Use Of HER2 Research Articles

BIOM-34. INTRACRANIAL MANAGEMENT OF HER-2 OVEREXPRESSION BREAST CANCER WITH EXTENSIVE VOLUME OR SYMPTOMATIC BRAIN METASTASES

Abstract BACKGROUND HER-2 overexpression in breast cancer often leads to brain metastases, necessitating effective intracranial control strategies. This study aimed to evaluate the correlation between intracranial disease volume, symptomatic presentation, and treatment outcomes in HER-2 overexpressing breast cancer patients with brain metastases. METHODS A retrospective analysis was conducted on cases of HER-2 overexpressing breast cancer patients with brain metastases. Clinical records were reviewed to extract patient demographics, treatment modalities, and intracranial disease characteristics. Intracranial tumor burden was quantified at diagnosis and post-initial treatment. High intracranial tumor burden was defined as either total metastatic volume >15 cc, or the largest lesion >3 cm. Responses were assessed using established criteria. The correlation between intracranial disease parameters and intracranial progression-free survival (PFS) and overall survival (OS) was determined. RESULTS The study comprised 65 patients with HER-2 overexpression breast cancer and brain metastases. Symptomatic presentation was observed in 69.2% of patients at the diagnosis of brain metastases. Treatment with HER-2 target therapy alone or in combination with other modalities resulted in substantial intracranial responses, with 81.5% achieving at least a partial response at 3 months from therapy initiation. Median intracranial PFS and OS for patients with high intracranial burden were 9 and 22 months, respectively. Patients with high intracranial burden and symptomatic presentation at diagnosis demonstrated worse PFS and OS to those with lower burden and absence of symptoms (p < 0.05 for each). CONCLUSION Intracranial control in HER-2 overexpressing breast cancer patients with large volume or symptomatic brain metastases appears promising with combination with HER-2 targeted therapy and radiotherapy. Despite the varying intracranial disease burdens and symptomatic presentations, the use of HER-2 targeted therapy combined with radiotherapy demonstrates favorable intracranial responses, highlighting their potential in managing such cases.

Intracranial management of HER-2 overexpression breast cancer with extensive volume or symptomatic brain metastases.

This study aimed to evaluate the impact of high intracranial burden and symptomatic presentation of brain metastases on treatment outcomes in patients with HER-2 positive breast cancer. Through a retrospective analysis, we explored the intracranial responses following the application of HER-2 targeted therapy alone or in combination with other modalities and further elucidated the relationship between treatment efficacy, intracranial progression-free survival (PFS), overall survival (OS), and the burden of intracranial lesions and symptomatic presentations. A retrospective analysis was conducted on cases of HER-2 overexpressing breast cancer patients with brain metastases. Clinical records were reviewed to extract patient demographics, treatment modalities, and intracranial disease characteristics. Intracranial tumor burden was quantified at diagnosis and post-initial treatment. High intracranial tumor burden was defined as either total metastatic volume >15 cc, or the largest lesion >3 cm. Responses were assessed using established criteria. The correlation between intracranial disease parameters and intracranial progression-free survival (PFS) and overall survival (OS) was determined. The study comprised 65 patients with HER-2 overexpression breast cancer and brain metastases. Symptomatic presentation was observed in 69.2% of patients at the diagnosis of brain metastases. Treatment with HER-2 target therapy alone or in combination with other modalities resulted in substantial intracranial responses, with 81.5% achieving at least a partial response at 3 months from therapy initiation. Median intracranial PFS and OS for patients with high intracranial burden were 9 and 22 months, respectively. Patients with high intracranial burden and symptomatic presentation at diagnosis demonstrated worse PFS and OS to those with lower burden and absence of symptoms (p < 0.05 for each). Her-2 overexpressing breast cancer and brain metastases face significant challenges, particularly those with high intracranial tumor burden, which correlates with poorer outcomes and higher incidence of leptomeningeal metastasis. Most patients responded positively to initial therapies, especially anti-HER-2 treatments combined with radiotherapy. Larger tumors necessitated more comprehensive treatment approaches, such as WBRT and SRS. Key factors influencing intracranial tumor control included the Ki-67 index, intracranial tumor burden, and continuous use of HER-2 targeted therapy post-diagnosis.

