initial radiologically confirmed progression or death due to any cause. Secondary study objectives encompassed objective response rate (ORR), clinical benefit rate (CBR), and safety assessment. ORR referred to the proportion of patients with confirmed complete response (CR) or partial response (PR). The percentage of patients who attained a CR, PR, or stable disease (SD) lasting for ≥ 6 months was known as CBR.
2.5. Propensity Score Matching (PSM) and Multivariable Analysis
To reduce confounding by baseline factors, we first estimated propensity scores via a logistic regression model, and then performed 1:1 propensity score matching (PSM) based on these scores. This model covered a set of covariates, including age, menopausal status, ECOG performance status (ECOG PS), hormone receptor status, HER2 status, Ki‐67, disease stage at diagnosis, previous (neo)adjuvant trastuzumab, metastatic sites, and taxane regimen. The matching procedure employed the nearest‐neighbor algorithm, applying a caliper width of 0.2. Balance in baseline characteristics post‐matching was assessed using standardized mean differences (SMD), and an SMD < 0.1 was considered indicative of satisfactory covariate balance [11]. After PSM, multivariable Cox regression was performed, adjusting for all baseline characteristics used in the PSM model plus taxane cycles and concomitant endocrine therapy.
2.6. Data Analysis
Descriptive statistical techniques were used to describe the tumor responses and baseline patient characteristics. While continuous data were given as medians with interquartile ranges (IQR), categorical variables were displayed as counts and percentages. Between‐group comparisons of categorical variables were performed via Fisher's exact test. PFS was estimated using Kaplan–Meier curves, and group differences were evaluated using the log‐rank test. Cox proportional hazards regression models were used to calculate hazard ratios (HR) and their related 95% confidence intervals (CI). Exploratory subgroup analyses were prespecified to include age, menopausal status, ECOG PS, disease stage at diagnosis, hormone receptor status, HER2 status, Ki‐67, previous (neo)adjuvant trastuzumab therapy (yes vs. no), metastatic sites, and center type (primary center vs. other centers). All statistical analyses were performed using SPSS 27.0, GraphPad Prism 10.1, and R software (version 4.2.2). We defined statistical significance as a two‐sided P value of less than 0.05.
3. Results
3.1. Patient Characteristics
In total, 469 patients were initially screened, 411 patients satisfied the eligibility standards and were formally recruited into the study, with 263 assigned to the THPy cohort and 148 to the THP cohort (Figure 1). All baseline clinical characteristics, along with their distribution before and after PSM, are detailed in Table 1. Age, menopausal status, ECOG PS, hormone receptor status, HER2 status, disease stage at diagnosis, the presence of lung or bone metastasis, and center type did not differ significantly between the groups (p > 0.05). However, the frequency of brain metastasis was considerably greater (17.9% vs. 3.4%, p < 0.001), and the percentage of patients with prior trastuzumab therapy was higher in the THPy group compared to the THP group (28.1% vs. 18.2%, p = 0.025). On the other hand, compared with the THP group, both the incidence of liver metastasis (28.9% vs. 39.9%, p = 0.023) and the percentage of patients with Ki‐67 > 20% were considerably lower in the THPy group (78.3% vs. 89.9%, p = 0.003).
FIGURE 1.
Patient screening, enrollment, and propensity score matching flowchart. T, taxane (include: Paclitaxel, nab‐paclitaxel, and docetaxel); H, trastuzumab; Py, pyrotinib; DFI, disease‐free interval; PSM, propensity score matching.
TABLE 1.
Comparison of baseline characteristics before and after matching.
