anti-HER2 Therapy In Patients Research Articles

HER2 Genetic Intratumor Heterogeneity Is Associated With Resistance to Trastuzumab and Trastuzumab Emtansine Therapy in Recurrent High-Grade Endometrial Cancer

Anti-HER2 targeted therapies have recently demonstrated clinical activity in the treatment of high-grade endometrial carcinomas (ECs), particularly serous carcinomas with HER2 amplification and/or overexpression. Intratumor heterogeneity of HER2 amplification or HER2 genetic intratumor heterogeneity (G-ITH) has been associated with resistance to anti-HER2 therapies in breast and gastroesophageal cancers; however, its clinical relevance in EC is unknown. To characterize HER2 G-ITH in EC, archival specimens from a clinically annotated cohort of 57 ECs treated with trastuzumab or trasutuzmab emtansine in the recurrent (n = 38) or adjuvant (n = 19) setting were subjected to central pathology review, HER2 assessment by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and next-generation sequencing. HER2 G-ITH, defined as HER2 amplification in 5% to 50% of tumor cells examined by FISH, was identified in 36% (19/53) of ECs and was associated with lower HER2 copy number and levels of protein expression. HER2 IHC revealed spatially distinct areas of strong expression juxtaposed with areas of low/absent expression in tumors with the “cluster” pattern of G-ITH, whereas the “mosaic” pattern was typically associated with a diffuse admixture of cells with variable levels of HER2 expression. HER2 G-ITH was frequently observed in cases with IHC/FISH or FISH/next-generation sequencing discrepancies and/or with an equivocal/negative FISH result (9/13, 69%). Although the objective response rate to anti-HER2 therapy in recurrent ECs was 52% (13/25) for tumors lacking HER2 G-ITH, none (0%, 0/10) of the patients with HER2 G-ITH achieved a complete or partial response (P = .005). HER2 G-ITH was significantly associated with worse progression-free survival (hazard ratio, 2.88; 95% CI, 1.33-6.27; P = .005) but not overall survival. HER2 IHC score, HER2/CEP17 ratio, HER2 copy number, histologic subtype, and other genetic alterations, including PIK3CA hotspot mutations, were not significantly associated with therapeutic response or survival outcomes. Treatment responses were not restricted to serous carcinomas, supporting consideration of anti-HER2 therapy in patients with HER2-positive high-grade ECs of non-serous histology. Our results demonstrate that HER2 G-ITH is an important determinant of response to trastuzumab and trastuzumab emtansine in EC, providing a rationale for the development of novel therapeutic strategies to target HER2-nonamplified resistant tumor subpopulations, such as HER2 antibody-drug conjugates with bystander effects.

SDPS-20 THE HER2 FLIP: HER2 AMPLIFICATION OF TUMOR CELLS IN THE CEREBROSPINAL FLUID (CSF-TCS) OF PATIENTS WITH LEPTOMENINGEAL METASTASIS HAVING SOLID TUMORS; IMPLICATIONS FOR TREATING THE LM TUMOR WITH ANTI-HER2 THERAPY