Abstract PO1-17-08: Post-approval treatment patterns and tolerability of neratinib in HER2+ early-stage breast cancer

Abstract Background: While the approval status for neratinib in HER2+ early-stage breast cancer (EBC) allows its use following any trastuzumab-based therapy, the phase 3 ExteNET trial (NCT00878709), which yielded an improvement in disease-free survival, was conducted when single-agent adjuvant trastuzumab was standard of care (SOC) and before approvals of adjuvant pertuzumab + trastuzumab (FDA-approved 2017) or trastuzumab emtansine (T-DM1; FDA-approved 2019). Given recent changes in SOC for HER2+ EBC, health care professionals may seek contemporary and real-world information regarding treatment patterns and tolerability of neratinib. Methods: A literature review was performed to identify studies that characterized trends in use of extended adjuvant neratinib in HER2+ EBC. Due to differences in study design (interventional, observational, claims data) and populations studied, a descriptive summary of data is presented in lieu of statistical cross-study comparisons. Results: Following FDA approval of neratinib in HER2+ EBC in 2017, five studies have reported treatment patterns of extended adjuvant neratinib in a clinical trial or real-world setting; three studies included safety data (Table 1). In the phase 2 CONTROL trial (NCT02400476; N=563; 2015–2021), approx. 82%, 17%, and 1% of neratinib-treated pts received prior adjuvant trastuzumab, pertuzumab, or T-DM1, respectively, and prior neoadjuvant/adjuvant pertuzumab did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration.1 In an interim analysis of the observational ELEANOR study (NCT04388384; N=187; 2020–ongoing), approx. 41%, 33%, and 19% of neratinib-treated pts received prior adjuvant trastuzumab (as their only anti-HER2 treatment), pertuzumab + trastuzumab, or T-DM1, respectively; corresponding rates of grade ≥3 diarrhea were 19%, 25%, and 14%, respectively, with no new safety signals reported.2 In a chart review from the US Oncology Network (N=166; 2017–2020), approx. 99%, 43%, and 2% of neratinib-treated pts received prior adjuvant trastuzumab (56% as their sole anti-HER2 treatment), pertuzumab, or T-DM1, respectively.3 Diarrhea was mainly moderate (29%; n=43/150) or mild (22%; n=33/150), with few severe cases (1%; n=2/150).3 In a retrospective analysis employing the IQVIA claims database (N=385; 2017–2021), prior use of recently approved adjuvant agents increased over time, with rates of prior pertuzumab + trastuzumab or prior T-DM1 as high as 52% and 14%, respectively, in 2020.4 In the Neat-HER virtual registry (N=46; 2018–2021), approx. 41% and 11% of neratinib-treated pts received prior adjuvant pertuzumab or T-DM1, respectively.5 Conclusions: Recent studies have observed neratinib use in clinical practice following adjuvant trastuzumab-based therapy including pertuzumab + trastuzumab or T-DM1. Preliminary data suggest a similar safety profile for pts with/without prior pertuzumab. These datasets are limited by the fact that: (1) some pts were enrolled in the CONTROL trial prior to launch of adjuvant T-DM1 and pertuzumab; (2) the interval between T-DM1 launch in Europe and start of the ELEANOR study was relatively short; and (3) not all toxicity measures were formally graded. A summary of available safety and effectiveness results is forthcoming. Additional interventional and non-interventional studies will continue to evaluate the safety and effectiveness of neratinib following current SOC adjuvant therapy in HER2+ EBC. Table 1. Treatment patterns of HER2-targeted adjuvant agents preceding neratinib use in HER2+ EBC ITT, intent-to-treat; T-DM1, ado-trastuzumab emtansine. aTherapies were recorded as used for adjuvant therapy in CONTROL, ELEANOR, US Oncology, and Neat-HER. CONTROL includes unpublished data. In the IQVIA claims analysis, HER2-targeted agent(s) used within 12 months prior to neratinib initiation were assumed to be adjuvant therapies. Pertuzumab use was generally taken in combination with trastuzumab as dual HER2 blockade and some pts received more than one anti-HER2 adjuvant treatment, for example T-DM1 in addition to pertuzumab plus trastuzumab. bAdjuvant trastuzumab monotherapy or in combination with chemotherapy unless noted otherwise. cThe proportion of patients who took at least one tablet of neratinib for ≥75% of the prescribed treatment days and did not take neratinib on days when neratinib was not prescribed. dData forthcoming. eIncludes prior trastuzumab monotherapy and trastuzumab used in combination with pertuzumab; 93/166 pts (56%) received trastuzumab as their only anti-HER2 agent (monotherapy or in combination with chemotherapy; unpublished data). fIncludes prior trastuzumab monotherapy as well as trastuzumab used in combination with pertuzumab. References Citation Format: Kelly McCann, Nadia Harbeck, Debu Tripathy, Arlene Chan, Jay Andersen, Joyce O'Shaughnessy, Gregory Vidal. Post-approval treatment patterns and tolerability of neratinib in HER2+ early-stage breast cancer [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 PO1-17-08.