| Characteristics | Unmatched | Matched | ||||
|---|---|---|---|---|---|---|
| THPy N = 263 | THP N = 148 | P | THPy N = 139 | THP N = 139 | P | |
| Age (%) | 0.487 | 0.905 | ||||
| < 55 | 132 (50.2) | 69 (46.6) | 69 (49.6) | 68 (48.9) | ||
| ≥ 55 | 131 (49.8) | 79 (53.4) | 70 (50.4) | 71 (51.1) | ||
| Menopausal status (%) | 0.063 | 0.901 | ||||
| Non‐postmenopausal | 81 (30.8) | 59 (39.9) | 51 (36.7) | 52 (37.4) | ||
| Postmenopausal | 182 (69.2) | 89 (60.1) | 88 (63.3) | 87 (62.6) | ||
| ECOG PS (%) | 0.284 | 0.936 | ||||
| 0 | 154 (58.6) | 96 (64.9) | 92 (66.2) | 91 (65.5) | ||
| 1 | 100 (38.0) | 50 (33.8) | 44 (31.6) | 46 (33.1) | ||
| ≥ 2 | 9 (3.4) | 2 (1.4) | 3 (2.2) | 2 (1.4) | ||
| Hormone receptor status (%) | 0.675 | 0.809 | ||||
| ER‐negative and PgR‐ negative | 114 (43.3) | 61 (41.2) | 61 (43.9) | 59 (42.4) | ||
| ER‐positive and/or PgR‐ positive | 149 (56.7) | 87 (58.8) | 78 (56.1) | 80 (57.6) | ||
| HER2 status (%) | 0.487 | 0.879 | ||||
| IHC2 + and FISH positive | 41 (15.6) | 27 (18.2) | 26 (18.7) | 27 (19.4) | ||
| IHC3+ | 222 (84.4) | 121 (81.8) | 113 (81.3) | 112 (80.6) | ||
| Ki‐67 (%) | 0.003 | 1.000 | ||||
| > 20% | 206 (78.3) | 133 (89.9) | 124 (89.2) | 124 (89.2) | ||
| ≤ 20% | 57 (21.7) | 15 (10.1) | 15 (10.8) | 15 (10.8) | ||
| Disease stage at diagnosis (%) | 0.065 | 0.548 | ||||
| I–III | 144 (54.8) | 67 (45.3) | 62 (44.6) | 67 (48.2) | ||
| IV | 119 (45.2) | 81 (54.7) | 77 (55.4) | 72 (51.8) | ||
| Previous (neo)adjuvant trastuzumab therapy (%) | 0.025 | 0.642 | ||||
| No | 189 (71.9) | 121 (81.8) | 115 (82.7) | 112 (80.6) | ||
| Yes | 74 (28.1) | 27 (18.2) | 24 (17.3) | 27 (19.4) | ||
| Liver metastasis (%) | 0.023 | 0.803 | ||||
| No | 187 (71.1) | 89 (60.1) | 90 (64.7) | 88 (63.3) | ||
| Yes | 76 (28.9) | 59 (39.9) | 49 (35.3) | 51 (36.7) | ||
| Lung metastasis (%) | 0.689 | 0.902 | ||||
| No | 160 (60.8) | 93 (62.8) | 86 (61.9) | 87 (62.6) | ||
| Yes | 103 (39.2) | 55 (37.2) | 53 (38.1) | 52 (37.4) | ||
| Bone metastasis (%) | 0.710 | 0.714 | ||||
| No | 155 (58.9) | 90 (60.8) | 81 (58.3) | 84 (60.4) | ||
| Yes | 108 (41.1) | 58 (39.2) | 58 (41.7) | 55 (39.6) | ||
| Brain metastasis (%) | < 0.001 | 0.555 | ||||
| No | 216 (82.1) | 143 (96.6) | 132 (95.0) | 134 (96.4) | ||
| Yes | 47 (17.9) | 5 (3.4) | 7 (5.0) | 5 (3.6) | ||
| Visceral metastasis (%) | 0.866 | 0.708 | ||||
| No | 92 (35.0) | 53 (35.8) | 49 (35.3) | 52 (37.4) | ||
| Yes | 171 (65.0) | 95 (64.2) | 90 (64.7) | 87 (62.6) | ||
| Taxane regimen (%) | 0.744 | 0.967 | ||||
| Docetaxel | 102 (38.8) | 55 (37.2) | 54 (38.8) | 52 (37.4) | ||
| Nab‐paclitaxel | 122 (46.4) | 74 (50.0) | 66 (47.5) | 68 (48.9) | ||
| Paclitaxel | 39 (14.8) | 19 (12.8) | 19 (13.7) | 19 (13.7) | ||
| Taxane cycles | 0.083 | 0.148 | ||||
| Median (IQR) | 6 (5,9) | 7 (6,10) | 7 (6,10) | 7 (6,10) | ||
| Concomitant endocrine Therapy (%) a | 0.454 | 0.804 | ||||
| Yes | 58 (22.1) | 31 (20.9) | 32 (23.0) | 28 (20.2) | ||
| No | 170 (64.6) | 103 (69.6) | 94 (67.6) | 99 (71.2) | ||
| Unknown b | 35 (13.3) | 14 (9.5) | 13 (9.4) | 12 (8.6) | ||
| Center type (%) | 0.885 | 0.472 | ||||
| Primary center | 126 (47.9) | 72 (48.6) | 65 (46.8) | 71 (51.1) | ||
| Other centers | 137 (52.1) | 76 (51.4) | 74 (53.2) | 68 (48.9) | ||
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; IQR, interquartile range; PgR, progesterone receptor; THP, Taxanes + trastuzumab + pertuzumab; THPy, Taxanes + trastuzumab + pyrotinib.
