Trastuzumab In Metastatic Breast Cancer Research Articles

Oncology drug-companion diagnostic combinations

With the development of trastuzumab for metastatic breast cancer a new era began in cancer drug development. The drug-diagnostic codevelopment model with its clinical enrichment trial design has enabled development of target specific drugs for molecular defined subsets of patients. Since the simultaneous approval of trastuzumab and the HercepTest in 1998, the number of FDA-approved drug-companion diagnostic combinations within oncology and hematology have steadily increased. By June 2021, the number of drugs that have a companion diagnostic (CDx) linked to its use has reached 46. For these drugs, the CDx assays play an important role in defining the patient population likely to respond and without the assay they will often lose their value. This short article is based on an analysis of the FDA List of Cleared or Approved Companion Diagnostic Devices and relevant information in the Drugs@FDA, and will focus on the drug-CDx combinations, drug classes, clinical development, and the regulatory path and status.

287P Efficacy, safety and pharmacokinetics of a proposed trastuzumab biosimilar HLX02 compared with trastuzumab in metastatic breast cancer: A global phase III study

287P Efficacy, safety and pharmacokinetics of a proposed trastuzumab biosimilar HLX02 compared with trastuzumab in metastatic breast cancer: A global phase III study

A systematic review of the economic evaluations of trastuzumab in metastatic breast cancer.

A systematic review of the economic evaluations of trastuzumab in metastatic breast cancer.

Abstract P4-10-29: Identifying novel molecular markers of response to trastuzumab in metastatic breast cancer

Abstract Background: The survival of women with HER2+ metastatic breast cancer (MBC) has improved with the introduction of the anti-HER2 antibody trastuzumab, but responses vary greatly among individuals. A predictive signature of response (and lack thereof) to trastuzumab may help personalize therapy for women with HER2+ MBC and enable the discovery of new “druggable” targets. Methods: In this retrospective cohort study, 256 patients with HER2+ MBC at the Sunnybrook Odette Cancer Centre were identified sequentially from January 1999 to December 2013 using the Cancer Care Ontario Registry. In total, 53 patients (21%) had archived metastatic tissue available for analysis, 29 (55%) of whom had samples obtained <3 years prior to the initiation of trastuzumab. Nanostring molecular testing was used to measure the expression of commonly known oncogenes and gene signatures using the Nanostring technologies nCounter Analysis System TM (Seattle, Washington, USA). Descriptive statistics were used to summarize patient results and prognostic scores. Patients were categorized into short-term survivors (died within 12 months) and long-term survivors (survived >30 months after starting trastuzumab). Results were compared between these two groups of patients using a Fisher’s exact test (dichotomous groups) and Wilcoxon rank sum tests (continuous scores). Univariable Cox regression models were evaluated using all patients, to evaluate if risk scores were prognostic of overall survival (OS). Statistical significance was set at the p=0.05 level and all tests were two-sided. Results: The median patient age was 60 years (interquartile range 53-65 years), 24% (n=7) had de-novo MBC and the majority of patients (52%) had ER or PR positive tumors. Among 29 included patients, the median OS was 23.4 months (95%CI 10.3-34.3 months); 10 patients died within 12 months and 10 patients survived >30 months after starting trastuzumab-based therapy. A median of 155 days (range 4-812) elapsed between metastatic biopsy and initiation of trastuzumab. The distribution of the Prosigna ROR Score, Basal Cor, HER2 Cor, Luminal A Cor, Luminal B Cor, Mammaprint Subtype/Risk Group, Oncotype Risk Score/Risk Group, IHC4 mRNA Risk Group and GGI Risk Score/Risk Group did not differ between the short- and long-term survivors. However, the Mammaprint Predictor Score was significantly higher [mean 0.34 (std 5.50) versus -4.95 (std 5.24), p=0.033] and the IHC4 Risk Score was significantly lower among long-term as compared to short-term survivors [mean 99.3 (std 67.1) versus 160.3 (std 40.9), p=0.044]. The association between molecular gene signatures and OS are described in Table 1. Conclusion: Several gene signatures were associated with OS in this exploratory analysis of women with HER2+ MBC who received trastuzumab-based therapy. The Mammaprint Predictor and the IHC4 Risk Scores differed among short- versus long-term survivors, warranting validation in an independent dataset. Table 1. Univariable Survival Results (n=29)ComparatorHR (95% CI)p-valueProsigna ROR Score/ 10 units1.23 (0.92, 1.65)0.17ProsignaHER2 vs Other1.25 (0.50, 3.13)0.64Basal Cor/ unit3.61 (1.10, 11.78)0.034Her2 Cor/ unit0.99 (0.15, 6.40)0.99Luminal A Cor/ unit0.22 (0.05, 0.95)0.042Luminal B Cor/ unit0.26 (0.06, 1.06)0.060Mammaprint Predictor Score/ unit1.10 (1.02, 1.19)0.015Mammaprint SubtypeHER2 vs Other0.85 (0.37, 2.00)0.72Mammaprint RiskHigh vs Low4.20 (1.37, 12.86)0.012Oncotype Risk Score/ 10 units1.27 (0.95, 1.70)0.11Oncotype Risk GroupHigh vs Intermediate4.83 (0.60, 39.07)0.14IHC4 Risk Score/ 10 units1.09 (1.00, 1.18)0.046IHC4 mRNA Risk GroupHigh vs Intermediate4.83 (0.60, 39.07)0.14GGI Risk Score/ 10 units1.63 (1.02, 2.61)0.043GGI Risk GroupHigh vs Low5.14 (1.13, 23.51)0.035 Citation Format: Katarzyna Joanna Jerzak, Danielle N Desautels, Phillip S Blanchette, Jane Bayani, Sharon Nofech-Mozes, Martin J Yaffe, Gregory Pond, Kathleen I Pritchard, John MS Bartlett. Identifying novel molecular markers of response to trastuzumab in metastatic breast cancer [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 P4-10-29.

