Use Of HER2-targeted Agents Research Articles

Abstract ES1-3: The ideal partner to HER2 directed therapies

Abstract Approximately ten percent of breast cancers are characterized by amplification/overexpression of HER2 with expression of one or both hormone receptors, deemed “double positive” or “triple positive” breast cancer. Though this cancer subtype has a lower chance of pathologic complete response with neoadjuvant therapy, it benefits as much from HER2-targeted therapies and has a long-term outcome that is as good or better than outcomes associated with the hormone receptor negative, HER2-positive subtype. Importantly, hormone receptor expression provides another opportunity to target additional signaling pathways implicated in tumor cell growth and survival, thus potentially expanding the armamentarium of effective therapeutics for this cancer subtype. In this presentation, clinical trial evidence evaluating the use of HER2-targeted agents plus endocrine therapy in the curative and advanced stage settings will be considered, including recent data directly comparing an endocrine-based versus chemotherapy-based approach. Results from studies evaluating whether the addition of endocrine therapy to chemotherapy plus HER2-directed treatment leads to antagonistic, null, or additive effects will be presented. The benefit of HER1/HER2-directed tyrosine kinase inhibitors such as lapatinib and neratinib based on tumor hormone receptor expression will be assessed. Finally, data from preclinical and clinical studies evaluating novel therapeutic strategies including the use of CDK4/6- or PI3K-pathway inhibitors will be considered and ongoing clinical trials addressing the optimal management of this disease subtype will be reviewed. Citation Format: S Hurvitz. The ideal partner to HER2 directed therapies [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES1-3.

Advances in therapy of breast cancer: overexpression and therapeutic implications of targeting human epidermal growth factor receptors

The human epidermal growth factor receptor 2 (HER2) ERbb2 gene is amplified in approximately 25% of breast cancers. Characteristics of HER2-amplified tumors include increased proliferation rates and a propensity for distant metastasis. The discovery of overexpression of HER2 in a subset of breast cancers was an important milestone in our understanding of the biology of the disease. This paved the way for the discovery of trastuzumab, a humanized monoclonal antibody targeting HER2. Trastuzumab is the foundation of treatment of HER2- positive breast cancers, demonstrating dramatic responses in patients with metastatic disease. Recent advances in our understanding of the interaction between HER2 and other members of the epidermal growth factor receptor family have led to the identification of newer agents, resulting in the expansion of the clinical armamentarium of available agents for the treatment of HER2-positive tumors. The biology of the ERbb receptor family, the use of HER2-targeted agents in breast cancer, and the advances in anti-HER2 agents that are currently in clinical development are reviewed here.

Diarrhea With HER2-Targeted Agents in Cancer Patients: A Systematic Review and Meta-Analysis.

To fully investigate the diarrhea of human epidermal growth factor receptor 2 (HER2)-targeted agents in cancer patients. The relevant studies of the randomized, controlled trials (RCTs) in cancer patients treated with HER2-targeted agents were retrieved, and the systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published until August 2018. Forty-two RCTs and 21633 patients were included. The current meta-analysis suggested that the use of HER2-targeted agents significantly increases the risk of developing all-grade diarrhea (RR, 2.78; 95%CI, 2.37-3.25; P < .00001) and high-grade diarrhea (RR, 4.89; 95%CI, 3.09-7.75; P < .00001). The RRs of all-grade diarrhea and high-grade diarrhea varied significantly according to drug type, control group, and treatment regimen. The RR of all-grade diarrhea varied significantly according to tumor type. Afatinib and neratinib tended to associate with the highest risk of all-grade diarrhea and high-grade diarrhea, respectively. Trastuzumab was associated with the lowest risk of diarrhea. Breast cancer patients tended to have a higher risk of all-grade diarrhea than patients with nonbreast cancer when receiving a HER2-targeted agent. The available data suggested that the use of HER2-targeted agents is associated with a significantly increased risk of diarrhea in cancer patients.

NSABP FC-11: A phase II study of neratinib (N) plus trastuzumab (T) or n plus cetuximab (C) in patients (pts) with "quadruple wild-type (WT)" (KRAS/NRAS/BRAF/PIK3CA WT) metastatic colorectal cancer (mCRC) based on HER2 status—Amplified (amp), non-amplified (non-amp), WT, or mutated (mt).

