Comment on "Long-Term Safety and Efficacy of the Fixed-Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Injection in Patients With HER2-Positive Early Breast Cancer in PHranceSCa, a Randomized, Open-Label Phase II Study".

Pertuzumab plus trastuzumab, administered intravenously (IV) with chemotherapy, is standard treatment for HER2-positive metastatic or high-risk early breast cancer. Pertuzumab and trastuzumab are administered over 1-2.5 h traditionally; however, the need for IV infusions places a strain on medical centers with respect to scheduling, preparation, and administration. A novel fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PHESGO®, PH FDC SC) can be administered in approximately 5-8 min. PH FDC SC was non-inferior to IV pertuzumab plus trastuzumab in terms of pertuzumab and trastuzumab serum levels in the phase III FeDeriCa study, which enrolled 500 patients with HER2-positive early breast cancer. Total pathologic complete response rates were comparable after PH FDC SC (59.7%) or IV pertuzumab plus trastuzumab (59.5%), as was the incidence of grade ≥3 (48.8% vs 52.8%) and serious adverse events (16.1% vs 17.9%). The results of a phase II clinical trial (PHranceSCa) showed that a majority of patients (85%) preferred PH FDC SC treatment over IV pertuzumab plus trastuzumab. A US multicenter expanded access study (NCT04395508) is evaluating the safety of PH FDC SC administered at home by nurse providers in patients receiving maintenance HER2-targeted therapy every 3 weeks. This product takes much less time to administer than IV pertuzumab-trastuzumab and has the potential to alleviate time constraints for patients and busy clinics. In this review we provide an overview of PH FDC SC, and discuss our experience in preparing and administering this product to patients with HER2-positive breast cancer during clinical trials.

Preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer (PHranceSCa): A randomised, open-label phase II study

Letter to the Editor Regarding the Article "Long-Term Safety and Efficacy of the Fixed-Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Injection in Patients with HER2-Positive Early Breast Cancer in PHranceSCa, a Randomized, Open-Label Phase II Study".

Long-Term Safety and Efficacy of the Fixed-Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Injection in Patients With HER2-Positive Early Breast Cancer in PHranceSCa, a Randomized, Open-Label Phase II Study.