Calculated based on the entire patient population. Within the HR‐positive subgroup, the rates were 38.9% (58/149) in the THPy group vs. 35.6% (31/87) in the THP group. After matching, the rates were 41.0% (32/78) and 35.0% (28/80), respectively.
Represents HR‐positive patients with incomplete follow‐up or unavailable treatment records, making it impossible to confirm whether they received concomitant endocrine therapy.
To address the baseline imbalances, a balanced cohort of 139 matched pairs was constructed using PSM (Table 1). After PSM, the SMD for all factors was below 0.1 (Table S2), indicating well‐balanced baseline characteristics between the groups. This balancing effect was visually demonstrated in the Love plot (Figure S1).
3.2. Tumor Responses
Table 2 shows the treatment responses of patients before and after PSM. Before PSM, the THPy group had a considerably lower ORR than the THP group (69.2% vs. 81.1%, p = 0.009). CR was achieved in 16 patients (6.1%) of the THPy group, compared with 2 patients (1.4%) in the THP group. PR was observed in 166 (63.1%) and 118 (79.7%) patients in the THPy and THP groups, respectively. SD ≥ 6 months occurred in 66 patients (25.1%) receiving THPy, compared with 19 patients (12.8%) in the THP group. The CBR was nearly identical in both treatment arms (94.3% vs. 93.9%, p = 0.875). After PSM, the ORR of 74.1% for THPy and 79.9% for THP were not significantly different (p = 0.254). Similarly, the CBR remained comparable at 97.7% vs. 93.5% (p = 0.426).
TABLE 2.
Tumor Responses before and after matching.
| Type of response, no. (%) | Unmatched | Matched | ||||
|---|---|---|---|---|---|---|
| THPy N = 263 | THP N = 148 | P | THPy N = 139 | THP N = 139 | P | |
| Complete response | 16 (6.1) | 2 (1.4) | — | 8 (5.8) | 2 (1.4) | — |
| Partial response | 166 (63.1) | 118 (79.7) | — | 95 (68.4) | 109 (78.4) | — |
| Stable disease | 76 (28.9) | 25 (16.9) | — | 34 (24.5) | 25 (17.8) | — |
| Stable disease (≥ 6 months) | 66 (25.1) | 19 (12.8) | — | 30 (21.6) | 19 (13.7) | — |
| Progressive disease | 5 (1.9) | 3 (2.0) | — | 2 (1.4) | 3 (2.2) | — |
| Objective response rate | 182 (69.2) | 120 (81.1) | 0.009 | 103 (74.1) | 111 (79.9) | 0.254 |
| Clinical benefit rate | 248 (94.3) | 139 (93.9) | 0.875 | 133 (97.7) | 130 (93.5) | 0.426 |
Abbreviations: THP, Taxanes + trastuzumab + pertuzumab; THPy, Taxanes + trastuzumab + pyrotinib.
3.3. Progression‐Free Survival (PFS)
By July 1, 2025, the median follow‐up time was 20.2 months (95% CI: 17.1–22.5) in the THPy group and 19.3 months (95% CI: 12.2–29.4) in the THP group. Before PSM, Kaplan–Meier curves (Figure 2A) demonstrated that the THPy group had a median PFS of 23.6 months (95% CI: 21.2–30.4), whereas the median PFS in the THP group was 19.3 months (95% CI: 13.2–23.3). THPy was linked to a substantially decreased risk of progression or death compared with THP (HR = 0.72, 95% CI: 0.53–0.97, p = 0.031). After PSM (Figure 2B), the PFS benefit remained significant with THPy (23.6 vs. 17.3 months, HR = 0.68, 95% CI: 0.48–0.97, p = 0.033). In a multivariable Cox regression analysis within the matched cohort, adjusting for baseline characteristics used in PSM plus taxane cycles and concomitant endocrine therapy (Table S3), the THPy remained associated with a significant PFS benefit (HR = 0.44, 95% CI: 0.30–0.66, p < 0.001).
