Year Of Trastuzumab Research Articles

Efficacy and Safety Profile of Different Schedules of Adjuvant Trastuzumab Therapy among Patients with HER2-Positive Breast Cancer: Real-World Experience from a Tertiary Cancer Center in South India

One year of adjuvant trastuzumab is the standard of care for HER2-positive breast cancer. In low–middle income countries, delivery of 1-year trastuzumab is challenging due to significant financial burden. Evidence for shorter durations of adjuvant trastuzumab is gaining popularity in this regard. In this study, we compared the effectiveness and safety of 1 year versus shorter durations of adjuvant trastuzumab practiced in our center. In total, 312 patients were included in this analysis. The median age was 52 years. More than two-thirds of patients (67.6%) had stage 2 disease and majority were hormone-receptor-positive (62.5%). The median follow-up duration was 50 months. The 4-year disease-free survival was 97.3%. The 4-year disease-free survival for shorter durations of adjuvant trastuzumab was 98% compared with 96.7% in 1-year trastuzumab therapy group. In univariate analysis, stage at diagnosis was the only factor which had statistically significant association with disease-free survival. In multivariate analysis, none of the variables were found to be predictive of survival. Two patients (0.6%) had significant left ventricular ejection fraction decline.Shorter durations of adjuvant trastuzumab have comparable 4-year disease-free survival to standard 1-year therapy and is an alternative adjuvant treatment option for HER2-positive breast cancer patients in resource-limited settings.

Long-Term Outcomes of Adjuvant Trastuzumab for 9 Weeks or 1 Year for ERBB2-Positive Breast Cancer

The standard adjuvant treatment for patients with ERRB2-positive breast cancer is chemotherapy plus 1 year of trastuzumab. Shorter durations of trastuzumab administration improve cardiac safety, but more information is needed about their effect on survival. To compare survival outcomes after 9-week vs 1-year administration of trastuzumab with the same adjuvant chemotherapy. This post hoc secondary analysis of an open-label, multicenter, noninferiority-design randomized clinical trial included women aged 18 years or older with early ERBB2-positive, axillary node-negative or axillary node-positive breast cancer who were enrolled from January 3, 2008, to December 16, 2014, at 65 centers in 7 European countries. The current exploratory analysis was conducted after achieving the maximum attainable follow-up data when the last patient enrolled had completed the last scheduled visit in December 2022. Chemotherapy consisted of 3 cycles of docetaxel administered at 3-week intervals followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide at 3-week intervals. Trastuzumab was administered in both groups for 9 weeks concomitantly with docetaxel. In the 9-week group, no further trastuzumab was administered after chemotherapy, whereas in the 1-year group, trastuzumab was continued after chemotherapy to complete 1 year of administration. The primary objective was disease-free survival (DFS). Distant DFS and OS were secondary objectives. Survival between groups was compared using the Kaplan-Meier method and log-rank test or univariable Cox proportional hazards regression. Among the 2174 women analyzed, median age was 56 years (IQR, 48-64 years). The median follow-up time was 8.1 years (IQR, 8.0-8.9 years); 357 DFS events and 176 deaths occurred. Trastuzumab for 9 weeks was associated with shorter DFS compared with trastuzumab for 1 year (hazard ratio [HR], 1.36; 90% CI, 1.14-1.62); 10-year DFS was 80.3% in the 1-year group vs 78.6% in the 9-week group. The 5-year and 10-year OS rates were comparable between the 9-week and 1-year groups (95.0% vs 95.9% and 89.1% vs 88.2%, respectively; HR for all time points, 1.20; 90% CI, 0.94-1.54). In multivariable analyses, 9-week treatment was associated with shorter DFS compared with 1-year treatment (HR for recurrence or death, 1.36; 95% CI, 1.10-1.68; P = .005), but there was no between-group difference in OS (HR, 1.22; 95% CI, 0.90-1.64; P = .20). Only 4 patients (0.2%) died of a cardiac cause. In this secondary analysis of a randomized clinical trial, 1-year vs 9-week adjuvant trastuzumab was associated with improved DFS among patients with ERRB2-positive breast cancer receiving chemotherapy, but there was no significant difference in OS between the groups. ClinicalTrials.gov Identifier: NCT00593697.

Abstract PO2-19-05: Randomized Phase II trial evaluating three anti-diarrhoeal prophylaxis strategies in patients with HER2+/HR+ early breast cancer treated with extended adjuvant neratinib (DIANER GEICAM/2018-06)