Background: Intravenous pertuzumab (P IV) + trastuzumab (H IV) + chemotherapy (CT) improves outcomes in patients (pts) with HER2-positive breast cancer, compared with H + CT.A new subcutaneous (SC) formulation, for the first time combining two monoclonal antibodies, P + H, with recombinant human hyaluronidase in one vial, was developed. This ready-to-use fixed-dose combination (PH FDC) is administered subcutaneously into the thigh over 5-8 minutes. The dose of H SC was confirmed in the phase III HannaH trial (NCT00950300) and the dose of P SC was established in a phase Ib study (NCT02738970). We report the first results from FeDeriCa (NCT03493854), which was designed to assess the pharmacokinetics, efficacy, and safety of this novel SC PH FDC compared with H IV + P IV in pts with HER2-positive early breast cancer in the neoadjuvant-adjuvant setting. Methods: Pts with centrally confirmed HER2-positive invasive breast cancer (tumor >2 cm, or node-positive disease; Stage II-IIIC) were randomized 1:1 to receive 8 cycles of CT in the neoadjuvant setting with H IV (loading dose 8 mg/kg, maintenance 6 mg/kg) + P IV (loading dose 840 mg, maintenance 420 mg) (Arm A) or CT per Arm A + PH FDC (loading dose 1200 mg P SC/600 mg H SC, maintenance 600 mg each; Arm B) administered q3w during cycles 5-8. CT was investigator’s choice of either 4 cycles of dose-dense doxorubicin + cyclophosphamide q2w → 4 cycles of weekly paclitaxel (total: 12 weeks), or 4 cycles of doxorubicin + cyclophosphamide q3w → 4 cycles of docetaxel q3w. Post-surgery, pts continued anti-HER2 treatment per randomization to complete 18 cycles. The primary objective was noninferiority (NI) of the pre-dose cycle 8 P serum trough concentration (Ctrough) within the PH FDC versus P IV (NI margin for the lower bound of the 90% confidence interval [CI] of the geometric mean ratio [GMR]: ≥0.8). Key secondary objectives were NI of pre-dose cycle 8 H Ctrough within the PH FDC versus H IV, total pathologic complete response in the breast and axilla (ypT0/is, ypN0; tpCR), and safety (primary cardiac events were defined as heart failure [New York Heart Association III + IV] with significant left ventricular ejection fraction [LVEF] decline; cardiac death. Secondary cardiac events were defined as LVEF decline ≥10% from baseline to below 50% and confirmed LVEF decline). Results: Five-hundred pts were randomized (252 to Arm A, 248 to Arm B - ITT and safety populations) from 06/14/18-12/24/18 at 122 sites. At clinical cutoff (07/04/19), 242 pts (96.0%) in Arm A and 234 (94.4%) in Arm B completed the neoadjuvant treatment phase. Baseline pt demographics and disease characteristics were well balanced between arms.The study met its primary endpoint: P GMR was 1.22 (90% CI 1.14-1.31) with the lower limit of the 90% CI being above the prespecified NI margin of 0.8. H GMR was 1.33 (90% CI 1.24-1.43), meeting the NI criteria. tpCR rates were comparable between arms (59.5%; 95% CI 53.2-65.6 in Arm A and 59.7%; 95% CI 53.3-65.8 in Arm B) and were similar to other P + H + CT trials. Overall safety, including cardiac safety, was comparable between arms (Table). Safety was as expected for P + H + CT trials. Conclusions: SC PH FDC demonstrated noninferior pre-dose cycle 8 P + H Ctrough to that of P IV + H IV, with comparable efficacy and safety. PH FDC offers a faster and simpler method of P + H administration for HER2-positive breast cancer. Pts, %Arm A n = 252Arm B n = 248Any AE in >50% of pts99.6100Alopecia70.277.0Nausea60.358.9Diarrhea55.258.5Grade ≥352.848.8Serious17.916.1CardiacPrimary00.8Secondary3.61.6Asymptomatic LVEF decline needing treatment/discontinuation4.02.0Death0.4*0.4** Unrelated to HER2 treatment Citation Format: Antoinette R Tan, Seock-Ah Im, Andre Mattar, Ramon Colomer, Daniil Stroyakovskii, Zbigniew Nowecki, Michelino De Laurentiis, Jean-Yves Pierga, Kyung Hae Jung, Christian Schem, Sarah Heeson, Mahesh Shivhare, Whitney P. Kirschbrown, Eleonora Restuccia, Tanja Badovinac Crnjevic, Christian Jackisch. Subcutaneous administration of the fixed-dose combination of trastuzumab and pertuzumab in combination with chemotherapy in HER2-positive early breast cancer: Primary analysis of the phase III, multicenter, randomized, open-label, two-arm FeDeriCa study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD4-07.