Optimising Extended Adjuvant Neratinib Use in HER2+/HR+ Early Breast Cancer: Memo for Nurses

Neratinib (NERLYNX®) is indicated for the extended adjuvant treatment of adult patients with early-stage HR+/HER2-overexpressed/amplified breast cancer, who completed adjuvant trastuzumab-based therapy &lt;1 year ago. This infographic offers valuable guidance to nurses in effectively managing neratinib patients to ensure they reap the maximum advantages from this therapy.

Preclinical development of a first-in-class vaccine encoding HER2, Brachyury and CD40L for antibody enhanced tumor eradication

The induction of antiviral innate immunity by systemic immunization with live virus can be employed to positively impact the response to therapeutic vaccination. We previously demonstrated that systemic immunization with a non-replicating MVA encoding CD40 ligand (CD40L) enhances innate immune cell activation and function, and triggers potent antitumor CD8+ T cell responses in different murine tumor models. Antitumor efficacy was increased when combined with tumor targeting antibodies. Here we report the development of TAEK-VAC-HerBy (TVH), a first-in-class human tumor antibody enhanced killing (TAEK) vaccine based on the non-replicating MVA-BN viral vector. It encodes the membrane bound form of human CD40L, HER2 and the transcription factor Brachyury. TVH is designed for therapeutic use in HER2- or Brachyury-expressing cancer patients in combination with tumor targeting antibodies. To preclude possible oncogenic activities in infected cells and to prevent binding of vaccine-encoded HER2 by monoclonal antibodies trastuzumab and pertuzumab, genetic modifications of HER2 were introduced in the vaccine. Brachyury was genetically modified to prevent nuclear localization of the protein thereby inhibiting its transcriptional activity. CD40L encoded in TVH enhanced human leukocyte activation and cytokine secretion in vitro. Lastly, TVH intravenous administration to non-human primates was proven immunogenic and safe in a repeat-dose toxicity study. Nonclinical data presented here highlight TVH as a first-in-class immunotherapeutic vaccine platform currently under clinical investigation.

Neratinib as a Potential Therapeutic for Mutant RAS and Osimertinib-Resistant Tumours

Neratinib was developed as an irreversible catalytic inhibitor of ERBB2, which also acts to inhibit ERBB1 and ERBB4. Neratinib is U.S. Food and Drug Administration (FDA)-approved as a neo-adjuvant therapy for use in HER2+ breast cancer. More recently, chemical biology analyses and the authors’ own bench work have demonstrated that neratinib has additional targets, which open up the possibility of using the drug in cell types that either lack ERBB receptor family expression or who rely on survival signalling downstream of growth factor receptors. Neratinib rapidly disrupted mutant RAS nanoclustering, which was followed by mutant rat sarcoma virus proteins translocating via LC3-associated phagocytosis into the cytosol where they were degraded by macroautophagy. Neratinib catalytically inhibited the MAP4K mammalian STE20-like protein kinase 4 and also caused its degradation via macroautophagy. This resulted in ezrin dephosphorylation and the plasma membrane becoming flaccid. Neratinib disrupted the nanoclustering of RAC1, which was associated with dephosphorylation of PAK1 and Merlin, and with increased phosphorylation of the Merlin binding partners large tumour suppressor kinase 1/2, YAP, and TAZ. YAP and TAZ exited the nucleus. Neratinib retained its anti-tumour efficacy against NSCLC cells made resistant to either afatinib or to osimertinib. Collectively, these findings argue that the possibilities for the further development of neratinib as cancer therapeutic in malignancies that do not express or over-express members of the ERBB receptor family are potentially wide-ranging.

Does the 21-gene recurrence score have clinical utility in HR+/HER2+ breast cancer?

The 21-gene recurrence score assay has been validated as a predictive biomarker in early-stage HR+ and HER2-breast cancer. It is not indicated for use in HER2+ disease based on national guidelines. In this study, we assessed the value of 21-gene recurrence score (RS), or OncotypeDX (ODX), testing in HR+/HER2+ breast cancer.We used the National Cancer Database to identify patients with stages I-II, HR+/HER2+ breast cancer who received multi-gene testing with ODX. We then explored the prognostic and predictive value of this biomarker through various forms of survival modeling.ODX testing was performed in n = 5,280 patients. N = 2,678 patients (50.7%) had a RS < 26, while n = 2,602 (49.3%) had a RS ≥26. In Kaplan-Meier survival modeling for patients with recurrence scores <26, there was no significant difference in overall survival (p = 0.445) between patients receiving different systemic treatment regimens. However, when recurrence scores were ≥26, there was a statistically-significant difference in overall survival between systemic treatment regimens (p < 0.001). 5-year overall survival was highest (97.4%) for patients receiving triple therapy (anti-HER2 with chemotherapy and endocrine therapy), followed by those receiving dual therapy with endocrine and anti-HER2 (96.7%), and endocrine with chemotherapy (94.9%). Patients receiving endocrine therapy alone exhibited the lowest 5-year overall survival (88.5%). ResultsAnalysis from this large national cancer registry suggests that multigene testing may have predictive value in treatment selection for patients with early-stage, HR+/HER2+ breast cancer. Prospective trials are warranted to identify subgroups of patients with HR+/HER2+ breast cancer who can be spared anti-HER2 treatments and cytotoxic chemotherapy.