TPS716 Background: HER2 has been shown to be a validated therapeutic target for the treatment of mCRC. Preclinical and clinical evidence supports the use of HER2-targeted agents in each of these mCRC cohorts. In HERACLES, treatment–refractory, KRAS exon 2 (codons 12 and 13) WT, HER2 amp mCRC pts were treated with T and lapatinib (L). Objective response rate (CR or PR) was 8/27 and disease control rate (CR, PR, and SD &gt; 16 wks) was 16/27. Duration of response ranged from 24-94+ wks. Anecdotal reports have shown activity of N in HER2 mts from several cancer types. In mCRC PDX models with qualifying HER2 mts, T plus N is more active than either drug alone. In quad WT, HER2 non-amp PDX models, C plus TKI resulted in major tumor regressions not seen with C monotherapy. In NSABP FC-7, a trial of C + N in cetuximab refractory pts, HER2 amp was observed in 2/23 primary tissue samples; after C exposure, HER2 amp was seen in 5/17 samples, presumably signal upregulation under selective pressure of C. HER2 amp was concordant in tissue (CISH) and blood using cfDNA. Methods: This multi-center 3-cohort phase II trial is currently enrolling pts (total planned N = 35). Pts with quad WT, HER2 amp (n = 15) with prior anti-EGFR therapy and/or HER2 mt mCRC (n = 5) will receive T 4 mg/kg iv loading dose followed by 2 mg/kg/wk and N 240 mg po daily (Arm 1). Pts with quad WT, HER2 non-amp (n = 15) with no prior anti-EGFR therapy will receive C 400 mg/m2 iv loading dose followed by 250 mg/m2/wk, and N 240 mg (Arm 2). Specific pt eligibility for quad WT and HER2 status are defined below: Arm 1: HER2 amp confirmed in blood by Guardant360 assay, and prior treatment with C or panitumumab (P). HER2 mt (with qualifying mt) with or without prior treatment with C or P. Arm 2: HER2 non-amp or HER2 amp and no prior therapy with C or P. The primary aim is 6-mos progression-free survival for each cohort. Secondary aims: response rates and toxicity. Exploratory aims: genetic and molecular analyses. Specific drug combinations will be evaluated in PDX models. NCT03457896. Support: Puma Biotechnology, Inc.; NSABP Foundation, Inc. Clinical trial information: NCT03457896.

Retrospective analysis of HER2 therapy interruption in patients responding to the treatment in metastatic HER2+ breast cancer

IntroductionHuman epidermal growth factor receptor 2 (HER2)-targeted-therapy regimens can lead to prolonged tumour responses in metastatic HER2+ breast cancer. Clinical trials have concerned use of HER2-targeted agents until disease progression, but it is unknown whether the therapy can be interrupted in cases of a good response.MethodsSingle institute, retrospective collection of data on patients with HER2+ metastatic breast cancer (n=68) was carried out through a pharmacy search for patients who had received trastuzumab in 2006–2014. Clinical and pathological factors, treatment history and survival data were collected from patient records.ResultsMedian survival in metastatic disease (all patients) was 32 months and survival times were dramatically different in patients with and without trastuzumab as adjuvant or primary metastatic disease (median 16, 77 and 35 months, respectively; p=0.0004). More importantly, HER2 therapy was intentionally interrupted in 21 responding patients, and these patients experienced long HER2-therapy-free intervals (median 51 months), with excellent long-term survival. A lack of previous adjuvant trastuzumab was the only statistically significant factor predictive of HER2 therapy interruption.ConclusionsThese results from our retrospective study show that HER2 therapy interruption in patients with metastatic HER2+ breast cancer, who have responded to the therapy, is associated with low risk of rapid disease progression. Study suggests that therapy interruption in cases of response and reinitiation in progression is feasible.