Abstract Background: Neratinib (NER), and irreversible pan-HER tyrosine kinase inhibitor, is approved for the extended adjuvant treatment of HER2+/HR+ early breast cancer (EBC) patients within 1 year of trastuzumab (T)-based therapy completion. The ExteNET trial showed that the extended adjuvant NER compared with placebo modifies the risk of recurrence by an absolute rate of 2.5% at 5 years in HR+/HER2+ patients (Martin et al., 2017). However, without prespecified prophylaxis, diarrhoea was the most common reason for NER discontinuation in the first three cycles in said study. The CONTROL trial evaluated effectiveness of different anti-diarrhoeal strategies showing a reduction of severe diarrhoea and early discontinuation when indirectly compared to ExteNET (Chan et al., 2022). DIANER (NCT05252988) evaluates the 3 best reported anti-diarrhoeal strategies from CONTROL in patients receiving NER as per European approved label. Trial design and patients: DIANER is an international, multicenter, controlled, randomized, phase II study. Patients with HER2+/HR+ EBC (stage IB-IIIC) who completed prior neo/adjuvant T-based therapy within 2 weeks and 1 year will be included and randomized 1:1:1 to 3 treatment arms. Arm A: NER (240 mg/day[d] x 1 year) + loperamide (12 mg/d x 14 d → 8 mg/d till end of cycle 2 → as needed [PRN]), Arm B: NER dose escalation (120 mg/d x 7 d → 160 mg/d till d 14 → 240 mg/d x 13 cycles) + loperamide PRN, and Arm C: NER (like Arm A) + loperamide (12 mg/d x 14 d → 8 mg/d till end of cycle 1 → PRN) + colesevelam (3,750 mg/d x 28 d). Patients are stratified by menopausal status and prior anti-HER2 therapy (T versus T + pertuzumab). Specific aims: Primary objective is incidence of NER discontinuations due to diarrhoea in the first 3 cycles. Secondary objectives are: incidence of NER discontinuations; AEs and hospitalizations; duration, severity, and treatments for diarrhoea; NER exposure; and health-related quality of life (HRQoL) using FACT B and EQ5D-5L. Exploratory objectives include HRQoL using STIDAT; minimal residual disease and molecular alterations. Statistical methods: A maximum of 315 pts (105 per arm) will be needed using a Simon’s optimal two-stage design with the hypotheses of a desirable early discontinuation rate of 5% (H1) versus an undesirable early discontinuation rate of 13% (H0). In the first stage, arms with ≥ 4 pts discontinuing due to diarrhoea in the first 3 cycles, will be closed for enrolment. The 2-sided 90% confidence intervals using the method described by Koyama et al. (Koyama and Chen 2008) will be provided for the primary endpoint at the end of the 2nd stage of the Simon 2-stage design. Present accrual and target accrual: DIANER will take place in 81 sites in 5 European countries. As of Jul 10/2023 the study is open in 52 sites in Spain with 80 randomized patients. Contact information for people with a specific interest in the trial: Evelia Cortazar (Geicam PM): ecortazar@geicam.org Citation Format: Miguel Gil-Gil, Miguel Martín, Eva Carrasco, Elena Galve, Noelia Martínez-Jáñez, Santiago González-Santiago, Barbara Adamo, María Valero, Clara Martínez, Angel Guerrero, Silvia Antolin Novoa, Manuel Ruíz - Borrego, Isabel Blancas, Raquel Andrés, José L Alonso-Romero, ANDREA Vethencourt, J. Ignacio Chacón, Natalia Chavarría, Enrique Espinosa, Blanca Hernando, Encarnación Adrover, Federico Rojo, Maribel Casas, Leanne McCulloch, Jean-Claude Vedovato. Randomized Phase II trial evaluating three anti-diarrhoeal prophylaxis strategies in patients with HER2+/HR+ early breast cancer treated with extended adjuvant neratinib (DIANER GEICAM/2018-06) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-05.

Abstract PO2-20-10: Exceptional long-term disease control on pembrolizumab monotherapy in a patient with TMB-high PMS2-mutated MMR-deficient triple negative breast cancer brain metastasis

Abstract Introduction The brain is among the most common sites of breast cancer (BC) spread. Prognosis of BC brain metastasis (BCBM) differs by receptor subtype, with poorest median overall survival (OS) for triple-negative (TN) BCBM at under 5 months. Though treatment guidelines have evolved in recent years, most strategies have focused on local therapies including surgery and stereotactic radiotherapy (SRT), rather than on systemic agents. The 2020 FDA approval of pembrolizumab (pembro) for patients (pts) with metastatic high-tumor mutational burden (TMB-h, ≥ 10 mutations/megabase) solid tumors, agnostic of primary site, combined with clinical trials in melanoma reporting efficacy of immune checkpoint inhibitors (ICI) against BM, suggest a potential use of ICI for pts with TMB-h BCBM. Results of the TAPUR study supported modest therapeutic benefit of pembro for 28 pts with metastatic BC selected for TMB-h, with median OS of 30.6 weeks, but did not include pts with active BCBM. TMB-h is uncommon in BC, and further genomic signatures remain to be elucidated to identify pts with BCBM responsive to ICI. We present a remarkable case of a pt with Lynch Syndrome (LS) due to a germline PMS2 mutation, who developed TMB-h, mismatch repair (MMR)-deficient TN BCBM, and has maintained stable disease for over 6 years on pembro monotherapy. Case description A 62-y.o. woman underwent screening mammography that identified a right breast mass. Pt has a family history of a mother with uterine and pancreatic cancer, and father with bladder cancer. Biopsy confirmed invasive ductal carcinoma (IDC), grade 1 (G1), ER/PR-positive, HER2 score 0. She underwent partial mastectomy, axillary dissection, radiation, and received adjuvant anastrozole. Three years later, while still on anastrozole, she presented with a 6 cm right breast mass. Mastectomy disclosed G3, ER/PR-negative, HER2-positive (3+, Her2:CEP17 ratio 5.6) IDC. She received adjuvant chemotherapy (AC-T) and 1 year of trastuzumab. Seven years later, pt presented with headaches and word finding difficulties. MRI identified a 3.6 cm frontal mass, which biopsy revealed as TN BCBM. Systemic imaging ruled out distant metastases. Pt proceeded with SRT and exemestane (despite receptor staining ER- in case of a possible false negative result). Despite radiotherapy, pt had BCBM progression within the same year with the largest mass diameter grown to 4.8 cm. Resection (followed by SRT) identified the dominant histology as G3 TNBC. Following transition of care to our institution, germline testing revealed a pathogenic mutation in PMS2 (c943C >T). Tumor sequencing of the resected brain metastasis showed TMB of 48 and MMR deficiency. Therefore, systemic therapy with pembro monotherapy was initiated and maintained with good tolerability. Two years later, concern for progression from rising tumor markers led to addition of concurrent carboplatin/gemcitabine for 5 cycles. Imaging and tumor markers stabilized, and pt returned to pembro monotherapy. Today, 3 years later, and over 6.5 years after initial TN BCBM diagnosis, pt continues to have stable disease on pembro with an excellent performance status (ECOG 0) and no evidence of intracranial or extracranial progression. Discussion We document an exceptional case of prolonged benefit to pembro in a pt with TMB-h PMS2-mutated MMR-deficient TN BCBM. This case highlights two major pragmatic points to clinical practice; (i) the significance of germline testing in all pts with metastatic BC, and (ii) the impact of molecular testing of tumor tissue to identify rare alterations which may have dramatic effects on pt outcomes. Altogether, this case is a remarkable addition to growing evidence that TMB could be a biomarker for predicting response to ICI therapy and provides an example of ICI efficacy in the setting of BCBM. Further research on additional genomic, clinical, and pathologic features associated with ICI responsiveness is warranted for greater precision in BCBM management. Citation Format: Jaeyoon Cha, Albert Grinshpun, Lauren Buckley, Brian Alexander, Sara Tolaney, Nancy Lin. Exceptional long-term disease control on pembrolizumab monotherapy in a patient with TMB-high PMS2-mutated MMR-deficient triple negative breast cancer brain metastasis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-10.