PCN2 Recurrences Avoided and Life Years Saved Attributable to Trastuzumab Use in HER2+ Early and Metastatic Breast Cancer in the United States

We estimated the cumulative life years saved and recurrences avoided after incorporating trastuzumab as therapy for metastatic breast cancer (MBC) in 1999 and early breast cancer (EBC) in 2006 in the United States. We constructed a model to estimate population survival and recurrence among patients who received trastuzumab each year, and compared it to a counterfactual model in which trastuzumab treatment was not available. We incorporated US population counts, the age-, year-, and nodal status-specific incidence rates of HER2+ EBC, the age- and year-specific rates of de novo MBC, recurrence rates in HER2+ EBC, and year-specific trastuzumab utilization rates in EBC and MBC. Women with low-risk, node-negative EBC were excluded. The risk of recurrence with and without trastuzumab were based on 10-year trial data. Recurrences were estimated for 15 years after diagnosis by carrying the year 10 rate forward. Survival after local and regional recurrences was estimated using the 5-year relative survival for HER2+ EBC. In MBC, the survival estimates with and without trastuzumab were pooled across seven studies. Uncertainty intervals (UI) were estimated using Monte Carlo simulation with 500 replicates. We estimate that between 2006-2019, trastuzumab use in HER2+ EBC led to the avoidance of 4,500 (95% UI 2,900-6,200) loco-regional and 10,100 (95% UI 6,400-13,800) distant recurrences. This in turn resulted in an incremental 407,900 (95% UI 291,800-528,500) life years saved compared to projected survival with chemotherapy alone. In HER2+ MBC from 1999-2019, there were 72,300 (95% UI 68,300-76,900) women with de novo or recurrent metastatic cancer treated with trastuzumab, leading to an additional 155,200 (95% UI 144,900-166,100) life years relative to projected survival with chemotherapy alone. Trastuzumab has substantially increased the years lived, and reduced recurrences for women with HER2+ MBC and EBC in the United States.

Acquired NF2 mutations confer resistance to HER2 targeted therapy in HER2-mutant breast cancer.

e12518 Background: Preclinical studies suggest that HER2 mutations lead to constitutive HER2 activation, but knowledge about effective treatment options and clinical resistance mechanisms remain uncharacterized. Methods: We performed dynamic monitoring of &gt;300 serial plasma samples collected from 49 metastatic breast cancer patients used targeted sequencing of 425 clinically relevant genes, to detect HER2 mutations and track resistance to HER2-targeted treatments in HER2-mutant breast cancer. Results: We identified activating HER2 mutations (S310F、D769Y、V777L、778insGSP) in ctDNA and paired tissue samples from four patients with ER positive/HER2-amplification negative metastatic breast cancer, who had developed resistance to multi-line (&gt;3) endocrine therapy. Two patients achieved a durable partial response (approximately 1 years) to trastuzumab combined with everolimus. Intriguingly however, analysis of ctDNA revealed that the NF2 mutation was acquired from a patient with HER2S310F/V777L who had developed resistance to HER2-targeted treatments. We showed that HER2S310F/D769Y/V777L/778insGSP mutations were constitutively active, and T47D and MCF7 overexpressing HER2S310F/V777L/778insGSP were sensitive to HER2 targeted therapies combined with everolimus. Consistent with our clinical findings, NF2 knockdown in HER2 S310F/V777L/778insGSP overexpressing T47D and MCF7 contributed to HER2-targeted therapy resistance. Furthermore, MEK inhibitor remarkably sensitized NF2 knockdown and HER2 mutations co-expressing T47D and MCF7 cells to trastuzumab. Conclusions: Dynamic monitoring of ctDNA could provide the candidate resistance genes for metastatic HER2-mutant breast cancer. Our findings validated NF2 mutations as a potential mechanism of resistance to HER2-targeted therapy, and the combined use of HER2 and ERK inhibitors may overcome resistance to HER2 targeted therapy in HER2-mutant breast cancer.