Purpose Basal-like breast cancer, as defined by gene expression profiling, is associated with aggressive phenotype and poor clinical outcome. Recent immunohistochemical validation suggested that basal-like subtype could be characterized by staining for cytokeratin (CK) 5/6 and epidermal growth factor receptor (EGFR) in triple negative breast cancers (TNBCs). Most of studies evaluated surrogate immunopannel of biomarkers to define basal-like breast cancer subtypes only in the TNBCs, although not all basal-like breast cancers are triple negative breast cancers (TNBCs). The significance of basal marker expression in other than triple negative breast cancer remains to be evaluated. To define prognostic impact of basal marker expression in HER2 positive breast cancer, we investigated cytokeratin (CK) 5/6 and epidermal growth factor receptor (EGFR) expression in patients with HER2 positive early breast cancer. Patients and Methods: Biomarker evaluation was performed using five immunohistochemical surrogate panel of estrogen receptor (ER), progesterone receptor (PR), HER2, CK 5/6 and EGFR in HER2 positive early breast cancers. Amplification of HER2 was confirmed by fluorescent in situ hybridization. HER2-positive breast cancer was classified by expression of basal markers (either EGFR or CK5/6) as “basal HER2- positive” (patients with HER2- positive disease who express basal markers) and “non-basal HER2” (patients with HER2-positive disease who did not express basal markers). We compared the prognostic significance of the basal marker expression between two groups. RESULTS: HER2 overexpression was found in 24.8% of early breast cancers with available tissue specimens from the primary tumor (236 of 952 cases). Basal marker co-expression was identified in 12.7% of HER2 positive early breast cancers. (30 of 236 patients) Basal HER2 positive breast cancer was significantly associated with age greater than 50 years (P=0.012), absence of ER (P < 0.001) and PR (P=0.004). The basal marker co-expression in patients with HER2 amplified early breast cancers demonstrated poorer overall survival (basal positive vs. basal negative, 85.6 months [95% confidence interval (CI), 70.8- 100.3 months] vs. 122.3 [C.I. 133.7-139.9], P=0.001) and disease free survival (DFS) (44.6 months [95% CI, 14.7-74.8] vs 110.7 months [95% CI, 96.4-123.9]; P=. 008) respectively. In lymph node positive group, basal marker expression retained its statistical significance at the multivariate level (P=0.047) HER2 positive breast cancer with lymph node involvement with basal marker expression showed substantially poorer overall survival with 2.1-fold (95% CI, 1.0-4.2) risk for death. CONCLUSION: Considerable number of HER2 positive breast cancer co-expressed basal markers. Our data demonstrated that simultaneous basal marker expression in HER2 positive early breast cancer is associated with poor clinical outcome. The molecular significance of basal marker expression in HER2 positive breast cancer needs to be further investigated. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-03.

Background: Trastuzumab (T), a recombinant monoclonal antibody against HER-2 receptor, significantly improves overall (OS) and disease-free survival (DFS) in women with HER2 positive (HER2+) early breast cancer (EBC) when administered concurrent with or sequentially after adjuvant chemotherapy. Material and Methods: HERA (BIG 1-01) is an international, multicenter, phase III randomized trial involving 5102 women with HER2-positive (HER2+) EBC either nodal negative (tumor-size ≥ 1cm) or nodal positive. After completion of primary therapy, including surgery, chemotherapy and radiotherapy as indicated, patients (pts.) were randomized to T every 3 weeks for 1 yr, 2 years (yrs), or observation. Primary endpoint is DFS and secondary endpoints are OS and time to distant recurrence (TTDR). Here, we are presenting the HERA final analysis after 10 years of follow-up. Results: The clinical data cut-off for this final analysis of the HERA trial is June 2015. Data are being cleaned and final safety and efficacy analyses will be available for presentation at the meeting. Cardiac toxicity remained low and occurred mostly during the treatment phase. Citation Format: Jackisch C, Piccart MJ, Gelber RD, Procter M, Goldhirsch A, DeAzambuja E, Castro Jr G, Untch M, Smith I, Gianni L, Baselga J, Al-Sakaff N, Lauer S, Mcfadden E, Leyland-Jones B, Bell R, Dowsett M, Cameron D. HERA trial: 10 years follow up of trastuzumab after adjuvant chemotherapy in HER2 positive early breast cancer – Final analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD5-01.

97P Efficacy and safety of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer: Long-term data from the PHranceSCa study

Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study.

PurposeTo characterize pertuzumab pharmacokinetics (PK) in FeDeriCa (NCT03493854: fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] versus intravenous pertuzumab plus trastuzumab); derive individual pertuzumab exposures in the PH FDC SC arm for subsequent pertuzumab exposure–response (ER) analyses; compare observed trastuzumab PK with predicted exposures from a previous SC trastuzumab model; assess whether pertuzumab affects trastuzumab PK; evaluate pertuzumab exposure–efficacy and –safety relationships and support the approved SC dosing regimen.MethodsPopulation pharmacokinetic modeling and simulations were used to describe the data. Standard goodness-of-fit diagnostics and prediction-corrected visual predictive checks were used for model performance assessment. Covariates were included from previously reported models. ER analysis was conducted using logistic regression.ResultsSC pertuzumab PK was described adequately by a two-compartment model with first-order absorption; significant covariates included in the final model were albumin, lean body weight, and Asian region; however, these appeared not to be clinically relevant. Trastuzumab concentrations were described adequately by the previous model; there was no evidence of a pertuzumab effect on trastuzumab PK as part of PH FDC SC and higher model-predicted pertuzumab exposure was not associated with differences in pathologic complete response rate or an increased probability of selected grade ≥ 3 adverse events of interest.ConclusionThe approved PH FDC SC dose [loading: 1200/600 mg pertuzumab/trastuzumab (15 mL); maintenance: 600 mg pertuzumab/trastuzumab (10 mL) and 2000 U/mL recombinant human hyaluronidase every 3 weeks] provides a positive benefit–risk profile with comparable efficacy and safety to intravenous pertuzumab plus trastuzumab.