The Use of Trastuzumab in Metastatic Breast Cancer

The Use of Trastuzumab in Metastatic Breast Cancer

The Use of Trastuzumab in Metastatic Breast Cancer

The Use of Trastuzumab in Metastatic Breast Cancer

Inclusion of Metastatic Breast Cancer Treatments in the SUS (Public Health Care System): Strategic Actions

Background and context: Thousands of women suffering from HER2+ metastatic breast cancer (MBC) in Brazil had limited access to treatment in the public health system (SUS). There were no innovative therapies (only standard chemotherapy) available for them. Trastuzumab is included in WHO´s essential medicines list and it began to be commercialized in Brazil in 1998, being available in SUS in 2012, but only for patients with local breast cancer. Pertuzumab was never available in SUS for any stage of the disease. Aim: Contribute to the inclusion of trastuzumab and pertuzumab in MBC treatments in the SUS. Strategy/Tactics: Federação Brasileira de Instituições Filantrópicas de Apoio à Saúde da Mama’s (FEMAMA´s) main strategy was to develop several projects with the same purpose. Program/Policy process: The cycles of debates with parliamentarians and public hearings (events) to discuss with politicians the incorporation of new treatments in 15 state legislative branches and also in the National Congress; Organization of 8 public hearings after the first event (mentioned above) and elaboration of a one-year plan of actions to be carried out alongside NGOs associated with FEMAMA for carrying out local actions; The Women´s Cancer Fight Forum (event) to strength and empower the role of NGOs in public health policies; The National Conference of Female Mayors and Governors and the National Conference of First Ladies (event), where women´s leaders from all regions and local NGOs worked together discussing problems and suggesting actions to combat them; The Ambassadors Project - Women in Defense of Breast Health, empowering patients to be spokespeople for the cause in their regions; Carry out surveys that show the difference in MBC treatments available for patients with health insurance and patients treated in the SUS; Participation in several events on this topic organized at the House of Representatives and at the Senate; Add this topic to the agenda of the National Health Council and of the 2015 National Health Conference; Awareness and mobilization campaigns for expanding access to treatment and empowerment of patients: Para Todas as Marias, Por Mais Tempo, Acesso Já, #PacientesNoControle - Atitude Exige Coragem; National campaign to promote the public consultation of the Ministry of Health on the incorporation of trastuzumab and pertuzumab treatments in SUS, #PatientsInControl. Outcomes: Several outcomes were obtained as a result of these projects and campaigns. However, our main result undoubtedly is assuring access to metastatic breast cancer treatments in the Brazilian health care system. On August 2017, the Ministry of Health announced the incorporation of trastuzumab for metastatic breast cancer in the public health system and on December 2017, it announced the incorporation of pertuzumab for the same patients. What was learned: Patients and articulated NGOs have power to change scenarios. Empowering patients by providing them with information and tools is an important way to promote changes.