HER2 targeted therapy and outcome in HER2-equivocal cases after 2018 ASCO/CAP HER2 guideline modification.

e14729 Background: The best targeted therapeutic approach for HER2-equivocal cases remains unclear. New ASCO/CAP HER2 guidelines are intended to decrease this ambiguity by combining immunohistochemistry and in situ hybridization to resolve equivocal cases as positive or negative. However, the benefit of anti-HER2 therapy in HER2-equivocal cases is unknown. Methods: We retrospectively reviewed patients who visited MD Anderson from April 2017 to March 2018 with equivocal HER2 results based on the 2013 ASCO/CAP guidelines. The population was divided into 2 cohorts according to biopsy origin (primary cohort: biopsy from breast or axilla; recurrent/metastatic cohort: biopsy from recurrent or metastatic site). HER2 status was redefined using the 2018 ASCO/CAP guidelines. OS and PFS were calculated (Kaplan-Meier method) based on redefined HER2 status and use of HER2 targeted therapy. Results: A total of 139 equivocal results were found. Primary cohort had 90 patients (33 received neoadjuvant and 57 adjuvant therapy). HER2 IHC results were 0 (6.6%), 1+ (37.7%), 2+ (50%), 3+ (1.1%), and no IHC (4.4%). 94% of HER2-equivocal results became HER2 negative. Only 5 patients received anti-HER2 therapy, all of them in the HER2-negative group. After median follow-up of 1.91 yrs, 3 deaths and 8 progressions had occurred. There was no statistically significant association between anti-HER2 therapy and OS (p = 0.67) or PFS (p = 0.49). The recurrence/metastatic cohort had 49 cases with equivocal results. HER2 IHC results were 0 (6.1%), 1+ (22.4%), 2+ (26.5%), and no IHC (44.9%). 55% of HER2-equivocal results became HER2 negative, and only 1 patient received anti-HER2 therapy. After median follow-up of 2.96 yrs, 15 deaths and 35 progressions had occurred. There was no statistically significant association between anti-HER2 therapy and OS (p = 0.61) or PFS (p = 0.78). Conclusions: Most HER2-equivocal results were redefined as HER2 negative using the new ASCO/CAP guidelines. Association between anti-HER2 therapy and OS or PFS according to the new HER2 status was not observed. Although this is a small sample with short follow-up, patients with HER2-equivocal breast cancers seem to have clinical behavior similar to HER2-negative breast cancer.

Relationship Study of The Verified H uman Epidermal Growth Factor Receptor 2 Amplification with Other Tumor Markers and Clinicohistopathological Characteristics in Patients with Invasive Breast Cancer, Using Chromogenic In Situ Hybridization.

Objective Human epidermal growth factor receptor 2 (HER-2), as a crucial factor involved in about 20% of breast cancer cases, is one of the most reliable tumor markers to determine prognosis and therapeutic trend of this disease. This marker is generally assessed by immunohistochemistry (IHC) technique. In the cases that result of IHC test cast doubt (+2), the test should be repeated or validated by applying in situ hybridization techniques, like chromogenic in situ hybridization (CISH). In this regard, the goal of current study was to figure out the link between different clinicopathological characteristics of patients suffering from invasive breast cancer, using tumor markers, hormone receptor (HR) and HER-2. Comparing IHC and CISH techniques for evaluating diagnostic value and usefulness of HER-2 were also the other objective of this study. Materials and Methods Based on this retrospective study, histological markers of 113 individuals suffering from invasive breast cancer -such as estrogen receptor (ER), progesterone receptor, HER-2 receptor, E-cadherin, CK5/6, vimentin and Ki67 were examined by IHC technique. HER-2 amplification of all patients was also evaluated by CISH. Clinicopathological information of the patients was also extracted from medical documents and their associations with tumor markers were statistically evaluated. Results There is a significant relationship between tumor size, CK5/6 and tumor grade with HR status. Similar relationship was observed between HER-2 status and HR status, as well as vascular invasion (P<0.05). The comparison of HER-2 amplification showed no complete concordance of the result obtained from these two techniques, with score +3. ConclusionSince the status of HER-2 is very important in decision making of the treatment process, CISH technique is recommended in the malignant conditions as the primary test, instead of IHC. In this study, we also determined that HER-2 expression is greatly correlated with ER- and PR- status. This might propose a better prognosis for HER-2+ patients.

Frequency of locoregional recurrence among locally advanced HER2-positive breast cancer treated with modern multimodality therapy.

e12604Background: Prior to the advent of targeted therapies, patients with HER2-amplified (HER2+) breast cancers were at high risk for locoregional recurrence (LRR). The use of HER2 targeted therap...