FIGURE 2.
Kaplan–Meier curves of progression‐free survival(PFS). (A) Unmatched overall population; (B) Matched overall population; (C) Unmatched patients with prior (neo)adjuvant trastuzumab therapy; (D) Matched patients with prior (neo)adjuvant trastuzumab therapy; (E) Unmatched patients without prior (neo)adjuvant trastuzumab therapy; (F) Matched patients without prior (neo)adjuvant trastuzumab therapy. THPy, Taxanes + trastuzumab + pyrotinib; THP, Taxanes + trastuzumab + pertuzumab; HR, hazard ratio; CI, confidence interval.
Before PSM, among patients with previous trastuzumab exposure, those receiving THPy had a median PFS of 23.6 months, vs. 19.3 months in the THP group (HR = 0.83, 95% CI: 0.45–1.51, p = 0.541), indicating no statistically significant difference (Figure 2C). On the contrary, the median PFS was significantly extended in patients receiving THPy without previous exposure, relative to those in the THP group (24.9 vs. 20.6 months, HR = 0.67, 95% CI: 0.47–0.94, p = 0.022) (Figure 2E). After PSM, a consistent trend was maintained. The PFS difference between groups was not significant for patients with prior therapy (23.2 vs. 19.3 months, HR = 0.61, 95% CI: 0.26–1.40, p = 0.242) (Figure 2D). Conversely, in those without prior therapy, THPy showed a trend toward PFS benefit (23.6 vs. 16.3 months, HR = 0.69, 95% CI: 0.46–1.02, p = 0.062) (Figure 2F).
Exploratory subgroup analyses in the matched cohort confirmed a consistent PFS benefit for the THPy regimen in the majority of subgroups (Figure 3). THPy was associated with a markedly reduced risk of progression or death in patients with de novo stage IV disease (HR = 0.60, p = 0.037) and those with liver metastasis (HR = 0.47, p = 0.007). Substantial PFS benefits were also present in patients with non‐postmenopausal status (HR = 0.55, p = 0.034) and those with an ECOG PS 0 (HR = 0.61, p = 0.022). Furthermore, the suggestive potential benefit with THPy was noted in patients with a Ki‐67 ≤ 20% (HR = 0.38, p = 0.069) and those with HER2 IHC 3+ (HR = 0.68, p = 0.061). Exploratory analyses in the pre‐matching overall cohort showed similar trends (Figure S2). In particular, subgroup analysis stratified by center type showed favorable trends toward PFS benefit with THPy in both the primary center (matched HR = 0.67, p = 0.128; unmatched HR = 0.71, p = 0.116) and other centers (matched HR = 0.65, p = 0.088; unmatched HR = 0.71, p = 0.124). None of these reached statistical significance, but the HR results were consistent in direction across center types.
FIGURE 3.
Subgroup analysis of progression‐free survival (PFS) in the Matched Cohort. THPy, Taxanes + trastuzumab + pyrotinib; THP, Taxanes + trastuzumab + pertuzumab; ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; IQR, interquartile range; PgR, progesterone receptor; HR, hazard ratio; CI, confidence interval.
3.4. Safety
Of the 296 patients evaluable for safety, 176 were assigned to THPy and 120 to THP; the detailed data are summarized in Table S4. The THPy regimen was linked to a higher rate of gastrointestinal adverse events, with diarrhea being the most prominent (any grade: 76.1%; grade ≥ 3: 22.7%). Other symptoms, such as nausea and decreased appetite, were also relatively frequent. Hematologic toxicities were commonly observed in both groups; the incidences of neutropenia (any grade: 48.3%; grade ≥ 3: 15.0%) and leukopenia (any grade: 54.2%; grade ≥ 3: 9.7%) were slightly higher in the THP group.
4. Discussion
Based on real‐world data, this study compared the efficacy and safety of the THP and THPy regimens as first‐line therapy in patients with HER2+ MBC. The analysis showed that the THPy regimen yielded a statistically significant improvement in PFS, substantially reducing the risk of disease progression or death. Notably, in the matched cohort, the two regimens demonstrated comparable ORR and CBR. Subgroup analyses indicated that this PFS benefit was particularly pronounced in specific patient subgroups, including de novo stage IV disease and liver metastasis.
