PublishedOctober 7, 2026
JournalThe Oncologist
TrialRetrospective multicenter cohort (not a clinical trial; no registry ID)

Concurrent Radiotherapy With Adjuvant T-DM1 Shows More Thrombocytopenia, Liver Enzyme Elevation and Early Lung Changes Than With Trastuzumab in a Retrospective, Non-Randomized Study of 133 Patients

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Article Summary
  • In a retrospective, multicenter study of 133 women with HER2-positive stage I-III breast cancer treated at four hospitals in Istanbul between 2010 and 2024, concurrent adjuvant radiotherapy with T-DM1 (n = 50) was associated with higher rates of any-grade thrombocytopenia (70% vs 36.1%; P < .001), ALT elevation (20% vs 4.8%; P = .008), AST elevation (24.5% vs 2.4%; P < .001) and early pulmonary toxicity (48.8% vs 24.1%; P = .017) than concurrent radiotherapy with trastuzumab (n = 83).
  • In the full multivariable model, T-DM1 was not retained as an independent predictor; poorer ECOG performance status was the sole independent predictor of early pulmonary toxicity (adjusted OR, 11.9; 95% CI, 1.06-125.0; P = .044). Pertuzumab-adjusted sensitivity analyses kept the T-DM1 associations significant.
  • Treatment was not randomized and the groups differed at baseline, so the differences cannot be attributed to the drug alone. The authors describe the findings as hypothesis-generating and call for prospective validation.

Why This Study Matters

HER2 overexpression and/or ERBB2 amplification occurs in approximately 15%-20% of breast cancers. According to the authors, approximately 40-50% of patients with HER2-positive early breast cancer have residual disease after neoadjuvant therapy and surgery, and the KATHERINE trial established T-DM1 as the preferred adjuvant therapy for those patients (the authors cite 3-year DFS of 88.3% vs 77.0%, P < .001, from KATHERINE). Because adjuvant radiotherapy is typically given alongside systemic therapy, the safety of combining T-DM1 with radiotherapy matters in practice. The authors note that direct toxicity comparisons against standard trastuzumab with concurrent radiotherapy were lacking.

1
Any-grade thrombocytopenia: 70% (35/50) with T-DM1 vs 36.1% (30/83) with trastuzumab (P < .001); unadjusted OR 4.12 (95% CI, 1.94-8.74).
2
ALT elevation 20% vs 4.8% (P = .008); AST elevation 24.5% vs 2.4% (P < .001); all hepatic events were grade 1-2.
3
Early pulmonary toxicity: 48.8% vs 24.1% (P = .017), mostly grade 1, with one grade 3 event in the T-DM1 arm.
4
In the full multivariable model, T-DM1 was not retained as an independent predictor; poorer ECOG performance status was the sole independent predictor of early pulmonary toxicity (adjusted OR, 11.9; 95% CI, 1.06-125.0; P = .044).
5
The authors describe the findings as hypothesis-generating and call for prospective validation.

Study Design

Investigators reviewed clinical records from 2010 to 2024 at four hospitals in Istanbul, Türkiye (Medipol University, Koç University, Ümraniye Training and Research Hospital, and Acıbadem Maslak Hospital). Patients with HER2-positive stage I-III breast cancer who completed neoadjuvant chemotherapy with HER2-targeted therapy, had definitive surgery, and then received adjuvant HER2-targeted therapy with concurrent radiotherapy were included, with complete 1-year toxicity follow-up required. Treatment was not randomized: patients with residual disease received T-DM1 and those with pathologic complete response received trastuzumab. The primary endpoint was treatment-related toxicity rate; toxicities were graded with CTCAE v5.0 over the 1-year period of HER2-targeted therapy. This was a retrospective cohort, not a clinical trial, and no ClinicalTrials.gov ID exists. The authors declared no external funding.

Study at a glance

133 women across 4 hospitals: 50 received T-DM1 (3.6 mg/kg every 3 weeks, 14 cycles) and 83 received trastuzumab. Median radiotherapy dose was 50 Gy in both groups.

Patient Population

Mean age was 51.7 ± 12.0 years (range, 27-83). The groups were not comparable at baseline, and the authors say so directly. T-DM1 patients had worse ECOG performance status (14.6% vs 2.4% with ECOG 1; P = .013), different pathological N stage distribution (P = .006), more breast-conserving surgery (22.0% vs 3.7%; P = .002), fewer pCR (8.3% vs 67.6%), more carboplatin (26.0% vs 2.4%; P < .001) and more dual HER2 blockade with trastuzumab plus pertuzumab (84.0% vs 51.8%; P < .001). Radiotherapy parameters were balanced (median 50 Gy in both groups, P = .845; median 25 fractions, P = .691; IMRT 42% vs 38%, P = .687).