Short term real world safety data of pertuzumab use in HER2 targeted treatment of metastatic breast cancer

With the development and widely use of HER2 targeted therapies, HER2 expressing metastatic breast cancer have no longer dismal prognosis as once expected. The combination of HER2 targeted therapies with chemotherapatic agents prolongs overall survival. Pertuzumab is a new monoclonal antibody molecule that binds to the extracellular portion of HER2 and works by inhibiting homo- and heterodimerization. The aim of this study is to document the real life data of toxicities seen in metastatic breast cancer patients treated with first line trastuzumab-pertuzumab combination therapy. A retrospective review of 26 cases from the medical oncology patient registry was conducted to include the dates October 2016 through December 2017. The number of cycles of treatment and doses, adverse events, dose changes and course delays, reasons for treatment change and types of second line treatments are noted. The imaging and laboratory test results were obtained from the electronic registration system. The cumulative toxicity incidence was accepted as the primary endpoint. The median age of the 26 cases was 54 years. The median cycle number of pertuzumab and docetaxel treatments were 9 and 7, respectively and the median duration of pertuzumab therapy was 6.75 months. As of the date of last follow-up, 80.7% of the cases were still under treatment. There was a total of 6 cases of delay in treatment, of which five were due to neutropenia, while in one case the cause was diarrhea. When the adverse events were examined, at least one side effect (excluding alopecia) was observed in 16 patients and 7 cases had no toxicity except alopecia. In terms of constitutional symptoms, eight of the 19 patients had grade 1 fatique, one case had itching, and three patients had asthenia. Hematologic toxicity was seen in twelve cases and all had at least grade 1 leukopenia. Grade 3-4 febrile neutropenia occurred only in one case. Left ventriculer ejection fraction was measured stable for all of the cases, none of them experienced any significant decrease. According to the results of this retrospective analysis, the use of pertuzumab-trastuzumab-docetaxel in the first line treatment of HER2 expressing metastatic breast cancer had good safety profile and had positive clinical results and paralleled with the results of the pivotal study.

C.03.03 - Optimisation of care in schizophrenia for relapse prevention with long-acting injectable antipsychotics

With the development and widely use of HER2 targeted therapies, HER2 expressing metastatic breast cancer have no longer dismal prognosis as once expected. The combination of HER2 targeted therapies with chemotherapatic agents prolongs overall survival. Pertuzumab is a new monoclonal antibody molecule that binds to the extracellular portion of HER2 and works by inhibiting homo- and heterodimerization. The aim of this study is to document the real life data of toxicities seen in metastatic breast cancer patients treated with first line trastuzumab-pertuzumab combination therapy.A retrospective review of 26 cases from the medical oncology patient registry was conducted to include the dates October 2016 through December 2017. The number of cycles of treatment and doses, adverse events, dose changes and course delays, reasons for treatment change and types of second line treatments are noted. The imaging and laboratory test results were obtained from the electronic registration system. The cumulative toxicity incidence was accepted as the primary endpoint.The median age of the 26 cases was 54 years. The median cycle number of pertuzumab and docetaxel treatments were 9 and 7, respectively and the median duration of pertuzumab therapy was 6.75 months. As of the date of last follow-up, 80.7% of the cases were still under treatment. There was a total of 6 cases of delay in treatment, of which five were due to neutropenia, while in one case the cause was diarrhea. When the adverse events were examined, at least one side effect (excluding alopecia) was observed in 16 patients and 7 cases had no toxicity except alopecia. In terms of constitutional symptoms, eight of the 19 patients had grade 1 fatique, one case had itching, and three patients had asthenia. Hematologic toxicity was seen in twelve cases and all had at least grade 1 leukopenia. Grade 3-4 febrile neutropenia occurred only in one case. Left ventriculer ejection fraction was measured stable for all of the cases, none of them experienced any significant decrease.According to the results of this retrospective analysis, the use of pertuzumab-trastuzumab-docetaxel in the first line treatment of HER2 expressing metastatic breast cancer had good safety profile and had positive clinical results and paralleled with the results of the pivotal study.

The use of trastuzumab in New Zealand women with breast cancer.

Trastuzumab was first funded in New Zealand for use in HER2+ve stage I-III breast cancer in 2007. This observational study aims to ascertain the patterns of use of trastuzumab in women with invasive HER2+ve breast cancer, and assess the effectiveness of adjuvant trastuzumab in women with stage I-III HER2+ve breast cancer. The Waikato and Auckland Breast Cancer Registries have clinical details of 12372 women diagnosed with invasive breast cancer between June 2000 and May 2013. The proportion of women with HER2+ve breast cancer treated with trastuzumab was examined by age, ethnicity, stage and year of diagnosis. Differences in outcomes including the development of metastases and death were assessed for women with stage I-III HER2+ve breast cancer treated with both chemotherapy and trastuzumab, compared to women treated with chemotherapy alone. Among the 1587 HER2+ve breast cancer patients, 888 (56.0%) women received trastuzumab. The probability of having trastuzumab decreased with higher age and comorbidity score and increased with year of diagnosis, tumor size and cancer stage. Māori and Pacific women were less likely to be treated with trastuzumab. After adjustment for potential confounding factors, the treatment with trastuzumab improved breast cancer-specific mortality (adjusted hazard ratio 0.57, 95% CI: 0.35-0.93). Overall, this observational study has shown a substantial improvement in survival for women with HER2+ve stage I-III breast cancer, and much of this improvement can be attributed to the introduction of trastuzumab. Changes in chemotherapy also appear to have led to improved outcomes.