Abstract P4-14-06: Neoadjuvant chemotherapy with docetaxel, carboplatin and weekly trastuzumab (TCH) is active in HER2-positive early breast cancer: Results after a median follow-up of over 4 years

Abstract Background: HER2-positive breast cancer is known to carry an adverse prognosis compared to HER2-negative disease, which may however be compensated by the use of HER2-targeted agents. Therefore, most patients with HER2-positive disease larger than 5 mm receive chemotherapy and trastuzumab. Data from adjuvant trials have shown that the combination of docetaxel, carboplatin and weekly trastuzumab (TCH) is well tolerated and as effective as anthracycline containing regimes. Previous investigations on neoadjuvant treatment with TCH showed pCR-rates in the range of 40%, however, survival data have not yet been presented. Here we present 4-year follow-up data for a cohort of 51 patients treated with neoadjuvant TCH. Methods: We treated 51 patients with operable HER2-positive breast cancer with a neoadjuvant schedule of docetaxel (75 mg/m2) and carboplatin (AUC 6) q3w and trastuzumab (2(4)mg/kg) q1w. Lymph node involvement was verified by SLNB or core-cut-biopsy. Patients were diagnosed at a mean age of 55 years, 68.6% had ER positive tumors, 39.2% presented with grade 3 disease and 49% of patients were node-positive. Patients were monitored every two cycles by ultrasound. After 6 cycles of chemotherapy all patients had surgery. Axillary dissection was performed in case of positive lymph node status prior to TCH. After surgery trastuzumab was continued q3w up to one year. Results: In 50 patients TCH could be administered as planned without dose reductions or delays. One patient suffered from an allergic reaction on taxane after the second cycle, resulting in replacement by gemcitabine. Side effects were mild, no grade III/IV toxicities occurred and no case of cardiomyopathia was observed. 21 (41.18%) patients achieved a pCR, 18 (72.0%) patients converted from cN+ to ypN0. Outcome data at a median follow-up of 51.6 months are as follows. All patients (n=51)pCR (n=21)N+ (n=25)cN+ → ypN0 (n=18)ER positive (n=35)G3 (n=20)DFS (n/%)42/82.3517/80.9517/68.016/88.8931/88.5716/80.0DDFS (n/%)46/90.219/90.4820/80.017/94.4433/94.2918/90.0OS (n/%)48/94.1821/100.022/88.018/100.034/97.1419/95.0 Conclusion: Outcome following neoadjuvant TCH as observed in our analysis compares well to outcome data observed in adjuvant trastuzumab trials such as HERA (4-year follow-up; DFS 78.6% and OS 89.3%) or BCIRG006 (36-month follow-up; DFS 82% and OS 91% in the TCH-arm). Particularly among patients with ER positive disease and those experiencing axillary conversion we obseverd an excellent outcome. Importantly, TCH was well tolerated in our cohort. Therefore our data support the use of TCH as neoadjuvant therapy regimen for patients with HER-positive breast cancer. They also strongly encourage the use of docetaxel and carboplatin as chemotherapy backbone in studies investigating the dual blockade with trastuzumab and pertuzumab in the neoadjuvant setting. Citation Format: Kolberg H-C, Akpolat-Basci L, Stephanou M, Hannig CV, Liedtke C. Neoadjuvant chemotherapy with docetaxel, carboplatin and weekly trastuzumab (TCH) is active in HER2-positive early breast cancer: Results after a median follow-up of over 4 years. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-06.

Recent advances in the HER2 targeted therapy of gastric cancer.

Recent advances in molecular targeted therapies, including targeting human epidermal growth factor receptor 2 (HER2), had a major forward step in the therapy for gastric cancer patients. Application of HER2-targeted therapies, in particular trastuzumab in combination with chemotherapy in metastatic HER2-positive gastric cancers, resulted in improvements in response rates, time to progression and overall survival. Nevertheless, as with breast cancer, many patients with gastric cancer develop resistance to trastuzumab. Several promising therapies are currently being developed in combination with chemotherapy to increase the efficacy and overcome the cancer-resistance. Here we review the current overview of clinical application of agents targeting HER2 in gastric cancer. We also discuss the ongoing trials supporting the use of HER2-targeted agents combined with cytotoxic agents or other monoclonal antibodies.

Disease and treatment (tx) characteristics in women with metastatic breast cancer (mBC) receiving HER2-targeted agents (H2Ts).

e11594 Background: While tx for HER2+ mBC have improved over the past decade, little information is available on the real-world use of H2Ts among important subgroups. The objectives of this retrosp...