Background: MetaPHER investigates fixed-dose subcutaneous trastuzumab (Herceptin® [H SC]) in combination with intravenous (IV) pertuzumab (PERJETA® [P IV]) plus docetaxel (D IV). The MetaPHER study treatment regimen is based on CLEOPATRA (phase III; NCT00567190), which demonstrated a significant progression-free and overall survival benefit in patients (pts) with HER2-positive metastatic breast cancer (BC) following first-line treatment with IV trastuzumab (Herceptin® [H IV]) plus P IV plus D IV. Fixed-dose H SC was non-inferior to H IV in terms of pathological complete response and serum trough concentration, and had a comparable safety profile to H IV, in pts with HER2-positive early BC in HannaH (phase III; NCT00950300). Furthermore, PrefHer (NCT01401166) results showed compelling patient preference for H SC vs H IV (88.9% vs 9.6%) in the HER2-positive early BC setting. To date, limited data exist for H SC in combination with P IV and D IV; we report the first results of safety and tolerability from MetaPHER for this combination in pts with HER2-positive advanced BC. Methods: MetaPHER enrollment is ongoing at >100 sites in 12 countries. Females aged ≥18 years with metastatic or locally recurrent HER2-positive BC previously untreated with non-hormonal anticancer therapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, and left ventricular ejection fraction (LVEF) ≥50% receive fixed-dose H SC 600 mg/5 mL q3w, P IV (840 mg loading dose, then 420 mg at subsequent cycles q3w), and D IV (at least 6 cycles with a recommended initial dose of 75 mg/m2 q3w; possible escalation to 100 mg/m2 q3w and continuation of D IV after Cycle 6 at the investigator's discretion). Study treatment is given until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end, whichever occurs first. The primary endpoint is safety and tolerability of H SC in combination with P IV and D IV in pts with HER2-positive advanced BC. Adverse events (AEs) and serious AEs (SAEs) were graded per National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0. Results are descriptive. Results: 150 pts were enrolled and received a median of 4 treatment cycles by the data cutoff date of June 23, 2016. Safety data are shown in the table. Pts with ≥1 event, n (%)H SC + P IV + D IV (N = 150)Any grade AEs136 (90.7)Grade ≥3 AEs59 (39.3)SAEs23 (15.3)Deaths2 (1.3)AEs leading to discontinuation of H SC, P IV, or D IV16 (10.7)AEs leading to discontinuation of H SC5 (3.3)AEs of Interest Administration-related and local injection-site reactions for H SC5 (3.3)*Cardiac: Grade ≥3 cardiac AEs†1 (0.7)Any grade congestive heart failure‡0Pts with a significant LVEF drop§1 (0.7)*Grade 1 & 2 AEs only; †Events classified as System Organ Class Cardiac Disorders; ‡Preferred terms of reported AEs; §≥10% from baseline to LVEF <50%. Conclusion: MetaPHER's first report of H SC with P IV and D IV as first-line treatment for pts with HER2-positive advanced BC is consistent with the known safety profile for H IV with P IV and D IV from CLEOPATRA, and no new safety signals were identified. Citation Format: Kümmel S, Abraham J, Martin M, Crepelle-Fléchais A, Swat A, Nüesch E, Shing M, Tondini CA. MetaPHER phase IIIb multicenter, open-label, single-arm safety study of subcutaneous trastuzumab in combination with pertuzumab and docetaxel in patients with HER2-positive advanced breast cancer: First results [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-42.