After PSM was performed to balance key baseline confounders, the ORR of the THPy and THP regimens was comparable. This may suggest that the significantly higher ORR observed for the THP regimen before matching was likely attributable to baseline imbalances. Notably, before PSM, the THPy group included a higher proportion of patients with brain metastasis and those previously treated with trastuzumab. These post‐matching ORR are consistent with those reported in key trials, approximately 80% for the THP regimen in CLEOPATRA and PUFFIN, and 83% for the THPy regimen in the PHILA study [5, 6, 12]. This result indicates that the two regimens may possess comparable initial tumor reduction capacity.
In this study, the THPy regimen yielded a statistically significant PFS improvement compared with the THP regimen, both before and after PSM. This finding is consistent with the trend of PFS benefit documented by Liu et al. [8]., despite the lack of statistical significance in their study's between‐group comparison. Numerically, the median PFS with the THP regimen was comparable to that reported in CLEOPATRA and PERUSE studies [5, 13], while the median PFS in the THPy regimen closely approximated that of the pyrotinib group in the PHILA study [6]. The collective findings from these studies are consistent with the effectiveness and generalizability of both THP and THPy regimens in real‐world clinical practice. This advantage of the THPy regimen may be explained by the synergistic mechanism between pyrotinib and trastuzumab. Specifically, trastuzumab targets subdomain IV of the HER2 receptor's extracellular region, while pyrotinib acts on the intracellular tyrosine kinase domain; their combined action creates a synergistic dual blockade. This combination not only achieves more comprehensive inhibition of the HER2 signaling pathway but also markedly enhances suppression of downstream key pathways [14, 15]. In addition, the combination promotes ubiquitination‐mediated degradation of HER2 receptors, resulting in profound suppression of the entire signaling network [16, 17].
Subgroup analyses demonstrated that the THPy regimen achieved significant PFS benefits in specific clinical subgroups. In the subgroup of patients diagnosed with liver metastasis, although such cases are typically associated with a poor prognosis [18], the THPy regimen still demonstrated significant disease control. This finding is consistent with the conclusions from the PHENIX and PHOEBE studies, which indicated clear benefits of pyrotinib in patients with visceral metastasis [19, 20]. Preclinical studies suggest that this benefit may arise from pyrotinib's modulation of the tumor microenvironment in liver metastasis [21, 22]. Additionally, the THPy regimen showed marked PFS efficacy in patients with de novo stage IV disease. However, we also noted that in the subgroup of patients who had previously received (neo)adjuvant trastuzumab, the PFS benefit of the THPy regimen did not reach statistical significance. This finding appears inconsistent with what was reported in some prior studies [6, 8]. Possible reasons include the subgroup's small sample size with limited statistical power, as well as the presence of other unmeasured confounding factors, such as a history of prior exposure to pertuzumab and/or HER2‐TKIs that was not systematically captured. Notably, the favorable trend of PFS benefit with THPy was generally consistent in direction across different center types, although subgroup analyses did not reach statistical significance. All subgroup analysis results are exploratory findings, and their definitive clinical significance requires validation in prospective studies.
Regarding safety, the main toxicity of the THPy regimen appeared to be gastrointestinal reactions, particularly diarrhea, which is consistent with the previously reported toxicity profile [6]. In contrast, the THP regimen was associated with more prominent hematologic toxicities, aligning with reports from prior literature [5]. It should be noted that safety data were missing for some patients in this study, and the analyses presented are primarily descriptive.
Although antibody‐drug conjugates (ADCs), represented by trastuzumab deruxtecan (T‐DXd), have shown exceptional benefit in the first‐line treatment of HER2+ MBC, as evidenced by the DESTINY‐Breast09 study, in which the T‐DXd plus pertuzumab regimen yielded a median PFS of 40.7 months and exhibited consistent PFS benefits across all predefined subgroups [23, 24], their widespread clinical application remains constrained by practical limitations such as drug accessibility, uneven distribution of medical resources, and treatment costs. Against this backdrop, the THPy regimen may have significant clinical value. This regimen not only offers high drug accessibility and favorable cost‐effectiveness but has also been recommended by multiple domestic guidelines, potentially providing an effective and feasible treatment alternative for patients who cannot access or are unsuitable for ADC‐based therapy. Further, more studies and health economic evaluations are needed to better define the optimal application scenarios and long‐term value of the THPy regimen within specific healthcare settings and patient populations.