Nine-Week Versus One-Year Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 10-Year Update of the ShortHER Phase III Randomized Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present the final analysis of the phase III noninferiority, randomized ShortHER trial comparing 9 weeks versus 1 year of adjuvant trastuzumab with chemotherapy in patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (BC). Women with HER2+ BC were randomly assigned to anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or 9-week trastuzumab (arm B, short). Here, we report the second coprimary end point overall survival (OS), updated disease-free survival (DFS), and outcomes according to hormone receptor status, age, and nodal status. At a median follow-up of 9 years, 10-year DFS is 77% versus 78% in the long versus short arm, respectively. Ten-year OS is 89% versus 88% in the long versus short arm, respectively. 10-year DFS rates in the long versus short arm according to nodal status are N0 81% versus 85%; N1-3 77% versus 79%; and N4+ 63% versus 53%. Ten-year OS rates in long versus short arm according to nodal status are N0 89% versus 95%%; N1-3 92% versus 89%; and N4+ 84% versus 64%. The updated analysis of the ShortHER trial shows that 1-year trastuzumab is the standard treatment for patients with HER2+ early BC as noninferiority cannot be claimed. However, numerically, the differences for the patients at low or intermediate risk (N0/N1-3) is negligible, while patients with N4+ have a clear benefit with 1-year trastuzumab.

Nine-weeks versus one-year trastuzumab for early-stage HER2+ breast cancer: 10-year update of the Short-HER phase III randomized trial.

LBA637 Background: The ShortHER trial is a phase III non-inferiority, randomized trial comparing 9 weeks (short arm) versus 1 year (long arm) of adjuvant trastuzumab combined with chemotherapy in HER2+ eBC patients. The first primary end point of the study was the event-driven analysis of disease-free survival which was achieved in 2017, presented at ASCO 2017 and published in Annals of Oncology in 2018. The HR was 1.13 (90% CI 0.89-1.42) and the non-inferiority could not be claimed as the upper border of CI crossed the upper limit of 1.29 chosen as non-inferiority margin. According to a pre-planned Bayesian analysis, the probability that the short arm was not inferior to the standard one was 80%. Methods: 1254 HER2+ early breast cancer patients were stratified according to nodal status and randomized. Median age was 55 years (range 25-78); 672 (54%) patients were node negative, 383 (30%) with 1-3 positive nodes, 198 (16%) 4 or more positive nodes. At the time of the event-driven analysis, median follow up was 6 years, 200 DFS events and 78 deaths were reported. Here we report the overall survival,+ which was the second co-primary end point, updated DFS and outcomes according to nodal status. Results: Median follow-up is now 9 years, 248 DFS events and 116 deaths have been reported. The 10 year DFS is 77% in the long arm and 78% in the short arm (HR 1.06; 90% CI 0.86-1.31). The 10-year OS is 89% in the long arm and 88% in the short arm (HR 1.15; 90% CI 0.85-1.56). The DFS and OS data overall and by nodal status are summarized in the table below. Conclusions: At a median follow-up of 9 years, the ShortHER trial shows that 1 year trastuzumab is still the standard treatment for HER2+ eBC patients as non-inferiority cannot be claimed in terms of DFS or OS. Numerically however, the differences for the patients at low risk (N0) or intermediate risk (N 1-3) is negligible and patients with 4 or more positive lymph nodes have a clear benefit with 1 year trastuzumab. I. This long-term date can reassure clinicians if, for any reason a patient at low/intermediate risk has to stop trastuzumab and, more important, might facilitate access to a far less expensive treatment to the thousands of patients worldwide who cannot afford the cost of one year of trastuzumab. Clinical trial information: NCT00629278 . [Table: see text]

Perioperative HER2 targeted treatment in early stage HER2-positive breast cancer.