Primary Endpoint: Toxicity Results

Toxicity (any grade)T-DM1 + RT (n=50)Trastuzumab + RT (n=83)PUnadjusted OR (95% CI)
Thrombocytopenia70.0%36.1%< .0014.12 (1.94-8.74)
ALT elevation20.0%4.8%.0084.94 (1.46-16.74)
AST elevation24.5%2.4%< .00113.14 (2.80-61.68)
Early pulmonary toxicity48.8%24.1%.0173.00 (1.25-7.19); P = .012
Late pulmonary toxicity35.0%52.7%.099Not specified in source
Peripheral neuropathy4.0%4.8%1.000Not specified in source
Skin reactions32.7%33.8%1.000Not specified in source

Neutropenia, leukopenia and anemia showed no statistically significant intergroup differences, and febrile neutropenia was not observed in either arm.

Concurrent adjuvant T-DM1 and RT demonstrated higher but manageable hematologic, hepatic, and pulmonary toxicity compared with trastuzumab.
— Abstract conclusion, Aysan et al., The Oncologist (T-DM1 = trastuzumab emtansine; RT = radiotherapy)

Adjusted and Subset Analyses

Treatment type was a significant predictor in univariable analysis, but in the multivariable model adjusted for variables with P < .10, T-DM1 was not retained as an independent predictor. Because pertuzumab use differed between groups, the authors ran sensitivity analyses adjusting for pertuzumab exposure, in which T-DM1 associations remained significant.

Pertuzumab-adjusted sensitivity analysisAdjusted OR (95% CI)P
Thrombocytopenia3.85 (1.76-8.42).001
ALT elevation4.12 (1.18-14.35).026
Early pulmonary toxicity2.64 (1.08-6.47).034

In a subset restricted to dual HER2 blockade (T-DM1, n = 42; trastuzumab plus pertuzumab, n = 43), thrombocytopenia (69.0% vs 37.2%; P = .004) and early pulmonary toxicity (50.0% vs 23.3%; P = .012) remained significantly higher with T-DM1.

Safety Profile

Although grade 1 events predominated, all higher-grade thrombocytopenia (grades 2-4) occurred in the T-DM1 arm (grade 2: 14.3% vs 0%; grade 4: 5.7% vs 0%; severity distribution P = .035). Among patients with thrombocytopenia, 80.0% of T-DM1 cases and 100% of trastuzumab cases were grade 1. Hepatic toxicities were all grade 1-2. Of affected patients, early pulmonary toxicity was grade 1 in 75.0% (T-DM1) vs 84.6% (trastuzumab), with a single grade 3 event in the T-DM1 arm. Adverse events were managed with standard supportive care without permanent treatment discontinuation, and no treatment-related deaths occurred.

Interpretation and Broader Context

The authors conclude concurrent adjuvant T-DM1 and radiotherapy was clinically feasible but carries a distinct safety profile requiring vigilant hematologic, hepatic and pulmonary surveillance. They note that the 70% thrombocytopenia rate exceeds the 28-32% typically reported with T-DM1 in non-irradiated populations (a cross-study comparison, not a result from this study), and suggest the early pulmonary toxicity rate of 48.8% is higher than previously reported likely because they captured all radiographic abnormalities rather than only clinically overt pneumonitis. Mechanistic explanations in the paper (e.g., DM1 effects on megakaryocyte maturation) are the authors' proposals, not tested findings.

Limitations

Per the authors: the design was retrospective and non-randomized, with selection bias and residual confounding; baseline imbalances limit attribution of toxicity differences to the drug alone; post-hoc power was about 80% only for a 25-percentage-point difference (about 45% for 15 points; under 30% for toxicities occurring in under 10% of patients); 1-year follow-up cannot capture late complications; there was no blinded independent radiologic review; and the study was conducted in a single region. The authors describe the findings as hypothesis-generating.

Primary source: DOI 10.1093/oncolo/oyag372 · PubMed 42768455 · PMC13645421

References

  1. Aysan M, Koylu B, Bayramgil A, et al. Comparative safety of concurrent adjuvant trastuzumab emtansine vs trastuzumab with radiotherapy in HER2-positive early breast cancer. The Oncologist. 2026. DOI: 10.1093/oncolo/oyag372. PMID: 42768455. PMCID: PMC13645421.