Abstract P2-12-01: Real-world use and outcomes of trastuzumab for HER2+ metastatic breast cancer in Australia: Analysis of the herceptin program, 2001-2015

Abstract Aims Between December 2001 and July 2015 Australian women with HER2-positive metastatic breast cancer (MBC) accessed trastuzumab in combination with taxane chemotherapy or as monotherapy via the government funded Herceptin Program (HP); we characterise their treatment patterns and survival outcomes. Methods This retrospective, whole-of-population cohort study used linked dispensing, medical services, and death records. We stratified patients into three year-of-trastuzumab-initiation groups: 1. 2001-2002 (may include patients accessing trastuzumab in later lines); 2. 2003 - October 2006 (likely first-line treated but prior to trastuzumab availability for early breast cancer (EBC)); and 3: October 2006–June 30 2015 (most representative of contemporary practice). Patients were observed until death or censored at June 30 2016. We estimated duration of trastuzumab therapy from the initial dispensing date for MBC until 30 days after the last dispensing. We considered a gap of ≥90 days between trastuzumab dispensings a separate course of treatment. We estimated overall survival (OS) as the time from first trastuzumab dispensing until death from any cause. We used Kaplan-Meier methods to estimate the total duration of trastuzumab therapy and OS. We used dispensing dates of cancer medicines to determine concomitant treatments and used claims for echocardiography and MUGA scans to determine the timing of cardiac monitoring. Results 5,895 patients accessed trastuzumab for MBC. Median age at trastuzumab initiation was 57 years (IQR: 48 – 66). 800 patients (22%) from Group 3 also received trastuzumab for EBC. Treatment details and OS are tabulated: Overall (n = 5,895)Group 1 (n = 495)Group 2 (n = 1,709)Group 3 (n = 3,691)Median time on trastuzumab for MBC, first course, months (IQR)13.2 (5.7 – 26.6)9.2 (3.8 – 22.5)12.3 (5.4 – 23.3)14.0 (6.1 – 29.8)Median OS from first trastuzumab dispensing for MBC, months (IQR)30.3 (13.4 – 68.7)19.8 (8.9 – 38.8)27.5 (12.5 – 58.9)34.6 (15.1 – 82.8)Patients initiating trastuzumab, n (%): monotherapy1,571 (27)226 (46)625 (37)720 (20)+ taxane3,150 (53)157 (32)800 (47)2,193 (59)+ hormonal therapy763 (13)47 (9)169 (10)561 (15)+ non-taxane chemotherapy376 (6)65 (13)115 (7)217 (6)Cardiac assessment: at baseline (60 days prior to 30 days following trastuzumab initiation)3,721 (63%)189 (38%)831 (49%)2,701 (73%)during treatment3,324 (56%)150 (30%)778 (46%)2,396 (65%) Conclusions Our real-world estimates of OS for each patient group are both similar to and shorter than those from clinical trials published during similar time periods. Group 3 median OS is 6 months shorter than the control arm of the CLEOPATRA study (34.6 v 40.8 months) while median duration of first trastuzumab course was 4 months longer (14.0 v 10.4 months), suggesting patients continue trastuzumab beyond progression. In Group 3, 25% of patients died within 15 months of starting trastuzumab, 50% survived beyond 3 years and 25% survived beyond 7 years. These estimates will be useful for clinicians discussing expected survival time with patients in routine practice. Although the cardiotoxicity of trastuzumab is well recognised, baseline cardiac assessment was not universal, even in the most recent cohort. Citation Format: Daniels B, Kiely BE, Lord SJ, Houssami N, Pearson S-A. Real-world use and outcomes of trastuzumab for HER2+ metastatic breast cancer in Australia: Analysis of the herceptin program, 2001-2015 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-12-01.

