QL1209 (pertuzumab biosimilar) versus reference pertuzumab plus trastuzumab and docetaxel in neoadjuvant treatment for HER2-positive, ER/PR-negative, early or locally advanced breast cancer: A multicenter, randomized, double-blinded, parallel-controlled, phase III equivalence trial.

BACKGROUND: This randomized, parallel-controlled, double-blinded, phase III equivalence study evaluated the equivalence of a proposed pertuzumab biosimilar QL1209 to the pertuzumab (Perjeta®) each with trastuzumab and docetaxel in neoadjuvant treatment of early or locally advanced breast cancer patients with HER2-positive, ER/PR-negative. METHODS: Eligible patients were randomly (1:1) assigned to receive 4 cycles of neoadjuvant QL1209 or pertuzumab each with trastuzumab and docetaxel, and adjuvant treatment. The primary endpoint was total pathologic complete response (tpCR), with equivalence margins of 0.76 to 1.32. RESULTS: Among the 585 patients enrolled, 257 and 259 patients were assigned to the QL1209 and pertuzumab groups, respectively. The tpCR rates were comparable in the QL1209 (109/255, 42.75%; 90% CI 37.65 to 47.84) and pertuzumab (117/259, 45.17%; 90% CI 40.09 to 50.26) groups. The tpCR risk ratio was 0.95 (90% CI, 0.80 to 1.11), and the 90% CI fell within the predefined equivalence margin. The most common grade ≥3 treatment-related adverse event was decreased neutrophil count (10. 9% vs. 12.7%) in the QL1209 and pertuzumab groups. CONCLUSIONS: QL1209 demonstrated equivalent efficacy and comparable safety profile to the reference pertuzumab in neoadjuvant treatment of HER2-positive, ER/PR-negative, early, or locally advanced breast cancer. TRIAL REGISTRATION: Chinadrugtrials.org CTR20201073; ClinicalTrials.gov NCT04629846.

Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer.

BACKGROUND: Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation-associated early breast cancer. METHODS: We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival. RESULTS: A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P = 0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest. CONCLUSIONS: Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.).

Unveiling the potential of breast MRI: a game changer for BI-RADS 4A microcalcifications.

PURPOSE: To assess the diagnostic performance of breast MRI for BI-RADS 4A microcalcifications on mammography and propose a potential clinical pathway to avoid unnecessary biopsies. METHODS: Bibliometrics analysis of breast MRI and BI-RADS 4 was provided. A retrospective analysis was conducted on 139 women and 142 cases of BI-RADS 4A microcalcifications on mammography from Fudan University Shanghai Cancer Center. The mammographic BI-RADS level and the MRI reports were compared with the final pathological diagnosis. RESULTS: Much attention has been given to breast MRI and BI-RADS 4 in the literature. However, studies on BI-RADS 4A are limited. Pathological results showed 117 cases (82.4%) were benign lesions, malignant cases of 25 (17.6%) in our study. The positive predictive values (PPV), specificity, sensitivity and negative predictive values (NPV) of MRI were 44.2% (23/52), 75.2% (88/117), 92.0% (23/25), and 97.8% (88/90), respectively. Therefore, 75.2% (88/117) of biopsies for benign lesions could potentially be avoided. There were 2.2% (2/90) malignant lesions missed. Logistic regression indicated that patients who are postmenopausal (HR = 2.655, p = 0.012), have a history of breast cancer (family history) (HR = 2.833, p = 0.029), and exhibit clustered microcalcifications (HR = 2.179, p = 0.046) are more likely to have a higher MRI BI-RADS level. CONCLUSIONS: Breast MRI has the potential to improve the diagnosis of BI-RADS 4A microcalcifications on mammography. We propose a potential clinical pathway that patients with BI-RADS 4A on mammography who are premenopausal, have no personal history of breast cancer (family history) or have non-clustered distribution of calcifications can undergo MRI to avoid unnecessary biopsies.

A randomized, multicenter phase III Study of once-per-cycle administration of efbemalenograstim alfa (F-627), a novel long-acting rhG-CSF, for prophylaxis of chemotherapy-induced neutropenia in patients with breast cancer.