5. Limitations
Nevertheless, this study has several limitations. Firstly, although PSM and multivariable Cox regression were used to adjust for confounding factors, the retrospective study design cannot fully eliminate the possibility of bias. Second, the absence of some safety data may affect the comprehensive evaluation of treatment safety. Third, the subgroup analyses are exploratory, and conclusions require further validation in prospective studies. Fourth, nearly half of the patients were enrolled from a single center, reflecting its role as the study initiator under the provincial regional responsibility system; although we took measures to minimize potential bias, caution is warranted when interpreting the results. Fifth, data on prior use of (neo)adjuvant pertuzumab and/or HER2‐TKIs were not systematically captured, which may have influenced outcome interpretation. These findings highlight that future investigations should integrate such data to fully assess their implications. Finally, the OS data were immature at analysis, requiring a longer follow‐up to confirm the final survival benefit.
6. Conclusion
In summary, among patients with previously untreated HER2+ MBC, the THPy regimen was associated with prolonged PFS compared with the THP regimen in this study population. Exploratory subgroup analyses suggested a potential PFS benefit with THPy in patients diagnosed de novo with stage IV disease and those with liver metastasis. However, this efficacy benefit was associated with a greater incidence of diarrhea and other gastrointestinal side effects with the THPy regimen. These findings suggest that THPy may represent a favorable treatment option in selected populations, although further validation is warranted.
Author Contributions
Meiqiong Kuang: writing – original draft, data curation, software, formal analysis, visualization, investigation. Jianbin Li: methodology, formal analysis, supervision, writing – original draft, funding acquisition,writing – review and editing, validation. Li Bian: data curation, supervision, writing – review and editing, resources. Shaohua Zhang: data curation, supervision, writing – review and editing, resources. Tao Wang: writing – review and editing, supervision, data curation, resources. Zhongsheng Tong: supervision, data curation, resources, writing – review and editing. Quchang Ouyang: data curation, resources, supervision, writing – review and editing. Zefei Jiang: conceptualization, methodology, funding acquisition, formal analysis, project administration, writing – review and editing, supervision, resources.
Funding
This work was supported by the National Science and Technology Major Project of China (2024ZD0519805) and the National Natural Science Foundation of China (82404074).
Ethics Statement
The Fifth Medical Center of Chinese PLA General Hospital's Ethics Committee granted approval for this study protocol (Approval No. KY‐2025‐7‐145‐1). As the study was retrospective in design, informed consent was not mandated.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1: Patient Distribution by Province and Leading Hospital.
Table S2: Baseline covariates before and after matching.
Table S3: Multivariable Cox Regression Analysis in PSM‐Matched Cohort (Adjusted for Baseline and Treatment Variables).
Table S4: Safety Profiles of the Two Regimens.
Figure S1: Love plot.
Figure S2: Subgroup analysis of progression‐free survival (PFS) in the unmatched Cohort.
Acknowledgements
We would like to offer our heartfelt appreciation to all participants for their invaluable contributions of clinical data to this study. We are also profoundly grateful to the clinicians, nursing staff, and data management professionals across all participating medical institutions.
Contributor Information
Jianbin Li, Email: docli1018@sina.com.
Zefei Jiang, Email: jiangzefei@csco.org.cn.
Data Availability Statement
A formal proposal detailing their intended usage may be submitted by researchers who are interested in the data. Access will be granted by the corresponding author, who is responsible for data stewardship, based on the reasonableness of the request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Patient Distribution by Province and Leading Hospital.
Table S2: Baseline covariates before and after matching.
Table S3: Multivariable Cox Regression Analysis in PSM‐Matched Cohort (Adjusted for Baseline and Treatment Variables).
Table S4: Safety Profiles of the Two Regimens.
Figure S1: Love plot.
Figure S2: Subgroup analysis of progression‐free survival (PFS) in the unmatched Cohort.
Data Availability Statement
A formal proposal detailing their intended usage may be submitted by researchers who are interested in the data. Access will be granted by the corresponding author, who is responsible for data stewardship, based on the reasonableness of the request.