Trastuzumab for metastatic breast cancer: Real world outcomes from an Australian whole-of-population cohort (2001–2016)

PurposeOutcomes for patients treated in clinical trials may not reflect the experience in routine clinical care. We aim to describe the real-world treatment patterns and overall survival (OS) for women receiving trastuzumab for metastatic breast cancer (MBC). MethodsRetrospective, whole-of-population cohort study using demographic, dispensing, and medical services data for women in the Herceptin Program for HER2+MBC. We estimated time on trastuzumab and OS from first dispensing of trastuzumab for MBC and rates of cardiac monitoring prior to and during treatment. We stratified outcomes by two groups based on year of initiation: 2001–2008 and 2009–2015. We benchmarked outcomes to two key trastuzumab clinical trials: H0648g (median OS 25 months) and CLEOPATRA (control group median OS 41 months). ResultsMedian age of the 5899 women at first trastuzumab dispensing was 57 years (interquartile range [IQR]: 48–66). Median time on trastuzumab increased from 15 months (7–33) in Group One to 18 months (8–42) in Group Two. Median OS increased from 27 months (12–57) in Group One to 38 months (16–83) in Group Two. Rates of cardiac monitoring increased at baseline (52%–76%), and on-treatment (47%–67%), in Group One and Two, respectively. ConclusionsOS, duration of trastuzumab, and frequency of cardiac monitoring increased over the study period. Outcomes for trastuzumab in this heterogeneous real world population were reassuringly comparable to those from clinical trials, with the median OS > 3 years in Group Two and 25% of patients living 7 years or longer.

Survival outcomes for Australian women receiving trastuzumab for HER2-positive metastatic breast cancer following (neo)adjuvant trastuzumab: a national population-based observational study (2006\u20132014)

Background:Patients treated with (neo)adjuvant trastuzumab who relapse and receive trastuzumab for metastatic breast cancer (MBC) are a growing population with little outcome data given their exclusion from most clinical trials. We aim to estimate survival outcomes for this trastuzumab ‘pre-treated’ population.Methods:Population-based study of Australian women receiving trastuzumab for HER2-positive MBC between 2006 and 2014, who also received (neo)adjuvant trastuzumab. We used Kaplan–Meier methods to estimate the following: overall survival (OS) from initiation of trastuzumab for MBC; duration of trastuzumab for MBC; and time from last (neo)adjuvant trastuzumab to first trastuzumab for MBC.Results:Of 3199 patients dispensed trastuzumab for MBC, 634 (20%) had received (neo)adjuvant traztuzumab. Pre-treated patients had a median (interquartile range) OS of 21.8 months (10.9–51.6), trastuzumab duration of 12.8 months (4.7–17.5), and time from last (neo)adjuvant trastuzumab to first trastuzumab for MBC of 15.6 months (6.5–28.6). Median OS for patients initiating trastuzumab <12 months and ⩾12 months from their last (neo)adjuvant trastuzumab were 17.1 months and 24.8 months, respectively.Conclusions:Patients starting trastuzumab for MBC following (neo)adjuvant trastuzumab had a median treatment duration of 1 year and OS of almost 2 years. These data help inform clinical practice and service planning for this under-researched population.