BACKGROUND: F-627 (efbemalenograstim alfa) is a novel long acting granulocyte colony-stimulating factor (G-CSF) that contains two human G-CSF fused to a human immunoglobulin G2 (hIgG2) -Fc fragment with a peptide linker. This studyevaluated the efficacy and safety of F-627, also known as efbemalenograstim alfa (Ryzneuta®) in reducing neutropenia compared with filgrastim (GRAN®). METHODS: This was a multicenter, randomized, open-label, active-controlled non-inferiority study. Two hundred thirty nine (239) patients were enrolled in thirteen centers and received the chemotherapy with epirubicin (100 mg/m2) and cyclophosphamide (600 mg/m2) on day 1 of each cycle for a maximum of four cycles. Patients were randomized to receive either a single 20 mg subcutaneous (s.c.) injection of F-627 on day 3 of each cycle or daily s.c. injection of filgrastim 5 µg/kg/d starting from day 3 of each cycle. The primary endpoint was the duration of grade 3 or 4 neutropenia in cycle 1. The safety profile was also evaluated. RESULTS: The mean (SD) duration of grade 3 or 4 neutropenia in cycle 1 was 0.68 (1.10) and 0.71 (0.95) days for the F-627 and the filgrastim groups, respectively. The Hodges-Lehmann estimate of the between-group median difference (F-627 vs filgrastim) in the duration of grade 3 or 4 neutropenia in cycle 1 was 0 day and the upper limit of the one-sided 97.5% CI was 0 day, which was within the prespecified non-inferiority margin of 1-day. Results for all efficacy endpoints in cycles 2 - 4 were consistent with the results in cycle 1, however a trend towards a lower incidence and a shorter duration of grade 3 or 4 neutropenia and grade 4 neutropenia was observed in the F-627 group compared with the filgrastim group. The ANC nadir in the F-627 group was significantly higher than that in the filgrastim group in each cycle. A single fixed dose of F-627 was well tolerated and as safe as standard daily filgrastim. CONCLUSIONS: A single fixed dose of 20 mg of F-627 in each cycle was as safe and effective as a daily dose of filgrastim 5 µg/kg/d in reducing neutropenia and its complications in patients who received four cycles of EC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04174599, on 22/11/2019.

Adjuvant medial versus entire supraclavicular lymph node irradiation in high-risk early breast cancer (SUCLANODE): a protocol for a multicenter, randomized, open-label, phase 3 trial.

BACKGROUND: Supraclavicular nodal (SCL) irradiation is commonly used for patients with high-risk breast cancer after breast surgery. The Radiation Therapy Oncology Group (RTOG) and European Society for Radiotherapy and Oncology (ESTRO) breast contouring atlases delineate the medial part of the SCL region, while excluding the posterolateral part. However, recent studies have found that a substantial proportion of SCL failures are located in the posterolateral SCL region, outside of the RTOG/ESTRO-defined SCL target volumes. Consequently, many radiation oncologists advocate for enlarging the SCL irradiation target volume to include both the medial and posterolateral SCL regions. Nevertheless, it remains uncertain whether adding the posterolateral SCL irradiation improves survival outcomes for high-risk breast cancer patients. METHODS: The SUCLANODE trial is an open-label, multicenter, randomized, phase 3 trial comparing the efficacy and adverse events of medial SCL irradiation (M-SCLI group) and medial plus posterolateral SCL irradiation (entire SCL irradiation, E-SCLI group) in high-risk breast cancer patients who underwent breast conserving-surgery or mastectomy. Patients with pathological N2-3b disease following initial surgery, or clinical stage III or pathological N1-3b if receiving neoadjuvant systemic therapy, are eligible and randomly assigned (1:1) to M-SCLI group and E-SCLI group. Stratification is by chemotherapy sequence (neoadjuvant vs. adjuvant), T stage (T3-4 vs. T1-2), N stage (N1-2 vs. N3), and ER status (positive vs. negative). Other radiation volumes are identical in the two arms, including breast/chest wall, undissected axillary lymph node, and internal mammary node. Advanced intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), or tomotherapy techniques are recommended. Both hypofractionated and conventional fractionation schedules are permitted. The primary end point is invasive disease-free survival, and secondary end points included overall survival, SCL recurrence, local-regional recurrence, distance recurrence, safety outcome, and patient-reported outcomes. The target sample size is 1650 participants. DISCUSSION: The results of the SUCLANODE trial will provide high-level evidence regarding whether adding posterolateral SCL irradiation to medial SCL target volume provides survival benefit in patients with high-risk breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05059379. Registered 28 September 2021, https://www. CLINICALTRIALS: gov/ct2/show/NCT05059379 .

Highly-efficient low-cost polarization-sensitive organic photodetectors based on laminated self-assembly planar and bulk heterojunctions.