BACKGROUND: Neoadjuvant therapy with trastuzumab and pertuzumab (HP) combined with chemotherapy (ChT) is the standard of care in ≥ cT2cN0 or N+ HER2-positive early breast cancer (EBC). Although cardiotoxicity is a known adverse effect of anti HER2-therapy and anthracyclines, recently BERENICE final analysis showed cardiac safety of HP in combination with standard or dose-dense anthracycline-based ChT. However, real-world data is lacking, specifically in patients (pts) with identified cardiovascular (cv) risk factors. Our study aimed to evaluate cardiac safety of HP and anthracyclines in HER2+ EBC and explore potential impact of body mass index (BMI). METHODS: This retrospective analysis included HER2+ EBC pts receiving neoadjuvant HP and anthracycline- and taxane- based ChT, at our institution, between 2016 and 2021. Baseline clinical, demographic, histopathological and immunohistochemical features were reported. Pts were categorized as underweight (< 18.5kg/m2), normal (≥18.5;< 25kg/m2), overweight (≥25;< 30kg/m2) and obese (≥30kg/m2), according to basal BMI WHO categories. The primary objective was to evaluate cardiac safety, assessed by incidence of left ventricular ejection fraction (LVEF) declines (≥10% from baseline and to a value < 50%) and NYHA class III/IV heart failure. Univariate and multivariate logistic regression analysis were performed using BMI as a categorical variable. Safety data were compared in subgroup analyses for underweight/normal and overweight/obese pts. Statistics were performed with IBM™ SPSS software, version 23. RESULTS: Our analysis enrolled 112 female pts, with a median age of 54 years (30-78), including 22pts (19.6%) with ≥65years and 55 (49.1%) postmenopausal women. Most pts (n=89; 79.5%) had HR-positive disease. 44pts (39.3%) had stage II and 68pts (60.7%) had stage III disease. According to BMI, pts were classified as underweight (n=3; 2.7%), normal (n=40; 35.7%), overweight (n=47; 42%) and obese (n=22; 19.6%). No association was found between BMI and tumor stage (p=0.829), grade (p=0.753) and HR status (p=0.212). Other baseline cv risk factors were identified: former/active smoker (n=34;30.4%), diabetes (n=10;8.9%), hypertension (n=30;26.8%), and dyslipidemia (n=32;28.6%). Most pts had ≥2 cv risk factors (n=66;58.9%). Two diferent regimes were used FEC100-D+HP (2016-2019, n=84) and ddAC-wkPaclitaxel+HP (2020-2021, n=28). Overall, pCR was achieved in 62 pts (55.4%). Regarding cardiac safety evaluation, 4 pts (3.6%) experienced at least one LVEF decline ≥10% from baseline and to a value < 50%, including 3 pts that were overweight/obese. Declines were reversible in all pts, with recovery by next assessment. Two pts (1.8%) experienced one NYHA class III heart failure event. Both pts were overweight/obese and had another concomitant risk factor for cardiovascular disease. Both pts discontinued treatment. No statistically significant association was found between overweight/obesity and cardiac events (OR 1.26, 95%CI 0.22-7.20; p=0.792). Median follow-up duration was 39 months. No new safety signals were identified. CONCLUSION: Cardiac safety of neoadjuvant HP in combination with anthracyclines in HER2-positive EBC in our real-world data is consistent with previous studies. Despite most cardiac events occurred in overweight/obese pts, no statistically significant effect was found. Further studies are needed to evaluate cardiotoxicity in pts with cv risk factors and evaluate impact of therapeutic interventions. Citation Format: Diana Simão, Mariana Sardinha, Lúcia Gil, Alexandra Montenegro, José Mendes, Leonor Fernandes, Patrícia Winckler, Ricardo Luz, Sónia Oliveira. Neoadjuvant trastuzumab and pertuzumab in combination with anthracyclines in HER2-positive early breast cancer: real-world data on effect of body mass index in cardiac safety [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-55.