Opportunities for post-market surveillance of high cost medicines in Australia: Observing trastuzumab-treated women from early through late stage HER2-positive breast cancer (HER2BC)

ABSTRACT&#x0D; ObjectivesIn 2001 the Australian government circumvented traditional drug subsidy listing processes to create the Herceptin Program (HP) for HER2 metastatic breast cancer (MBC) patients; in 2006 trastuzumab was subsidised for early breast cancer (EBC) on the Pharmaceutical Benefits Scheme (PBS) creating opportunities for data linkage and observing patients across both treatment settings. Clinical trials established the efficacy of trastuzumab for MBC in trastuzumab-naïve patients but little is known about patients initiating trastuzumab in the adjuvant setting and subsequently receiving trastuzumab for MBC. We characterise patterns of treatment and outcomes for these patients in Australia. We estimate time from adjuvant trastuzumab initiation to metastatic trastuzumab initiation and overall survival (OS).&#x0D; ApproachWe identified a cohort of patients with a trastuzumab claim in both PBS and HP records. We calculated duration of EBC treatment as date of first trastuzumab dispensing until 21 days after the last PBS dispensing for trastuzumab or observation of a trastuzumab dispensing record in HP claims, whichever came first. We used Kaplan-Meier methods to estimate time-to-MBC treatment and OS.&#x0D; ResultsOf 11,477 EBC patients treated with trastuzumab between December 2006 and December 2012, 637 were also treated with trastuzumab for MBC. Median age at EBC treatment initiation was 53 (range 17 – 87). 94% of EBC patients received a taxane, anthracycline, cyclophosphamide and/or carboplatin as part of their treatment protocol. 61% of MBC patients received trastuzumab with a taxane, 18% as monotherapy and 7% with capecitabine. Median duration of trastuzumab therapy in EBC and MBC therapy was 11.3 (95% CI 10.7-11.6) and 9.3 (8.6-10.4) months, respectively. Median time-to-MBC therapy was 27.3 (25.5-28.2) months. Median OS from initiation of EBC and MBC treatment was 58.1 (52.9-65.7) and 23.2 (20.5-25.4) months, respectively.&#x0D; ConclusionHER2BC patients initiating trastuzumab for EBC therapy and progressing to MBC treatment are little examined in the clinical trial and observational literature. Australia’s unique funding arrangements allowed us to clearly distinguish between treatment for EBC and MBC which is not always possible in dispensing claims alone. We demonstrated: most EBC patients are treated according to guideline recommendations; that this patient cohort receive approximately 20 months of trastuzumab therapy across both settings; and median OS from initiation of MBC trastuzumab is approximately 2 months shorter than in the pivotal clinical trial (25.1 months).

Trastuzumab in metastatic breast cancer after complete remission: an expensive commitment for an entire life?

Metastatic breast cancer has consistently been considered an incurable disease. [...]

Screening of Clinical Practice in Management of Progression on Trastuzumab in metastatic breast cancer

Background: Guidelines regarding treatment post progression on Trastuzumab have recently varied with lots of options available. Decision whether to continue on Trastuzumab or to switch to other anti-Her2 treatment varies due to many factors, including the guidelines recommendations, definition of resistance to Trastuzumab, availability of drugs, and socioeconomic factors. The objective of our survey is to evaluate and asses these factors. Material and methods: The survey was emailed to more than 600 oncologists worldwide through BGICS database. Three main questions were covered by the survey; Definition of progression on Trastuzumab, how to deal with progression, and the factors affecting decision making. Results: The survey was send to 612 oncologists worldwide, 167 replied. Participants were mainly from Egypt, Romania, and France. 28.7% consider resistance to Trastuzumab if progression happened while on Trastuzumab, 28.7 % consider resistance if any progression happened after receiving Trastuzumab whatever the duration or the site of progression, 18% consider resistance if progression took place after less than 6 months of receiving Trastuzumab. In case of CNS progression 35.3% had chosen start on Lapatinib, while 25.1% had chosen to change the chemotherapy and continue on Trastuzumab. 18.6% had chosen to give combination of Lapatinib with Trastuzumab. Conclusion: This is the second publication of Medicalsurveys-17 Research Group. Our data revealed that more effort is required to define resistance to Trastuzumab and how to manage patients based on type of resistance and site of progression. Mini Abstract Through this survey, we tried to define the oncologist perspective about resistance to Trastuzumab, the approach to deal with this progression and the factors that affect decision making.