To overcome the severe problems arising from the insufficient light absorption of ultrathin self-assembly active layers and the high cost use of atomic force deposition (ALD)-grown low-leakage-current transport layers, we successfully developed a low-cost, simple and facile strategy of floating-film transfer and multilayer lamination (FFTML) for constructing highly-efficient ALD-free broadband polarization-sensitive organic photodetectors (OPDs) with the two commonly used structures of donor/acceptor planar heterojunction (PHJ) and donor:acceptor multilayer bulk heterojunction (BHJ). It was found that the PHJ-based polarization-sensitive OPD by FFTML possesses a low dark current due to the high carrier injection barrier, indicating it is more suitable to be applied in low polarized light detection scenarios. In contrast, the BHJ-based device by FFTML has a higher spectral responsivity in the whole wavelength due to more photo-excitons transferred to the donor:acceptor interface and dissociated into photoexcited carrirers. Furthermore, the film thickness, which is tuned by increasing lamination number of BHJ layers, has a big effect on the polarization-sensitive photodetection performance. The polarization-sensitive 4-BHJ OPD by FFTML finally achieved a high specific detectivity of 8.33 × 1010Jones, which was much higher than 2.72 × 1010Jones for the 2-BHJ device at 0 V. This work demonstrates that layer-by-layer lamination of self-assembly films can effectively improve the polarized-light detection performance, contributing significantly to the rapid development of the field.

Pamiparib in patients with locally advanced or metastatic HER2-negative breast cancer with germline BRCA mutations: a phase II study.

PURPOSE: To evaluate the efficacy and safety of pamiparib in patients with locally advanced or metastatic human epidermal growth factor receptor 2-negative (HER2-) breast cancer, with deleterious or suspected deleterious germline BRCA1/2 mutations (gBRCA1/2 m). METHODS: In this open-label, phase II, multicenter study in China (NCT03575065), patients with triple-negative breast cancer (TNBC cohort) or hormone receptor-positive (HR+)/HER2- breast cancer (HR+/HER2- cohort) and ≤ 2 prior lines of chemotherapy received pamiparib 60 mg orally twice daily in 28-day, continuous cycles. The primary endpoint was objective response rate (ORR; RECIST v1.1) by independent review committee. RESULTS: In total, 88 patients were enrolled (TNBC cohort: 62; HR+/HER2- cohort: 26). Median age was 45.5 (range: 27-67) years, and 60 patients (68.2%) had received 1 or 2 prior lines of chemotherapy; 42 patients (47.7%) had previously received platinum chemotherapy. In the TNBC cohort, ORR was 38.2% (95% confidence interval [CI] 25.4-52.3) and median duration of response (DoR) was 7.0 months (95% CI 3.9-not estimable). In the HR+/HER2- cohort, ORR was 61.9% (95% CI 38.4-81.9) and median DoR was 7.5 months (95% CI 5.6-14.8). The most common treatment-emergent adverse events (TEAEs), treatment-related TEAEs, and ≥ Grade 3 TEAEs were hematologic (including anemia, decreased neutrophil count, and decreased white blood cell count). Overall, 64.8% of patients had TEAEs leading to dose reduction and 2.3% had TEAEs leading to treatment discontinuation. CONCLUSION: Pamiparib showed encouraging efficacy and an acceptable safety profile in patients with locally advanced and metastatic HER2- breast cancer with gBRCA1/2 m. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03575065; July 2, 2018.

Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer.

BACKGROUND: Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy. METHODS: We conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease-free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause). RESULTS: At the interim analysis, among 1486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P<0.001). Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone. CONCLUSIONS: Among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone. (Funded by F. Hoffmann-La Roche/Genentech; KATHERINE ClinicalTrials.gov number, NCT01772472 .).

Integration of radiogenomic features for early prediction of pathological complete response in patients with triple-negative breast cancer and identification of potential therapeutic targets.

BACKGROUND: We established a radiogenomic model to predict pathological complete response (pCR) in triple-negative breast cancer (TNBC) and explored the association between high-frequency mutations and drug resistance. METHODS: From April 2018 to September 2019, 112 patients who had received neoadjuvant chemotherapy were included. We randomly split the study population into training and validation sets (2:1 ratio). Contrast-enhanced magnetic resonance imaging scans were obtained at baseline and after two cycles of treatment and were used to extract quantitative radiomic features and to construct two radiomics-only models using a light gradient boosting machine. By incorporating the variant allele frequency features obtained from baseline core tissues, a radiogenomic model was constructed to predict pCR. Additionally, we explored the association between recurrent mutations and drug resistance. RESULTS: The two radiomics-only models showed similar performance with AUCs of 0.71 and 0.73 (p = 0.55). The radiogenomic model had a higher predictive ability than the radiomics-only model in the validation set (p = 0.04), with a corresponding AUC of 0.87 (0.73-0.91). Two highly frequent mutations were selected after comparing the mutation sites of pCR and non-pCR populations. The MED23 mutation p.P394H caused epirubicin resistance in vitro (p < 0.01). The expression levels of γ-H2A.X, p-ATM and p-CHK2 in MED23 p.P394H cells were significantly lower than those in wild type cells (p < 0.01). In the HR repair system, the GFP positivity rate of MED23 p.P394H cells was higher than that in wild-type cells (p < 0.01). CONCLUSIONS: The proposed radiogenomic model has the potential to accurately predict pCR in TNBC patients. Epirubicin resistance after MED23 p.P394H mutation might be affected by HR repair through regulation of the p-ATM-γ-H2A.X-p-CHK2 pathway.