e12609 Background: Neoadjuvant therapy is an important treatment strategy for HER-2 positive early breast cancer and Trastuzumab combined with Pertuzumab (HP) plus chemotherapy is the current standard treatment scheme. In recent years, multiple studies have revealed that the combination of Trastuzumab and Pyrotinib (HPy) has satisfactory efficacy and controllable toxic side effects. In clinical practice, how to choose a target regimen (HP or HPy) for HER-2 positive breast cancer patients is one of the key problems to be solved urgently. Methods: In this prospective, multicenter, observational real-world study (ChiCTR220056467), patients with stage II-III HER-2 positive breast cancer were assigned to the HP group or the HPy group according to the doctor's recommendation and their own wishes (specific programs include: 6 * TCbHP/6 * TCbHPy, 4 * EC-4 * THP/4 * EC-4 * THPy and 6 * THP/6 * THPy). The primary endpoint was total pathological complete response rate (tpCR, ypT0/isypN0), while the secondary endpoints were safety indicators, EFS and OS. Results: From January 2022 to December 2024, 687 patients from 10 hospitals were enrolled in the real-world study. As of now, 386 patients have completed neoadjuvant therapy and surgery with complete data, including 204 in the HP group and 182 in the HPy group, respectively. Statistical difference were observed in neoadjuvant chemotherapy and the expression levels of Ki-67. To reduce selection bias and ensure comparability of baseline data between two groups, propensity score matching (PSM) was performed in a 1:1 ratio. After PSM, 136 patients were equally divided and there was no statistically significant difference in baseline characteristic between the two groups. Before PSM, there was a statistically significant difference in tpCR rates between the HP group and the HPy group (63.24% vs 48.35%, P = 0.003); After PSM, the tpCR rate of the HPy group was consistent with that of the HP group, with no statistically significant difference (60.29% vs 61.76%, P = 0.860). Subgroup analysis showed that there was no statistically significant difference in tpCR rates between the HPy group and the HP group in each subgroup (all P interactions > 0.05). In terms of safety, 386 cases were included in the analysis, among which the most common adverse reactions in the HPy group were diarrhea (82.7%), nausea (80.4%), and vomiting (78.1%), while the most common adverse reactions in the HP group were anemia (66.7%), vomiting (55.9%), and leukopenia (49.3%). Conclusions: In the real-world study, HER-2 positive early breast cancer patients are more likely to use HP as neoadjuvant therapy, and HP are more likely to be used in combination with platinum drugs. Our study has confirmed that there is no significant difference in tpCR rates between HPy or HP. Clinical trial information: ChiCTR220056467 .

Background: Trastuzumab has been shown to be able to improve disease free survival(DFS) and overall survival(OS) in HER2-positive breast cancer patients. Adjuvant trastuzumab is empirically recommended for 1 year as a standard regimen. However, several studies claimed that shorter duration of adjuvant trastuzumab is non-inferior to 12 months treatment with reduced cardiac toxicities and costs. Methods: PubMed, EMBASE, Cochrane Library, Google scholar Web, ISI Web of Science, BIOSIS and CNKI, and major conference abstracts were searched systematically in June 2018 to identify eligible non-inferiority studies comparing the intervention outcomes of adjuvant trastuzumab in chemotherapy for women with HER-2 positive breast cancer between short-term and 1-year treatments. Hazard-Ratios(HR) and corresponding 95% Confidence Intervals(CI) were calculated to compare OS and DFS of trastuzumab between short-term and long-term treatments. Pooled data of Odds-Ratio was analyzed for cardiac toxicities. Results: 5 articles were finally eligible in the study. Totally, there were 11,376 women with HER-2 positive early breast cancer, with 5,684 in short-term group and 5,692 in the 1-year group. We found a distinct difference of DFS (HR=1.19, 95% CI=1.08-1.30) and OS (HR=1.22, 95% CI=1.07-1.39) between short-term and 12 months trastuzumab in the total analysis, which demonstrated short-term treatment exhibited a worsening trend on DFS and OS. Subgroup analysis was performed based on estrogen receptor (ER) and lymph node status, and no statistical interaction could be found(p=0.12, 0.52, respectively). The two groups with different duration of trastuzumab treatment displayed statistically significant difference for cardiotoxicities, which favored shorter duration(OR=0.54, 95% CI=0.38-0.77). Conclusions: 1-year adjuvant trastuzumab remains the standard strategy for HER2 positive early breast cancer, however, a concomitant higher risk of associated cardiac adverse effects should not be ignored. Citation Format: Li J, Wang G, Wu Q, Chen C, Tu Y, Yao F, Wei W, Sun S, Santa-Maria CA, Geng P. Efficacy and safety of shorter duration of adjuvant trastuzumab for patients with HER2 positive early breast cancer: A meta-analysis of randomized controlled trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-16.