A Prospective Randomised Phase III Clinical Trial Testing the Role of Prophylactic Cranial Radiotherapy in Patients Treated with Trastuzumab for Metastatic Breast Cancer — Anglo Celtic VII

A high incidence of central nervous system (CNS) metastases has been reported in patients with HER2-positive tumours receiving trastuzumab therapy for metastatic breast cancer. This study tested whether prophylactic cranial irradiation (PCI) could reduce the incidence of CNS metastases in this setting. This was a prospective, randomised phase III trial. Patients were randomised 1:1 to no PCI or PCI delivered at around 6 weeks after study entry. Cognitive function was assessed prospectively. In total, 51 patients were randomised over a 3 year period; 25 received PCI and 26 did not. The cumulative incidence of CNS metastases at 2 years was 32.4% (standard error = 9.8%) on the no PCI arm and 21.0% (standard error = 8.6%) on the PCI arm; the associated hazard ratio was 0.57 (95% confidence interval 0.18–1.74; P = 0.32). There was no evidence of cognitive dysfunction in PCI patients.

Cost-effectiveness of trastuzumab in metastatic breast cancer: Mainly a matter of price in the EU?

Trastuzumab (TR), a monoclonal antibody approved by EMA in 2000 and one of the first examples of “targeted therapy”, is indicated to treat human epidermal growth factor receptor 2 (HER2) positive breast cancer. TR, whose patent will expire in 2015 in Europe, has been judged positively for reimbursement by most public authorities in the EU. Here we critically review the existing evidence on TR in metastatic breast cancer (MBC), in line with the multidisciplinary health technology assessment (HTA) approach, to assess whether the existing evidence supports TR positive reimbursement decisions taken in MBC by EU health authorities. We did a literature search for the main HTA topics (efficacy, quality of life and ethics) on the PubMed international database (2000–2013). Then, we did a specific literature search to select the full economic evaluations (FEEs) conducted in EU countries focused on TR as first-line innovative therapy in MBC. We retrieved scant evidence in the literature to support TR reimbursement in MBC. We found only two clinical trials and their results were unclear because of the large proportion of patients who crossed over. Moreover, the quality of methods was poor in all four European FEEs selected. This example of HTA exercise on a mature monoclonal antibody in a specific indication casts doubts on how often the reimbursement decisions taken by EU health authorities in emotional pathologies like cancer are rational. These decisions should at least be reconsidered periodically on the basis of the latest evidence.

Abstract NG05: Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53 null tumors

Abstract NG05: Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53 null tumors

Clinical and economic evaluation of trastuzumab for metastatic breast cancer in Brazil: A public health system perspective.

e17525 Background: Trastuzumab is a recombinant humanized monoclonal antibody that selectively targets the extra-cellular domain of the HER2 receptor, and has significantly improved outcomes for wo...

Vinorelbine with or without Trastuzumab in Metastatic Breast Cancer: A Retrospective Single Institution Series.

Background. We report our experience with vinorelbine, a widely used chemotherapeutic, in unselected metastatic breast cancer patients treated in clinical routine. Patients and Methods. The data of all patients with metastatic breast cancer receiving vinorelbine with or without trastuzumab during a six year period were reviewed. Patients received vinorelbine intravenous 25–30 mg/m2 or 60–80 mg/m2 orally in days 1 and 8 of a 21 day cycle. Results. Eighty-seven women were included. Sixty-two patients received vinorelbine alone and 25 patients received vinorelbine in combination with trastuzumab. In 67 patients this was the first line treatment for metastatic disease and in 20 patients it was 2nd or later line of treatment. The median TTP was six months (range: 1–45). The median overall survival was 11.5 months (range: 1–83). Seventy patients were evaluable for response. In patients receiving first line treatment 44.4% had a response while in the second and subsequent lines setting 12.5% of patients responded (P = 0.001). Objective response was obtained in 63.6% of patients receiving concomitant trastuzumab and in 25% of patients receiving vinorelbine alone (P = 0.0002). Conclusion. This study confirms a high disease control rate. Response rate and TTP were superior in first line treatment compared to subsequent lines.