Acetylation of MORC2 by NAT10 regulates cell-cycle checkpoint control and resistance to DNA-damaging chemotherapy and radiotherapy in breast cancer.

MORC family CW-type zinc finger 2 (MORC2) is an oncogenic chromatin-remodeling enzyme with an emerging role in DNA repair. Here, we report a novel function for MORC2 in cell-cycle checkpoint control through an acetylation-dependent mechanism. MORC2 is acetylated by the acetyltransferase NAT10 at lysine 767 (K767Ac) and this process is counteracted by the deacetylase SIRT2 under unperturbed conditions. DNA-damaging chemotherapeutic agents and ionizing radiation stimulate MORC2 K767Ac through enhancing the interaction between MORC2 and NAT10. Notably, acetylated MORC2 binds to histone H3 phosphorylation at threonine 11 (H3T11P) and is essential for DNA damage-induced reduction of H3T11P and transcriptional repression of its downstream target genes CDK1 and Cyclin B1, thus contributing to DNA damage-induced G2 checkpoint activation. Chemical inhibition or depletion of NAT10 or expression of an acetylation-defective MORC2 (K767R) forces cells to pass through G2 checkpoint, resulting in hypersensitivity to DNA-damaging agents. Moreover, MORC2 acetylation levels are associated with elevated NAT10 expression in clinical breast tumor samples. Together, these findings uncover a previously unrecognized role for MORC2 in regulating DNA damage-induced G2 checkpoint through NAT10-mediated acetylation and provide a potential therapeutic strategy to sensitize breast cancer cells to DNA-damaging chemotherapy and radiotherapy by targeting NAT10.

A Retrospective Cohort Study Comparing Traditional Breast Conservation With Oncoplastic Surgery in Breast Cancer Patients After Neoadjuvant Chemotherapy.

BACKGROUND: To better understand the difference between traditional breast-conserving surgery (BCS) and oncoplastic surgery (OPS), we conducted a retrospective cohort study involving breast cancer patients who received neoadjuvant chemotherapy (NAC) and then underwent breast conservation at the Fudan University Shanghai Cancer Center. METHODS: A retrospective chart review was conducted. All breast cancer patients who received NAC and then underwent traditional BCS or OPS at the Fudan University Shanghai Cancer Center from January 1, 2008, to December 31, 2019, were included. RESULTS: Three hundred ninety-nine breast cancer patients received NAC and underwent traditional BCS, and 99 patients underwent OPS. The average age of the patients in the OPS group was younger than that in the BCS group (43 vs 48 years, P = 0.017). The size of the tumor assessed by ultrasonography at baseline in the OPS group was larger than that in the BCS group (31.3 vs 28.1 mm, P = 0.013). The same trend was observed in the clinical T stage and overall staging assessments before the administration of NAC in these 2 groups. Oncoplastic techniques were more frequently applied when tumors were located in areas with relatively few glands, such as the upper inner quadrant. There were no significant differences in the margins and distributions of pathological types and molecular subtypes between these 2 groups. The rates of pathological complete response were similar in the traditional BCS and OPS groups. CONCLUSIONS: Unlike traditional BCS, in breast cancer patients after NAC, the adoption of oncoplastic techniques makes breast conservation feasible, even in patients with large tumors, late stages, and unfavorable tumor locations.

Adjuvant tamoxifen switched to exemestane treatment in postmenopausal women with estrogen receptor-positive early breast cancer: A pragmatic, multicenter, and prospective clinical trial in China.