Background: HER2-positive early breast cancer patients achieving a pathological complete response (pCR) during neoadjuvant therapy demonstrate a more favorable prognosis. The KATHERINE study indicated that for HER2-positive early breast cancer patients who did not achieve pCR (residual tumor lesions present) after neoadjuvant therapy, the administration of TDM-1 during postoperative adjuvant therapy significantly reduces the risk of disease recurrence compared to trastuzumab. This study aims to evaluate the efficacy and safety of trastuzumab in combination with pyrotinib and capecitabine in HER2-positive early breast cancer patients who did not achieve pCR following neoadjuvant therapy. Methods: This single-arm, open-label, multicenter study enrolled patients with HER2-positive early breast cancer who did not achieve pCR (defined as residual invasive tumor >1 cm or lymph node metastasis) following neoadjuvant therapy. Eligible patients received trastuzumab (initial loading dose of 8 mg/kg followed by 6 mg/kg every three weeks for one year, encompassing both neoadjuvant and adjuvant settings), pyrotinib (400 mg/day for one year post-surgery), and capecitabine (1000 mg/m2 twice daily for six 3-week cycles, with continuation at the investigator's discretion beyond six cycles). Primary prophylaxis with loperamide was administered to mitigate pyrotinib-induced diarrhea. The primary endpoint was 3-year invasive disease-free survival (iDFS), with secondary endpoints including distant disease-free survival (DDFS), overall survival, and safety. This study is registered with ClinicalTrials.gov (identifier NCT05292742). Results: From July 2021 to November 2023, a total of 102 patients were enrolled, all of whom did not achieve pCR following neoadjuvant therapy. As of May 31, 2024, with a median follow-up of 11.96 months, 8 iDFS events (all local recurrences or bone metastases, without distant metastases) and 4 DDFS events were reported. Regarding safety, 22 patients (21.6%) experienced grade ≥3 adverse events, with the most common being diarrhea (13.7%), white blood cell count decreased (2.0%), and hand-foot syndrome (1.0%). Adverse events led to the interruption of any agent in 66 patients (64.7%), discontinuation of any agent in 8 patients (7.8%), and dose reduction of any agent in 37 patients (36.3%). Conclusions: For patients with HER2-positive early breast cancer who did not achieve pCR (residual invasive tumor >1 cm or lymph node metastasis) following neoadjuvant therapy, the combination of pyrotinib, trastuzumab, and capecitabine as postoperative adjuvant therapy appears to improve prognosis. The overall safety profile of the regimen was acceptable, with no new safety signals identified. Primary prophylaxis with loperamide effectively reduced the incidence of grade ≥3 diarrhea during adjuvant therapy with pyrotinib. Citation Format: Chuan Wang, Fangmeng Fu, Shunguo Lin, Zhenchuan Song, Zhong Ouyang, Xiangjin Chen, Mengbo Lin, Guozhong Cui, Guohui Han, Wenhui Guo, Xia Chen, Lining Jia, Chuangui Song, Sumei Yang, Ruizhen Luo, Yu Yan, Yi Zeng, Debo Chen, Jianqing Lin, Fan Yang, Ruixue Huang, Yili Wang, Zhechao Zeng, Zhe Zhang. Trastuzumab Combined with Pyrotinib and Capecitabine as Postoperative Adjuvant Therapy in Non-Pathological Complete Response HER2-Positive Early Breast Cancer Following Neoadjuvant Therapy: A Multicenter Phase II Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-09-29.