Asymmetrical Fc Engineering Greatly Enhances Antibody-dependent Cellular Cytotoxicity (ADCC) Effector Function and Stability of the Modified Antibodies

Antibody-dependent cellular cytotoxicity (ADCC) is mediated through the engagement of the Fc segment of antibodies with Fcγ receptors (FcγRs) on immune cells upon binding of tumor or viral antigen. The co-crystal structure of FcγRIII in complex with Fc revealed that Fc binds to FcγRIII asymmetrically with two Fc chains contacting separate regions of the FcγRIII by utilizing different residues. To fully explore this asymmetrical nature of the Fc-FcγR interaction, we screened more than 9,000 individual clones in Fc heterodimer format in which different mutations were introduced at the same position of two Fc chains using a high throughput competition AlphaLISA® assay. To this end, we have identified a panel of novel Fc variants with significant binding improvement to FcγRIIIA (both Phe-158 and Val-158 allotypes), increased ADCC activity in vitro, and strong tumor growth inhibition in mice xenograft human tumor models. Compared with previously identified Fc variants in conventional IgG format, Fc heterodimers with asymmetrical mutations can achieve similar or superior potency in ADCC-mediated tumor cell killing and demonstrate improved stability in the CH2 domain. Fc heterodimers also allow more selectivity toward activating FcγRIIA than inhibitory FcγRIIB. Afucosylation of Fc variants further increases the affinity of Fc to FcγRIIIA, leading to much higher ADCC activity. The discovery of these Fc variants will potentially open up new opportunities of building the next generation of therapeutic antibodies with enhanced ADCC effector function for the treatment of cancers and infectious diseases.

High‐level ERBB2 gene amplification is associated with a particularly short time‐to‐metastasis, but results in a high rate of complete response once trastuzumab‐based therapy is offered in the metastatic setting

Despite patient selection based on ERBB2 overexpression, not all patients benefit from trastuzumab therapy. We have investigated whether a ERBB2 gene dosage effect might provoke increased biological aggressiveness and altered trastuzumab sensitivity. Absolute ERBB2 copy numbers ("CN") and ERBB2/centromer 17 ratios ("R") were measured by FISH analysis in tumors of 127 patients receiving trastuzumab-based treatment for Her-2/neu overexpressing metastatic breast cancer. CN and R were both significantly associated with shorter time to first metastasis (TTM) (CN: OR: 1.099, 95% CI: 1.042-1.159; R: OR: 1.211, 95% CI: 1.080-1.357) and longer PFS (CN: OR: 0.917, 95% CI: 0.867-0.969; R: OR: 0.840, 95% CI: 0.743-0.949) in a continuous variable Cox's regression model. Tumors with ERBB2/centromer 17 ratios of <2.2 had a significantly shorter TTM (p = 0.002) and significantly longer PFS (p = 0.003) than tumors with low-level (R: 2.2-6) and high-level amplification (R: >6). Interestingly, when ERBB2 copy numbers were analyzed, a significantly shorter TTM (p = 0.001) and longer PFS (p = 0.026) were observed in the group with high-level amplified CN (CN: >13), while no difference was observed between non- and low-level amplified CN. R, but not CN, was an independent predictor of complete (CR; OR: 1.685; 95% CI: 1.122-2.532) and partial (PR; OR: 1.704; 95% CI: 1.136-2.556) response in logistic regression analysis. CR (p = 0.016) rates were significantly higher in the high-level amplification group (R > 6), but no difference existed in response rates between non- and low-level amplified tumors in Chi-square tests. High-level ERBB2 amplification is associated with shorter TTM, but improved response to trastuzumab in metastatic breast cancer.