Objective: This post-approval safety study assessed the efficacy and safety of exemestane after 2-3 years of tamoxifen treatment among postmenopausal women with estrogen receptor-positive (ER+) early breast cancer in China. Methods: Enrolled patients had received 2-3 years of tamoxifen and were then switched to exemestane for completion of 5 consecutive years of adjuvant endocrine therapy. The primary endpoint was the time from enrollment to the first occurrence of locoregional/distant recurrence of the primary breast cancer, appearance of a second primary or contralateral breast cancer, or death due to any cause. Other endpoints included the proportion of patients experiencing each event, incidence rate per annum, relationships between human epidermal growth factor receptor 2 status and time to event, and relationship between disease history variables and time to event. Results: Overall, 558 patients were included in the full analysis set: 397 (71.1%) completed the study, 20 experienced an event, and 141 discontinued [47 owing to an adverse event (AE); 37 no longer willing to participate]. Median duration of treatment was 29.5 (range, 0.1-57.7) months. Median time to event was not reached. Event-free survival probability at 36 months was 91.4% (95% CI, 87.7%-95.1%). The event incidence over the total exposure time of exemestane therapy was 3.5 events/100 person-years (20/565). Multivariate analysis showed an association between tumor, lymph node, and metastasis stage at initial diagnosis and time to event [hazard ratio: 1.532 (95% CI, 1.129-2.080); P=0.006]. Most AEs were grade 1 or 2 in severity, with arthralgia (7.7%) being the most common treatment-related AE. Conclusions: This study supports the efficacy and safety of exemestane in postmenopausal Chinese women with ER+ breast cancer previously treated with adjuvant tamoxifen for 2-3 years. No new safety signals were identified in the Chinese population.

Trastuzumab emtansine (T-DM1) versus trastuzumab in Chinese patients with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy for HER2-positive breast cancer in the phase 3 KATHERINE study.

PURPOSE: In the KATHERINE study (NCT01772472), patients with HER2-positive early breast cancer (EBC) and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy who were treated with adjuvant trastuzumab emtansine (T-DM1) had a 50% reduction in the risk of an invasive disease-free survival (IDFS) event compared to patients treated with adjuvant trastuzumab. In metastatic disease, T-DM1 has resulted in higher rates of thrombocytopenia in Asian versus non-Asian patients. Here, we report safety and efficacy in Chinese patients from KATHERINE. METHODS: Patients with HER2-positive EBC and residual invasive disease after taxane- and trastuzumab-containing neoadjuvant chemotherapy followed by surgery were randomized 1:1 to 14 cycles of adjuvant T-DM1 or trastuzumab. The primary endpoint was time to an IDFS event. RESULTS: Among Chinese patients (T-DM1 n = 51, trastuzumab n = 50), T-DM1 treatment resulted in a 43% reduction in risk of an IDFS event compared to trastuzumab (HR = 0.57; 95% CI 0.25-1.31), with similar results for secondary endpoints. As in the global population, Chinese patients receiving T-DM1 versus trastuzumab had more grade ≥ 3 adverse events (AEs; 39.2% versus 4.1%) and AEs leading to treatment discontinuation (27.5% versus 0%). The most common grade ≥ 3 AE with T-DM1 was thrombocytopenia (21.6%), a frequency higher than the frequency in the global population (5.7%). Grade ≥ 3 hemorrhage was reported in 1 patient (T-DM1 arm). CONCLUSIONS: In the KATHERINE study, T-DM1 demonstrated increased efficacy compared to trastuzumab in Chinese patients. Consistent with previous data in Asian patients, T-DM1 was associated with more grade ≥ 3 AEs, and AEs leading to discontinuation, which was driven by an increase in thrombocytopenia.

Impact of clinical-pathological factors on locoregional recurrence in mastectomy patients with T1-2N1 breast cancer: who can omit adjuvant radiotherapy?