Although human epidermal growth factor receptor 2 (HER2)-positive breast cancer was associated with poor prognosis, it has been changed after the development of trastuzumab. There has been great progress in perioperative HER2-targeting treatment, and investigations of several novel drugs and their combinations are ongoing. Adjuvant trastuzumab with or without pertuzumab for 1 year in combination with concomitant chemotherapy has become a standard treatment in high-risk node-negative tumors or node-positive HER2-positive early breast cancer patients without residual disease or who have not received neoadjuvant treatment. For low-risk HER2-positive early breast cancer patients, adjuvant paclitaxel and 1-year trastuzumab are possible alternatives. For residual disease after neoadjuvant treatment, adjuvant trastuzumab emtansine (T-DM1) for 14 cycles is a standard treatment. Non-anthracycline chemotherapy with dual anti-HER2 targeting of trastuzumab and pertuzumab represents one of the preferred neoadjuvant regimens to achieve higher pathologic complete response (pCR) rates and better clinical outcomes. Further research is needed to develop and validate potential biomarkers to predict pCR, which could help escalate or de-escalate anti-HER2 therapy. Trials incorporating novel agents such as T-DM1, trastuzumab deruxtecan (T-DXd), and immune checkpoint inhibitors and trying to de-escalate treatments in neoadjuvant setting are ongoing. In the future, tailored treatments such as no adjuvant therapy, various HER2-directed therapies alone with chemotherapy, combinations of various HER2-directed therapies and chemotherapy, addition of immune checkpoint inhibitors, and omission of surgery will be individualized in HER2-positive early breast cancer patients.

Impact of chemotherapy on cognitive functioning in older patients with HER2-positive breast cancer: a sub-study in the RESPECT trial.

To investigate whether postoperative adjuvant trastuzumab plus chemotherapy negatively affected cognitive functioning during the post-chemotherapy period compared with trastuzumab monotherapy in older patients with HER2-positive breast cancer. In the randomized RESPECT trial, women aged between 70 and 80years with HER2-positive, stage I to IIIA invasive breast cancer who underwent curative operation were randomly assigned to receive either 1-year trastuzumab monotherapy or 1-year trastuzumab plus chemotherapy. Cognitive functioning was assessed using the Mini-Mental State Examination (MMSE) test at enrollment and 1 and 3years after initiation of the protocol treatment. The primary outcome was change in the MMSE total score from baseline. Secondary outcomes included prevalence of suspected mild cognitive impairment (MMSE total score < 28) and suspected dementia (MMSE total score < 24). The analytical population consisted of 29 and 26 patients in the trastuzumab monotherapy and trastuzumab plus chemotherapy groups, respectively. The group differences in mean changes of the MMSE total score were 0.6 (95% confidence interval [CI] - 0.3 to 1.6) at 1year and 0.9 (95% CI - 1.0 to 2.8) at 3years (P = 0.136 for the group difference pooling the two visits). The prevalence of suspected mild cognitive impairment at 3years was 41.7% in the trastuzumab monotherapy group and 28.6% in the trastuzumab plus chemotherapy group (P = 0.548). This randomized sub-study did not show worse cognitive functioning during the post-chemotherapy period with trastuzumab plus chemotherapy than with trastuzumab monotherapy in older patients with HER2-positive breast cancer. NCT01104935 (first posted April 16, 2010).

41O Nine weeks vs 1-year adjuvant trastuzumab: Long term outcomes of the ShortHER randomised trial

The ShortHER trial randomised 1254 patients with HER2+ early breast cancer to chemotherapy plus 9 weeks vs 1 year adjuvant trastuzumab. The study was designed as a non inferiority trial with a DFS hazard ratio (HR) < 1.29 as the non inferiority margin. At the event driven analysis, the HR for DFS was 1.13 (90% CI 0.89-1.42) therefore non inferiority could not be claimed (P Conte et al, Ann Oncol 29:2328-2333). Here we report the overall survival (co-primary end point of the study) and the updated DFS curves according to risk categories of long vs short treatment arms.

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

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. Patients were randomized to standard adjuvant chemotherapy plus 1year of trastuzumab with pertuzumab or placebo. Patients recruited in mainland China, Hong Kong and Taiwan are included in this descriptive analysis. 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. 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.

Long term continuous Trastuzumab use for HER2-positive advanced breast cancer

Objectives: Trastuzumab is the standard of care for locally advanced / metastatic her2-positive breast cancer. However, most of these patients will progress within 12 months of trastuzumab therapy. In contrast, there is a paucity of data available on the long-term treatment of patients with Trastuzumab. Our study was conducted to report efficacy and safety data for patients with locally recurrent / metastatic her2-positive breast cancer who received long-term therapy with Trastuzumab (≥5 years).&#x0D; Methods: This study was a prospective single-arm study of continuous Trastuzumab in patients who were histologically her2-positive and radiologically confirmed inoperable locally recurrent or metastatic breast cancer after complete one year of Trastuzumab plus chemotherapy (in hormone negative/hormone resistance) treatment then continuous Trastuzumab alone , or with hormone therapy (in sensitive hormone positive) without progression [complete or partial response or stable disease]. A total of 50 inoperable local recurrent and metastatic breast cancer patients were treated with continuous intravenous Trastuzumab therapy administered according to the standard Trastuzumab every 3-weeks (8 mg/kg loading dose followed by 3-weekly 6 mg/kg maintenance doses starting 3 weeks after the loading dose) schedule, from January 2014 to January 2019 at the Najaf Cancer Clinic (NCC).&#x0D; Results: All 50 patients were evaluated with CR occur only in 20% (10/50) with an OAR of 50% (25/50). The cardiac status of these patients remained stable over time for the majority of patients with no marked changes in LVEF%. No treatment-related death was observed. The median OS and median PFS is 61 months and 20 months, respectively.&#x0D; Conclusion: In her2-positive recurrent and metastatic breast cancer patients, who initially respond to palliative treatment with trastuzumab, continuous trastuzumab can achieve a long-term tumor remission of several years and had significantly improved survival with tolerated and acceptable adverse events.