Methods of selecting combination therapy for colorectal cancer patients: a patent evaluation of US20160025730A1

ABSTRACTIntroduction: Colorectal cancer (CRC) is the fourth most common cancer worldwide. Targeted therapy drugs (TTDs) are a valid treatment, epithelial growth factor receptor (EGFR) inhibitors being one of the most commonly used for CRC patients. However, this treatment is only useful for patients with wild-type KRAS (wtKRAS) and is effective only on about 40 to 60% of this subset due to the high plasticity of ErbB network.Areas covered: The invention proposes the use of ErbB protein levels and ErbB receptor dimer formation as biomarkers for selecting, predicting and monitoring CRC patients showing sensitivity to the action of EGFR inhibitors to benefit from the combination therapy of EGFR and HER2 inhibitors. The in vitro data on Lim1215 cells suggest the over-activation of HER3 signaling pathway in response to the use of EGFR inhibitors on monotherapy; the use of HER2 or HER3 or MEK inhibitors in combination with EGFR inhibitors reversed this activation.Expert opinion: To assess the clinical applicability of this invention, further studies are needed since the conclusions are derived solely based on the data obtained from only one CRC cell line (Lim1215). Furthermore, other biofactors/mutations should be considered to assure the potential benefits of the combination therapies proposed.

Rate of use of NCCN “preferred” chemotherapy regimens for the treatment of HER2 positive breast cancer.

163 Background: The National Comprehensive Cancer Network (NCCN) Guidelines represent a well-established standard of care for the treatment of HER2+ breast cancer patients. eviCore healthcare is a licensee of NCCN that uses the NCCN guidelines to support its proprietary chemotherapy management program. All regimens assigned NCCN Category of Evidence 1, 2A, or 2B are adherent treatments in the eviCore program. NCCN recommends many systemic treatment options for HER2+ breast cancer, and a limited group is designated by NCCN as “preferred” based on superior efficacy and/or safety. This study evaluated the frequency of NCCN-preferred regimen use by practicing oncologists in HER2+ breast cancer patients. Methods: Chemotherapy authorizations for all HER2+ breast cancer patients with ≥ 1 injectable drug from 4/1/2015-9/30/2016 for multiple payers were included; &gt; 90% of authorizations occurred in United HealthCare members. Cases with incomplete data were excluded. 3685 fully evaluable cases were stratified by stage, ER/PR status, and NCCN-preferred vs. NCCN-recommended status. The frequency of NCCN-preferred regimen selection was calculated for each subgroup. Results: There were 2883 HER2+/ER+ and/or PR+ cases and 802 HER2+/ER-/PR- cases. The highest frequency of NCCN-preferred regimen use occurred in neoadjuvant chemotherapy for patients with Stage III HER2+/ER+ and/or PR+ disease, where 88% of 289 patients used an NCCN-preferred regimen. Metastatic HER2+ patients had a markedly lower rate of NCCN-preferred regimen use at 62% of 557 cases. Only 48% of 1096 patients with Stage I/II HER2+/ER+ and/or PR+ disease received NCCN-preferred regimens. Conclusions: Patients receiving neoadjuvant chemotherapy for HER2+ breast cancer receive NCCN-preferred regimens at significantly higher rates than patients receiving adjuvant chemotherapy or metastatic treatment. Less than half of patients receiving adjuvant chemotherapy are receiving NCCN-preferred regimens. Further study is needed to determine the reasons for low preferred regimen use and ways to optimize preferred regimen use in HER2+ breast cancer.

Abstract P4-21-28: Trastuzumab improves outcomes of New Zealand women with HER2+ stage I-III breast cancer