PURPOSE: Postmastectomy radiation therapy (PMRT) in T1-T2 tumors with 1-3 positive axillary lymph nodes (ALNs) is controversial. This study was to identify prognostic factors of locoregional control (LRC) following mastectomy with or without PMRT for patients with T1-2N1 breast cancer and to discuss the selection of patients who might omit PMRT. MATERIALS AND METHODS: Between January 2006 and December 2012, the data of 1474 postmastectomy patients staged pT1-2N1 were analyzed. PMRT was applied in 663 patients. LRC and disease-free survival (DFS) were calculated using the Kaplan-Meier method. Cox regression model was applied in the univariate and multivariate analyses to recognize the recurrence risk factors. RESULTS: With the median follow-up duration of 93 months (range, 5-168 months), 78 patients (5.3%) failed to secure LRC and 220 patients (14.9%) experienced any recurrence. The 7.7-year LRC and DFS was 94.9% and 85.4% respectively in the entire cohort. PMRT significantly improved 7.7-year LRC from 93.4% to 96.6% (p = 0.005), but not the DFS (p = 0.335). Multivariate analysis revealed that PMRT was an independent prognostic factor of LRC (p < 0.001), meanwhile, age ≤ 40 years (p = 0.012), histological grade 3 (p = 0.004), 2-3 positive nodes (p < 0.001) and tumor size of 3-5 cm (p = 0.045) were significantly associated with decreased LRC. The 7.7-year LRC for patients with 0, 1, and 2-4 risk factors was 97.7% / 98.9% (p = 0.233), 95.3% / 98.0% (p = 0.092), and 80.3% / 94.8% (p < 0.001) in the non-PMRT and PMRT group, respectively. CONCLUSIONS: In patients with T1-2N1 breast cancer, clinical-pathological factors including young age, histological grade 3, 2-3 positive nodes, and tumor size of 3-5 cm were identified to be predictors of a poorer LRC following mastectomy. Patients with 0-1 risk factor might consider the omission of PMRT.

Randomized and dose-escalation trials of recombinant human serum albumin /granulocyte colony-stimulating factor in patients with breast cancer receiving anthracycline-containing chemotherapy.

BACKGROUND: To evaluate the efficacy and safety of recombinant human serum albumin /granulocyte colony-stimulating factor (rHSA/G-CSF) in breast cancer following receipt of cytotoxic agents. METHODS: The phase 1b trial assessed the pharmacokinetics, pharmacodynamics, and safety of dose-escalation, ranging from rHSA/G-CSF 1800 µg, 2100 µg, and 2400 µg. Randomized controlled phase 2b trial was further conducted to ensure the comparative efficacy and safety of rHSA/G-CSF 2400 µg and rhG-CSF 5 µg/kg. In multicenter, randomized, open-label, parallel, phase 2 study, participants treated with anthracycline-containing chemotherapy were assigned in a ratio 1:1:1 to receive double delivery of rHSA/G-CSF 1200 µg, 1500 µg, and continuous rhG-CSF 5 µg/kg. RESULTS: Between December 16, 2014, to July 23, 2018, a total of 320 patients were enrolled, including 25 individuals in phase 1b trial, 80 patients in phase 2b trial, and 215 participants in phase 2 study. The mean duration of agranulocytosis during the first chemotherapeutic intermission was observed as 1.14 ± 1.35 days in rHSA/G-CSF 1500 µg, which was comparable with that of 1.07 ± 0.97 days obtained in rhG-CSF control (P = 0.71). Safety profiles were assessed to be acceptable ranging from rHSA/G-CSF 1800 µg to 2400 µg, while the double delivery of HSA/G-CSF 2400 µg failed to meet the noninferiority in comparison with rhG-CSF. CONCLUSION: The prospective randomized controlled trials demonstrated that rHSA/G-CSF was efficacious and well-tolerated with an approachable frequency and expense of application for prophylactic management of agranulocytosis. The double delivery of rHSA/G-CSF 1500 µg in comparisons with paralleling G-CSF preparations is warranted in the phase 3 trial. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02465801 (11/17/2014), NCT03246009 (08/08/2017), NCT03251768 (08/07/2017).

Pertuzumab and trastuzumab as adjuvant treatment for HER2-positive early breast cancer: outcomes in Chinese patients in the APHINITY study.

BACKGROUND: The addition of pertuzumab to trastuzumab plus standard chemotherapy as adjuvant therapy following surgery significantly improved invasive disease-free survival (IDFS) in patients with HER2-positive early breast cancer in the multinational randomized APHINITY trial (NCT01358877, BIG 4-11/BO25126/TOC4939G). We analyzed clinical outcomes in the subgroup of patients recruited at Chinese sites. METHODS: Patients were randomized to standard adjuvant chemotherapy plus 1 year of trastuzumab with pertuzumab or placebo. Patients recruited in mainland China, Hong Kong and Taiwan are included in this descriptive analysis. RESULTS: Chinese patients had similar demographic characteristics to the global population, but a higher proportion had nodal involvement. Although this subgroup analysis was not powered to detect statistical significance, a numerical improvement in IDFS was observed with the addition of pertuzumab to trastuzumab in Chinese patients (hazard ratio, 0.69; 95% confidence interval: 0.39-1.19; 3-year IDFS event-free estimates 92.5% [pertuzumab] and 91.7% [placebo]), which was consistent with the primary analysis of the global population. Further subgroup analyses showed numerical improvements in the Chinese node-positive, hormone receptor-negative and -positive subgroups, although confidence intervals were wide due to the low number of events. The incidence of diarrhea was higher in the pertuzumab arm, and no primary cardiac events occurred in Chinese patients in either arm. CONCLUSIONS: Pertuzumab, used in combination with trastuzumab and chemotherapy in APHINITY, is effective as an adjuvant treatment regimen for Chinese patients with HER2-positive early breast cancer in a setting with curative intent. The safety profile in Chinese patients was consistent with that of the global population.