Evaluation of 1-Year vs Shorter Durations of Adjuvant Trastuzumab Among Patients With Early Breast Cancer

The optimum duration of adjuvant trastuzumab among patients with early breast cancer is uncertain but of great therapeutic relevance. To compare shorter durations with 1 year of adjuvant trastuzumab for patients with early breast cancer. PubMed, Embase, Cochrane Central Register of Clinical Trials, and conference proceedings were searched from January 1, 2005, to June 30, 2019, for relevant randomized clinical trials (RCTs). To be eligible, the trial had to be randomized, compare a shorter duration with 1 year of trastuzumab as adjuvant treatment, and include patients with early breast cancer. Individual patient data for disease-free survival (DFS) and overall survival (OS) were extracted from published survival curves of included RCTs; DFS and OS curves for each trial and the combined population were reconstructed. The DFS and OS hazard ratios (HRs) were estimated from the reconstructed survival curves as well as published estimates. The HR for DFS was used to test noninferiority using the median noninferiority margin of eligible RCTs. This study followed Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. The primary outcome was DFS; OS and cardiac toxic effects were secondary outcomes. There were 6 eligible RCTs with a median DFS noninferiority margin of 1.3 (range, 1.15-1.53), 5 of which had extractable individual patient data for 11 376 patients, 1659 DFS events, and 871 deaths. For shorter duration vs 1 year of trastuzumab, the 5-year DFS was 85.42% (95% CI, 84.41%-86.38%) vs 87.12% (95% CI, 86.15%-88.02%) (HR, 1.14; 95% CI, 1.03-1.25, 1-sided P for noninferiority = .004), and OS was 92.39% (95% CI, 91.61%-93.10%) vs 93.46% (95% CI, 92.73%-94.13%) (HR, 1.17; 95% CI, 1.02-1.33). Using trial-level published estimates from 6 RCTs, including 11 603 patients, 1760 DFS events, and 930 deaths, the HR for DFS was 1.15 (95% CI, 1.04-1.26; 1-sided P for noninferiority = .002) and, for OS, 1.17 (95% CI, 1.03-1.33). There was significantly less risk of congestive heart failure with shorter-duration trastuzumab (relative risk, 0.53; 95% CI, 0.38-0.74). In this study, a shorter duration of adjuvant trastuzumab was noninferior to its 1-year administration and resulted in lower rates of cardiac toxic effects. These results suggest that a shorter duration may be the preferred option for patients with low-risk disease or a predisposition to cardiac toxic effects.

Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): A randomized phase III trial.

501 Background: The multicenter phase III TRAIN-2 study showed high pathological complete response (pCR) rates after neoadjuvant chemotherapy with and without anthracylines plus dual HER2-blockade in stage II-III HER2-positive breast cancer patients (67% vs 68%, p = 0.95) (NCT01996267). Here we report 3-year efficacy and safety outcomes. Methods: Patients were randomly assigned (1:1) to receive 3 cycles 5-fluoruoracil (500mg/m2), epirubicin (90mg/m2), and cyclophosphamide (500mg/m2) followed by 6 cycles paclitaxel (80mg/m2 day 1 and 8) and carboplatin (AUC = 6mg/ml·min) (FEC-PC) or 9 cycles paclitaxel and carboplatin (PC). Both regimens were combined with trastuzumab (T; 6mg/kg, loading dose 8mg/kg) and pertuzumab (Ptz; 420mg, loading dose 840mg). Patients completed one year of trastuzumab, radiotherapy and endocrine therapy as indicated. The primary endpoint pCR was previously reported. Secondary efficacy endpoints reported here are event-free-survival (EFS) defined as time from randomization to first event (disease progression resulting in inoperability, recurrence [contralateral DCIS excluded], secondary primary malignancies, or death) and overall survival (OS), both in the intention-to-treat population. Safety endpoints are reported for patients treated with at least one dose of study medication. Results: 438 patients were randomized (219/arm) and evaluable for long-term efficacy endpoints. After a median follow-up of 48.8 months 23 EFS events occurred in the FECT-PTC-Ptz-arm and 21 in the PTC-Ptz-arm (HR 0.90; 95% CI 0.50-1.63). Three-year EFS estimates were 92.7% (95% CI: 89.3-96.2) for FECT-PTC-Ptz and 93.6% (95% CI: 90.4-96.9) for PTC-Ptz. Three-year OS estimates were 97.7% (95% CI: 95.7-99.7) for FECT-PTC-Ptz and 98.2% (95% CI: 96.4-100) for PTC-Ptz. These results were irrespective of hormone receptor and nodal status. LVEF decline ≥10% from baseline and &lt; 50% was more common in patients who received anthracyclines than in the PTC-Ptz arm (8.6% vs. 3.2%, p = 0.021). Two patients in the FECT-PTC-Ptz arm developed acute leukemia. No other new safety concerns were seen. Conclusions: The 3-year follow-up of the TRAIN-2 study confirms the results of the primary outcome that anthracylines do not improve efficacy and are associated with clinically relevant toxicity. A neoadjuvant carboplatin-taxane based regimen with dual HER2-blockade can be considered in all stage II-III breast cancer patients, regardless of hormone receptor and nodal status. Clinical trial information: NCT01996267 .