Abstract Introduction HER2 status has been routinely ascertained for stage I-III breast cancer since late 2005. Trastuzumab was first funded in New Zealand for use in HER2+ breast cancer in July 2007. This observational study aims to compare the difference in outcome between women with HER2+ stage I-III breast cancer who received trastuzumab as adjuvant therapy versus those who did not. Differences in presentation, treatment and outcomes between Māori and NZ European were studied. Methods The combined Waikato and Auckland Breast Cancer Registries have clinical details of 12377 women diagnosed with breast cancer between June 2000 and May 2013. 9506 women with breast cancer were tested for HER2 receptor status. Proportion of women with HER2+ (FISH amplified or IHC 3+), stage I-III breast cancer were examined by age, ethnicity and stage. Differences in use of trastuzumab for women with stage I-III breast cancer with a tumour size equal or larger than 1 cm and aged less than 75 years were assessed by ethnicity and year of diagnosis. Patients who had inflammatory breast cancer or developed metastatic disease or local recurrence within 3 months after diagnosis were excluded. Kaplan-Meier method and Cox proportional hazards model were used to examine the breast cancer-specific survival between women treated with trastuzumab and chemotherapy and those treated with chemotherapy without trastuzumab. Results 1454 patients with early invasive breast cancer were HER2+. The proportion of cases with HER2+, stage I-III breast cancer increased with stage (stage I-III: 11.5%-26.9%), but decreased with age (&amp;lt;40 years to 80+ years: 28.8%-9.7%). Māori women were more likely to have HER2+ cancers than NZ European (17.8% versus 14.9%; p=0.02). Among the eligible patients, 605 women received trastuzumab and chemotherapy within 12 months for stage I-III breast cancer, and 275 had chemotherapy without trastuzumab. A small proportion (10.2%, 34/333) of women diagnosed in 2000-2005 received trastuzumab as part of a clinical trial. The proportion of women who received trastuzumab increased to 60.3% in 2006-2009 and to 87.1% in 2010-2013. 46.2% of Māori women were treated with trastuzumab compared to 55.9% of NZ European (p=0.040). The cancer-specific survival estimated with Kaplan-Meier method is shown in Table 1. Women treated with chemotherapy without trastuzumab were 2.7 times (95% CI: 1.9-3.9) more likely to die of breast cancer compared to those treated with trastuzumab and chemotherapy, after adjustment for stage, tumour size and hormone therapy. Table 1. Breast cancer-specific survival between women with HER2+ stage I-III breast cancer who received trastuzumab as adjuvant therapy versus those who did notTreatmentNumber of patientsMedian follow-up time (months)5-year survival10-year survivalTrastuzumab+chemotherapy6055389.6%84.3%Chemotherapy without trastuzumab27510775.6%69.1% Conclusions Trastuzumab improved the breast cancer-specific survival of women with HER2+ stage I-III breast cancer. Māori women were more likely to have HER2+ cancer and less likely to be treated with trastuzumab. Rates of treatment with trastuzumab and the adjusted survival between Māori women and NZ European women were not significantly different. Citation Format: Lawrenson R, Lao C, Harvey V, Campbell I, Brown C, Seneviratne S, Edwards M, Scott N, Elwood M, Sarfati D, Kuper-Hommel M. Trastuzumab improves outcomes of New Zealand women with HER2+ stage I-III breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-28.

HER2 gene amplification in patients with prostate cancer: Evaluating a CISH-based method.

Prostate cancer (PCa) is one of the most widespread malignancies in the world. The role of the human epidermal growth factor receptor 2 (HER2) in the pathogenesis and progression of human PCa remains poorly understood. In contradiction with breast cancer, studies on HER2 overexpression and gene amplification in PCa have produced varying results, although the HER2 oncogene has been implicated in the biology of numerous tumor types, and serves as a prognostic marker and therapeutic target in breast cancer. Technical challenges are considered the main reasons for data discrepancies. Amplification of the HER2 gene has previously been reported in PCa, in which it was associated with tumor progression. The present study aimed to evaluate the prevalence and clinical significance of HER2 amplification in PCa. A total of 32 biopsy samples obtained from human prostate adenocarcinomas were evaluated by chromogenic in situ hybridization (CISH) to determine the frequency of patients with HER2 gene amplifications. High copy numbers of HER2 were detected in 19 of the prostate tumors analyzed. The results of the present study suggested that, in patients without amplification of HER2, high levels of prostate-specific antigen or a high Gleason score were not significantly correlated with a high pathologic stage. Furthermore, amplification levels of the HER2 gene were directly associated with pathologic stage in patients with PCa. Therefore, the potential use of HER2 as a prognostic factor or therapeutic target for PCa warrants further study.

Trastuzumab Emtansine in HER2+ Recurrent Metastatic Non–Small-Cell Lung Cancer: Study Protocol

The treatment outcome has been unsatisfactory for patients with non–small-cell lung cancer (NSCLC) refractory to standard first-line chemotherapy. Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T-DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T-DM1 could significantly inhibit the growth of HER2+ lung cancers. We have launched a nonrandomized phase II trial of T-DM1 monotherapy for patients with HER2+ lung cancers. The major eligibility criteria are as follows: age ≥ 20 years, pathologically diagnosed NSCLC with documented HER2 positivity (immunohistochemistry 3+, both immunohistochemistry 2+ and fluorescence in situ hybridization positive, or exon 20 insertion mutation), and previous chemotherapy. Thirty patients will receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate. This trial will provide information on whether T-DM1 monotherapy is effective against HER2+ lung cancer.