A nomogram for predicting axillary pathologic complete response in hormone receptor-positive breast cancer with cytologically proven axillary lymph node metastases.

BACKGROUND: The objective of this study was to determine an axillary pathologic complete response (pCR) and its influencing factors in patients with hormone receptor (HR)-positive breast cancer and cytologically proven axillary lymph node metastases. A prediction nomogram was established to provide information for the de-escalation of axillary management in these patients after neoadjuvant chemotherapy. METHODS: The authors retrospectively enrolled all patients with HR-positive breast cancer in the neoadjuvant chemotherapy data set of Fudan University Shanghai Cancer Center. All data were prospectively collected. From 2007 to 2016, 533 consecutive patients were included. Multivariate logistic regression analysis was performed, after which a nomogram was constructed and validated. RESULTS: An axillary pCR was achieved in 168 patients (31.5%), the which was much higher than the proportion of those who achieved a breast pCR (103 patients; 19.3%). Patients who had human epidermal growth factor receptor 2-positive disease (P = .004), a better primary tumor response (P = .001), earlier clinical stage (P = .045), and lower estrogen receptor expression (P < .001) were more likely to achieve a lymph node pCR. The nomogram indicated an area under the receiver operating characteristic curve (AUC) of 0.84 (95% CI, 0.78-0.89) in the training set. The validation set showed good discrimination with an AUC of 0.75 (95% CI, 0.69-0.81). The C-index was 0.834 and 0.756 in the training and validation cohort, respectively. The nomogram was well calibrated. CONCLUSIONS: The authors developed and validated a nomogram for predicting axillary pCR in patients with HR-positive disease accurately by using clinicopathologic factors available before surgery. The model will facilitate logical clinical decision making and clinical trial design.

Current Status and Factors Influencing Surgical Options for Breast Cancer in China: A Nationwide Cross-Sectional Survey of 110 Hospitals.

BACKGROUND: There are limited nationwide data regarding breast cancer surgery in China. The Chinese Anti-Cancer Association's Committee of Breast Cancer Society and the Chinese Society of Breast Surgeons conducted a nationwide survey to examine the use of and barriers associated with surgical options among patients with breast cancer. METHODS: Surveys were sent via e-mail to the directors of 110 centers that performed at least 200 breast cancer operations in 2017. The electronic questionnaire contained 183 questions and covered six aspects, including demographic information about the hospitals and surgeons, surgical practice, and application of breast reconstruction. RESULTS: The selected hospitals were from 31 provinces or municipalities. The overall proportion of breast-conserving surgery (BCS) was 22%. Local gross domestic product was significantly related to the rate of BCS (p = .046). Sentinel lymph node biopsy was performed routinely in 76% of hospitals. Only 14.5% (16/110) of hospitals used the dual-tracer method, including radioisotopes. For patients with cN0 disease receiving BCS with one or two positive sentinel lymph nodes, 20% (22/110) of hospitals accepted omitting axillary lymph node dissection (ALND). For patients who underwent mastectomy, only 4% (4/110) of hospitals accepted omitting ALND. There was an obvious polarization trend in the proportion of oncoplastic breast-conserving surgery (OPS); 35/110 (32%) performed OPS in fewer than 10% of cases, whereas 36/110 (33%) performed OPS in more than 50% of cases. OPS was more likely to be performed in academic hospitals. Volume displacement was more commonly used than volume replacement (p < .001). Breast reconstruction was routinely performed in 96/110 (87%) of hospitals, 62% of which involved cooperation with the plastic surgery department. Factors influencing breast reconstruction after mastectomy included the establishment of a plastic surgery department, regional economy, and cooperation between the plastic and general surgery departments. Overall, the proportion of breast reconstruction procedures after mastectomy was 10.7%, with 70% being implant-based reconstruction, 17% autologous tissue reconstruction, and 13% a combination. Overall, 22% of the hospitals predominantly performed immediate breast reconstruction. For delayed reconstruction, two-stage implant-based breast reconstruction was the first choice for 46% of centers, whereas 20% of centers chose autologous reconstruction. Among the 96 centers that performed autologous-based reconstruction, 96% performed latissimus dorsi flap reconstruction, 65% performed transverse rectus abdominis musculocutaneous flap reconstruction, and 45% used deep inferior epigastric artery perforator flaps. CONCLUSION: The results are of great value for promoting the implementation of a consensus on diagnostic and treatment standards, development of guidelines for breast cancer, and training of breast specialists. IMPLICATIONS FOR PRACTICE: This study aimed to establish comprehensive baseline data on the status of current breast cancer treatment in China by presenting the statistics on clinical treatments and surgeries, the distribution of clinical stages, and the demographic characteristics of patients. This report is based on a survey conducted by the Chinese Anti-Cancer Association's Committee of Breast Cancer Society and the Chinese Society of Breast Surgeons, which examined the use of breast cancer surgical options in hospitals all over the country and the factors hindering the adoption of procedures and techniques. This study makes a significant contribution to the literature because there are limited nationwide data regarding breast cancer surgery in China.