Apocrine Carcinoma of Breast in a Male Patient: Case Report

Introduction: Apocrine carcinoma of breast is a rare type of malignant tumor, the incidence of which varies between 0.3 - 0.4 % of all female breast cancers.Apocrine carcinoma is exceptional in male patients and very few cases have been described in literature. This tumor shows distinct microscopic and immunohistological features. We report an exceptional observation of apocrine carcinoma of breast in a man. Patient and observation: He’s a 54 years old man who had for 2months a painless nodule at the left axillary..The patient had family history of breast and prostate cancers. Physical examination revealed a left axilary lymphadenopathy movable relative to superficial and deep plans with no evidence mass of breasts. MRI of the breast was performed and revealed a mass that was 38 x 10 mm in size.A biopsy of the lymphadenopathy was performed. It objectified a carcinomatous proliferation. An immunohistochemical study showed that tumor cells express Her 2, but do not express estrogenic and progesterone receptors. A tumorectomy of the left breast was performed and didn’t show any malignant lesion of the breast. The axiler dissection of 13 lymphnodes showed 11 metastatics ones with 3 breaking capsular. The diagnosis of apocrine carcinoma of the breast was made in despite of the result of the tumorectomy. The CT did not indicate metastasis. The patient was administered adjuvant chemotherapy then he received radiation therapy on left susclavicular, axila and breast with a total dose of 42Gy,15 fractions of 2.8 Gy on 21 days with no late effects. 1 year of trastuzumab was administrated. There was no recurrence or metastasis approximately 2 years after radiation therapy. Then the patient presented a susclavicular lymphnode that was comfirmed on the pet-scanner with multiple mediastinal lymphnodes. A biopsy of the susclavicular lymphnode comfirmed the progression of the disease. The patient started chemotherapy in association with pertuzumab and trastuzumab. Discussion: Apocrine carcinoma of the breast is a rare malignant tumor whose incidence varies between 0.3% and 4% of all female’s breast cancer and represents 0.5 % of all invasive breast cancers. This tumor is exceptional in men. Indeed, only a dozen cases have been described in the literature . Most neoplasms are slowly progressive, small in size, and are most frequently seen in the axilla. They can be recurrent and metastasize to the lymph node, lung, and bone. Male patients have been advanced disease at presentation compared to women which may be due to lack of public awareness of breast cancer in male. Histologically, it has glandular structures with apocrine features and decapitation secretions. There is cytoplasmic PAS positivity of the tumor cells. The presence of neoplastic glands high in the dermis and immediate subepidermis favors the primary origin of tumor cells from apocrine sweat glands. Apocrine adenocarcinomas are positive for cytokeratins, carcinoembryogenic antigen (CEA) and epithelial membrane antigen (EMA) . Usually, these tumors do not express the estrogen receptor-alpha, progesterone receptors and bcl-2. Apocrine adenocarcinoma has poor prognosis and the prognostic factors include size, histological type, lymph node involvement, and distant metastasis. The 10-year disease free survival rate in the absence of metastasis to the lymph nodes is 56%. Treatment protocols of apocrine carcinoma are similar to non apocrine carcinoma of breast. However studies involving the use of anti androgens are in progress. The treatment of choice is wide local excision with clear margins, with or without regional lymph node dissection. The role of radiation therapy also remains uncertain in the absence of clinical trials. No clear correlation between treatment modality and recurrence in apocrine carcinoma was apparent, and survival rates of apocrine carcinoma were not different from other breast carcinomas. Conclusion: In conclusion, male apocrine carcinoma is a very rare, unique and morphologically-distinctive, invasive ductal carcinoma.. Although immunohistochemical staining might show differences in males, the prognosis is not different from other breast carcinomas. It has different hormonal profile, androgen receptor positivity makes patient with apocrine carcinoma eligible for targeted therapy.

Cost-effectiveness of six months versus 1-year adjuvant trastuzumab in HER2 positive early breast cancer in Egypt

Introduction: Breast cancer is the most prevalent cancer among women in Egypt. Trastuzumab is administered with chemotherapy for patients with HER2-positive advanced breast cancer (HER2 + ve ABC) in the metastatic and adjuvant settings resulting in improved treatment outcomes, and long-term follow-up. Some studies have evaluated whether equivalent outcomes can be achieved with reduced treatment duration. This study evaluates the cost-effectiveness of 6-month versus 1-year trastuzumab treatments from payer perspective over a 10 year time horizon.Methods: A half-cycle corrected Markov model was developed with five mutually exclusive health states; patient with HER2 +ve ABC, disease-free survival (DFS), local or regional relapse, metastatic relapse, and death. A cycle length of 6 months was applied, direct medical costs including cost of treatments, day-care, surgery, health states and follow-up visits were collected, and indirect costs such as lost productivity were not estimated. The transition probabilities and utilities were extracted from published literature, and deterministic sensitivity analyses were conducted.Results: Among the HER2 +ve ABC patient population in Egypt, the total QALYs of the 6-month trastuzumab were estimated to be 2.99 compared with 2.93 for the 1-year trastuzumab which resulted in a difference of 0.06 QALYs. The total costs were EGP 271,647 ($106,947) and EGP 381,248 ($150,097), respectively. These costs yielded an ICER of –109,600 EGP/QALY (–43,149 $/QALY) for the 6-month trastuzumab. The 6-month trastuzumab is a dominant strategy when compared to 1-year trastuzumab, resulting in improved effectiveness at a reduced cost. All analyses results confirmed the dominance of 6-month trastuzumab and our model robustness.Conclusions: This study concluded that 6-month trastuzumab is a cost-effective option when compared to 1-year trastuzumab in patients with HER2 +ve ABC in Egypt. Our findings provide health care decision makers with additional insights to best allocate available resources concurrently with the improvement of the Egyptian patient’s outcomes.