Breast Cancer Molecular Phenotype and the Use of HER2-Targeted Agents Influence the Accuracy of Breast MRI After Neoadjuvant Chemotherapy

To investigate whether the accuracy of magnetic resonance imaging (MRI) after neoadjuvant systemic therapy (NST) is affected by molecular features of primary breast cancer and the use of human epidermal growth factor receptor 2 (HER2)-targeted agents. Improved understanding of factors affecting the accuracy of breast MRI after NST can lead to more tailored use of MRI in deciding surgical extent after NST. We analyzed the imaging and clinicopathological data of 463 patients who underwent NST. We aimed to investigate whether the molecular subtypes, and the use of targeted therapies, were associated with changes in the accuracy of MRI predicting residual tumor extent. The accuracy of MRI predicting the residual tumor extent was most accurate in triple-negative breast cancer and was least accurate in Luminal A subtype (Pearson correlation coefficient of 0.754 and 0.531, respectively). Multivariate analysis suggested estrogen receptor (ER) status as an independent factor influencing the MRI accuracy. In HER2-amplified tumors, the use of HER2-targeted agents was associated with a less accurate MRI prediction. The accuracy of MRI in predicting residual tumor extent was lowest in ER-positive tumors treated with NST. In HER2-positive tumors, the use of HER2-targeted agents resulted in a less accurate MRI after NST. These factors should be considered for deciding the extent of breast conservation after neoadjuvant chemotherapy.

Targeting the Human Epidermal Growth Factor Receptor 2 Pathway in Breast Cancer

The discovery of amplification of human epidermal growth factor receptor 2 (HER2), a member of the epidermal growth factor receptor family, was an important milestone in our understanding of the biology of breast cancers. This heralded the discovery of trastuzumab, a humanized monoclonal antibody targeting HER2. Trastuzumab is the foundation of treatment of HER2-positive breast cancers, demonstrating dramatic responses in patients with metastatic disease. Unfortunately, most tumors will inevitably develop resistance to trastuzumab, necessitating the need for alternate HER2-directed therapeutic approaches. Recent advances in our understanding of the interaction between HER2 and other members of the epidermal growth factor receptor family have led to identification of newer agents, resulting in the expansion of the clinical armamentarium of available agents for the treatment of HER2-positive tumors. In this article, we review the molecular biology of the ERbb receptor family, the use of HER2-targeted agents in early and advanced breast cancer, and the next-generation anti-HER2 agents that are currently in clinical evaluation.

Effect of online education on use of molecular markers to guide treatment selection for advanced gastric or gastroesophageal (GE) cancer.

111 Background: Trastuzumab in combination with chemotherapy is recommended for advanced gastric cancer positive for human epidermal growth factor receptor 2 (HER2) overexpression. Despite this recommendation, an informal pilot survey suggested that many oncologists do not include HER2 testing as part of routine practice to identify patients most likely to benefit from adding trastuzumab to chemotherapy. Methods: An interactive online educational activity was developed to provide expert guidance on HER2 testing and use of HER2-targeted agents in gastric or GE cancer. Pre- and post-education surveys were administered as part of the activity to measure changes in participant competence. In addition, 3 months after completing the educational activity, participants were sent another follow-up survey by email to assess changes in practice. Results: To date, pre-and post-education surveys have been obtained for 122 oncologists and 3-month follow-up surveys obtained from 14 oncologists. In the pre-education survey, only 46% said they were testing all of their patients with advanced gastric or GE cancer for HER2 overexpression. However, immediately after participating in the educational intervention, this proportion increased to 93%. Importantly, a follow-up survey indicated that HER2 testing of all patients with advanced gastric or GE cancer was now part of routine practice for 79% of those surveyed. A final analysis of pre- and post-education and 3-month follow-up surveys will be presented. Conclusions: Expert guidance on HER2 testing and use of HER2-targeted agents in gastric or GE cancer provided through an interactive online educational intervention substantially improved oncologist competence and practice patterns.

The Role of Lapatinib in the Preoperative Therapy of Breast Cancer

Preoperative or neoadjuvant chemotherapy is a well-established modality in the treatment of nonmetastatic breast cancer. Patients initially considered inoperable may be able to achieve operable status after preoperative chemotherapy and patients initially considered not to be candidates for breast conservation may convert to breast conservation status. Human epidermal growth factor receptor 2 (Her2)-positive tumors have been shown to have a more aggressive course including early local relapse and metastasis when compared to Her2-negative breast cancers, but the optimal use of Her2-targeted agents is constantly evolving as new agents become available. Preoperative studies allow us to quickly assess the activity of new agents and combinations for particular biological subsets of breast cancer.