Neoadjuvant therapy and sentinel lymph node biopsy in HER2-positive breast cancer patients: results from the PEONY trial.

OBJECTIVE: The aim of the study is to evaluate the optimal timing of sentinel lymph node biopsy (SLNB) in patients with clinical negative axillary lymph nodes (ALNs) before neoadjuvant therapy (NAT) and the feasibility of SLNB substituting for ALN dissection in patients with positive ALNs who convert to node negative, for HER2-positive disease. METHODS: Patients receiving SLNB with dual tracer mapping in the PEONY trial were analyzed. RESULTS: For 80 patients with clinical negative ALNs, the node negative rate by pathology after NAT was 83.8%. SLNB was performed after NAT in 71 patients. The identification rate of sentinel lymph nodes (SLNs) was 100%. For patients with positive ALNs before NAT, the axillary pathologic complete response rate in the dual HER2 blockade arm was significantly higher than that in the single blockade arm (p = 0.002). SLNB was performed in 71 patients. The identification rate was 100% and the false-negative rate was 17.2%. The false-negative rates were 33.3%, 14.3%, and 0 when 1, 2, and more than 2 SLNs were detected. There was no false-negative case when more than 1 SLN and the clipped nodes were removed simultaneously. CONCLUSIONS: For clinical ALN negative patients, HER2-positive subtype is found to have high node negative rate by pathology and it is recommended to undergo SLNB after NAT. For patients with positive ALNs who convert to negative, the false-negative rate is high. Dual tracer mapping, more than 2 SLNs detected, more than 1 SLN identified plus the clips placed are the guarantees for lower false-negative rate.

Pertuzumab, trastuzumab, and docetaxel for Chinese patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer (PUFFIN): a phase III, randomized, double-blind, placebo-controlled study.

PURPOSE: The Chinese bridging study PUFFIN (NCT02896855) aimed to assess consistency of efficacy with CLEOPATRA (NCT00567190), investigating pertuzumab with trastuzumab and docetaxel versus placebo, trastuzumab, and docetaxel in patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer. METHODS: Patients were randomized 1:1, stratified by visceral/non-visceral disease and hormone receptor status. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included objective response rate (in patients with measurable baseline disease), overall survival, and safety. The consistency threshold for PFS (hazard ratio [HR] < 0.81) (maintaining ≥ 50% of the risk reduction determined in CLEOPATRA [HR 0.62]) determined the target sample size (n = 240). RESULTS: Two hundred forty-three patients were randomized. Median PFS was 14.5 months in the pertuzumab arm (95% confidence interval [CI] 12.5, 18.6) and 12.4 months in the placebo arm (95% CI 10.4, 12.7) in the intention-to-treat population (HR: 0.69 [95% CI 0.49, 0.99]). Objective responses were recorded in 83/105 (79.0%) and 67/97 (69.1%) patients, respectively. Grade ≥ 3 adverse events (70.5% and 69.2%, respectively) and serious adverse events (19.7% and 19.2%, respectively) were similar across both arms. No heart failure cases or symptomatic left ventricular ejection fraction declines were reported. CONCLUSIONS: PUFFIN met its primary objective. Overall, efficacy data were consistent with CLEOPATRA. Safety was consistent with the known pertuzumab safety profile. PUFFIN adds to the totality of data with pertuzumab in previously untreated HER2-positive locally recurrent or metastatic breast cancer and supports the favorable benefit-risk profile of pertuzumab in Chinese patients TRIAL REGISTRATION: ClinicalTrials.gov, NCT02896855, registered 7 September 2016.