Abstract P2-13-02: Chemotherapy-related amenorrhea (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT trial)

Abstract Background: CRA is a surrogate for ovarian toxicity and associated risk of infertility and long-term menopausal symptoms. Therefore, it is important to assess and report the rate of CRA when we study a new neoadjuvant treatment regimen. In the Adjuvant Paclitaxel and Tratuzumab (APT) trial, we found that CRA rate associated with adjuvant TH (12 weeks of paclitaxel and a year of trastuzumab) for human epidermal growth factor receptor-2 (HER2)-positive breast cancer was lower than historically seen with cyclophosphamide-based regimens. The ATEMPT trial allowed a direct comparison of the CRA rate associated with TDM1 and TH. Methods: The ATEMPT trial randomized patients (pts) with Stage I HER2+ breast cancer 3:1 to T-DM1 3.6 mg/kg IV every 3 weeks (w) x17 vs. T 80 mg/m2 IV with H qw x 12 (4 mg/kg load →2 mg/kg), followed by H (6 mg/kg q3w x 13). Participants who reported that they were premenopausal at enrollment were asked to complete menstrual surveys at baseline and every 6-12 months throughout a 36 month follow-up period. For this analysis, CRA was defined as report of no menstruation within the prior six months on a survey completed 18 months after enrollment. Results: Of 512 ATEMPT enrollees, 497 began protocol therapy, 130 (26%) were premenopausal at enrollment and answered baseline menstrual questions, 42 of these 130 were excluded from the current analyses because they did not complete the 18-month survey, and 7 of the remaining 88 had received gonadotropin-releasing hormone agonist before 18 months, leaving 81 for analysis. None had undergone hysterectomy or oophorectomy. Median age was 44 (range 23-53) among the TH patients (n=20), and 46 (range 34-54) among the T-DM1 patients (n=61). On the 18-month survey, 45% of women treated with TH reported at least one one episode of menses during the prior 6 months compared to 75% of women in the T-DM1 arm (p=0.011). Among those ≤ 40 years old, 50% of TH patients and 100% of T-DM1 patients reported menstruation at that timepoint. Please see Table for additional data in subgroups. Conclusions: In this relatively small sample, CRA at 18 months was less common after adjuvant T-DM1 than after TH (though even with TH, nearly half of women did menstruate after chemotherapy, even in the subset aged 41+). This will be reassuring to young patients with HER2-positive breast cancer who seek to maintain ovarian function. Larger studies are needed to confirm this finding and to assess a possible differential impact of these drugs on subgroups based on age, endocrine therapy, and body mass index. Additional research should also focus on menopausal symptoms and actual fertility after receipt of T-DM1. Menstruation in 61 T-DM1 arm patients with informative surveys at 18 monthsMenstruation in 20 TH arm patients with informative surveys at 18 monthsAge at study entry95% CI95% CI≤4012/12 (100%)74-100%4/8 (50%)16-84%41+34/49 (69%)55-82%5/12 (42%)15-72%BMI&amp;lt;3040/52 (77%)63-87%6/16 (38%)15-65%30+6/9 (67%)30-93%3/4 (75%)19-99%Endocrine therapy currentlyYes27/39 (69%)52-83%2/12 (17%)2-48%No19/22 (86%)65-97%7/9 (78%)40-97% Citation Format: Kathryn J. Ruddy, Lorenzo Trippa, Jiani Hu, William T. Barry, Chau T. Dang, Denise A. Yardley, Steven J. Isakoff, Vincente V. Valero, Meredith G. Faggen, Therese M. Mulvey, Ron Bose, Douglas J. Weckstein, Antonio C. Wolff, Katherine E. Reeder-Hayes, Hope S. Rugo, Bhuvaneswari Ramaswamy, Dan S. Zuckerman, Lowell L. Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit L. Cheng, Frederick M. Briccetti, Bryan P. Schneider, A. Merrill Garrett, P. Kelly Marcom, Kathy S. Albain, Patricia A. DeFusco, Nadine M. Tung, Blair M. Ardman, Rita Nanda, Rachel C. Jankowitz, Michelle K. DeMeo, Harold J. Burstein, Eric P. Winer, Ian E. Krop, Ann H. Partridge, Sara M. Tolaney. Chemotherapy-related amenorrhea (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT trial) [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 P2-13-02.

Cost Effectiveness of Trastuzumab for Management of Breast Cancer in India.

PURPOSEWe undertook this study to evaluate the incremental cost per quality-adjusted life-year (QALY) gained with use of adjuvant trastuzumab as compared with chemotherapy alone among patients with nonmetastatic breast cancer in India.METHODSWe used a Markov model to estimate the incremental cost of using trastuzumab (for 1 year, 6 months, or 9 weeks) as compared with chemotherapy alone using a societal perspective, excluding indirect productivity losses. Although the outcomes (QALYs) in the standard chemotherapy arm were estimated after calibrating the model as per survival data from 2 Indian cancer registries, effectiveness estimates from the HERA trial and a joint analysis of the NSABP B-31 and NCCTG N9831 trials were used to estimate the consequences of 1-year trastuzumab use. The cost of treatment was estimated using national standard treatment guidelines and real-world use estimates for different treatment modalities as per data from Indian cancer registries. Probabilistic sensitivity analysis was undertaken to evaluate parameter uncertainty.RESULTSFor 1 year of trastuzumab use, the incremental benefit per patient, incremental cost per QALY gained, and probability of being cost effective using HERA trial estimates were 1.29 QALYs, 178,877 Indian national rupees (INRs; US$2,558), and 4%, respectively, whereas the corresponding figures using joint analysis estimates were 1.69 QALYs, INR 134,413 (US$1,922), and 57.3%, respectively.CONCLUSIONUse of trastuzumab for 1 year is not cost effective in India at the current price. However, trastuzumab use for 9 weeks is cost effective and should be included in clinical guidelines and reimbursement policies. A price reduction of 15% to 35% increases the probability of 1-year trastuzumab use being cost effective, to 90%.

Updated Bayesian Network Meta-Analysis of Adjuvant Targeted Treatment Regimens for Early Human Epidermal Growth Factor Receptor-2 Positive Breast Cancer.

PurposeCombining targeted agents with adjuvant chemotherapy prolongs survival in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, but also increases the risk of adverse effects. The updated results of 3 randomized controlled trials (RCTs) were reported in 2019. Given the lack of adequate head-to-head pairwise assessment for anti-HER2 agents, network meta-analysis facilitates obtaining more precise inference for evidence-based therapy.MethodsRCTs comparing at least 2 anti-HER2 regimens in an adjuvant setting for HER2-positive early-stage breast cancer (EBC) were included. Hazard ratios for overall survival (OS) and disease free survival (DFS), with respective 95% confidence intervals were pooled for assessment of efficacy. A Bayesian statistical model was used, and odds ratios (ORs) for adverse events (AEs) were used to pool effect sizes.ResultsWe demonstrated that 1-year trastuzumab plus chemotherapy had increased efficacy compared to shorter or longer treatment duration. The OR of cardiac events gradually increased from 6 months to 1 and 2-year trastuzumab arms, relative to chemotherapy only. Compared to trastuzumab plus chemotherapy, dual HER2-targeting therapies increased DFS, especially for hormone receptor negative patients. Dual anti-HER2 blockade regimens revealed an increased probability of gastrointestinal reactions. As a second agent, pertuzumab showed significantly higher DFS and OS.ConclusionWe conclude that 1-year adjuvant trastuzumab should remain as the standard treatment for HER2-positive EBC patients, as it has greater efficacy and a manageable proportion of AEs. Clinical efficacy can be increased for hormone receptor-negative tumors by including a second HER2-targeted agent to the treatment regimen. For hormone receptor-positive cases with basal disease, it is acceptable to reduce the risk of cardiotoxicity by shortening the duration of trastuzumab.

When to Add Additional Anti-HER2 Therapy to Adjuvant Trastuzumab.

One year of trastuzumab dramatically improves outcomes in early HER2 positive breast cancer, irrespective of anatomic stage, receptor status and chemotherapy backbone. However, up to 25% of breast cancers treated with trastuzumab and chemotherapy recur. Here, we review the current role for additional HER2 blockade to adjuvant trastuzumab. Adjuvant pertuzumab and neratinib modestly improve disease-free survival in early breast cancer, particularly for those at highest risk of recurrence. Lack of complete pathologic response to preoperative chemotherapy and HER2 targeted therapies is associated with worse outcomes. In those with lack of pCR, adjuvant trastuzumab emtansine improves outcome in early breast cancer, irrespective of chemotherapy and HER2 targeted therapy backbone. Preoperative chemotherapy and HER2 targeted therapy should be discussed in early breast cancer, especially in tumors over 2cm. Future trials must focus on de-escalation of chemotherapy and biomarkers for further tailored therapy in early HER2 positive breast cancer.

A pooled analysis of the cardiac events in the trastuzumab adjuvant trials.

Trastuzumab-associated cardiotoxicity remains an issue for patients with HER2-positive breast cancer. This pooled analysis of 3 adjuvant trials investigated the incidence, timing, impact on treatment completion, and risk factors for trastuzumab-associated cardiotoxicity. This is an individual patient data level pooled analysis of HERA, NSBAP B-31, and NCCTG 9831 (Alliance Trials). Definitions of cardiac events were as per each individual study. A total of 7445 patients enrolled in the 3 trials were included in the analysis, of which 4017 were in the trastuzumab and 3428 in the control (observation) arms, respectively. Median follow-up exceeded 10years (119.2-137.2months). Nearly all patients (97.4%) in the trastuzumab arms received anthracycline-based chemotherapy. In total, 452 patients in the trastuzumab arms experienced a cardiac event (11.3%), with most being mildly symptomatic or asymptomatic left ventricular ejection fraction (LVEF) decrease (351 patients, 8.7%). Severe congestive heart failure was more common in the trastuzumab arm (2.3%) than in the control arm (0.8%). Most cardiac events occurred during trastuzumab treatment (78.1%) and cardiac events were the main cause of discontinuation across the sample (10.0%); nevertheless, a large majority of patients completed trastuzumab treatment (76.2%). Baseline risk factors that were significantly associated with the development of cardiac events were baseline LVEF < 60%, hypertension, body mass index > 25, age ≥ 60 and, non-Caucasian ethnicity. One year of trastuzumab increases the risk of cardiac events, though most consist of asymptomatic or mildly symptomatic LVEF drops. Adjuvant trastuzumab should be considered a safe treatment from a cardiac standpoint for most patients. Trastuzumab-associated cardiotoxicity is the main cause of discontinuation and further research is needed to individualize prevention and management.