Abstract INTRODUCTION Patients diagnosed with Leptomeningeal Metastasis (LM) have limited treatment options. However, they may benefit from targetable therapy. LM breast cancer patients with HER2 positive primary tumors treated with IT Trastuzumab experienced clinical benefit (Malani, 2020), and improved craniospinal PFS (Figura, 2019). HER2 amplification of the primary and metastatic tumors can be heterogeneous. Biocept’s CNSideTM is a CLIA validated Laboratory Developed Test and is used commercially at the discretion of Physicians to detect CSF tumor cells (CSF-TCs). We analyzed HER2 amplification on CSF-TCs in LM patients with breast-, upper GI cancer as well as Non-Small Cell Lung Cancer (NSCLC). METHODS CSF was collected from patients with suspected or confirmed LM having Breast Cancer (N=334 patients, N=181 evaluable), NSCLC (N=28 patients) or upper GI cancer (N=4 patients, N=2 evaluable). CSF TCs were tested for HER2 amplification by FISH using CNSide. RESULTS For the breast cancer patients, 38% (68/181) had HER2 FISH detected on CSF TCs, 60% (109/181) had a HER2 negative primary tumor of which 35% (38/109) had HER2 positive CSF-TCs. Furthermore, 8% (14/181) had an equivocal HER2 primary tumor, 21% (3/14) of which had HER2 positive CSF-TCs. For the NSCLC patients, 50% (14/28) showed HER2 amplification on the CSF-TCs. For the upper GI cancer patients, one patient had an equivocal HER2 primary tumor, and HER2 positive CSF-TCs. CONCLUSION HER2 amplification is detected on CSF-TCs of patients with LM having breast cancer, upper GI cancer or NSCLC cancer. For NSCLC patients, HER2 positivity in the LM can be associated with drug resistance. Patients who have a HER2 negative primary tumor can develop HER2 positive LM, allowing for an anti-HER2 targetable treatment. Additional studies are needed to establish the clinical utility of CNSide in the detection of HER2 on the CSF-TCs to direct treatment of anti-HER2 therapy in patients with LM.

Fulvestrant with or without anti-HER2 therapy in patients in a postmenopausal hormonal state and with ER-positive HER2-positive advanced or metastatic breast cancer: A subgroup analysis of data from the Safari study (JBCRG-C06).

The role of endocrine therapy in the treatment of patients in a postmenopausal hormonal state and with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer (AMBC) is unclear. We analyzed the data from 94 patients with ER-positive HER2-positive AMBC enrolled in the Safari study (UMIN000015168), a retrospective cohort study of 1072 ER-positive AMBC patients in a postmenopausal hormonal state who received fulvestrant 500 mg (F500): (1) to compare time to treatment failure (TTF) and overall survival (OS) by treatment group, and TTF by treatment line; (2) in patients who received endocrine therapy (including F500) or anti-HER2 therapy as initial systemic therapy before chemotherapy, to investigate relations between TTF for the first-line therapy or time to chemotherapy (TTC) and OS; (3) to investigate factors associated with OS. The TTF was longer in the patients treated with F500 as first- or second-line therapy (n = 20) than in those who received later-line F500 therapy (n = 74) (6.6 vs. 3.7 months; HR, 1.98; p = 0.014). In the 59 patients who received endocrine therapy or anti-HER2 therapy as initial systemic therapy before chemotherapy, those with TTC ≥3 years had longer median OS than those with TTC <3 years (10.5 vs. 5.9 years; HR, 0.32; p = 0.001). Longer TTC was associated with prolonged OS. In patients with ER-positive HER2-positive AMBC enrolled in the Safari study, TTF was longer in patients who received F500 as first- or second-line therapy. In patients who received chemotherapy-free initial systemic therapy, the prolonged OS in those with TTC ≥3 years suggests that this value may be a helpful cut-off for indicating clinical outcomes.

Efficacy of anti-HER2 drugs in the treatment of patients with HER2-mutated cancers: a systematic review and meta-analysis.

Anti-human epidermal growth factor receptor-2 (anti-HER2) therapy has shown excellent efficacy in patients with HER2 overexpression and amplification. Although HER2 mutations are rarely expressed in several cancers, when they occur, they can activate the HER2 signaling pathway. In recent years, studies have shown that anti-HER2 drugs have promising efficacy in patients with HER2 mutations. Based on keywords, we searched databases, such as PubMed, Embase, and Cochrane Library, and the main conference abstracts. We extracted data on objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) from studies on the efficacy of anti-HER2 therapies in patients with HER2-mutated cancers, and analyzed grade 3 or higher adverse events (AEs). We included 19 single-arm clinical studies and 3 randomized controlled trials (RCTs), containing a total of 1017 patients with HER2 mutations, involving seven drugs and nine cancers, and 18 studies enrolled a high proportion of heavily pretreated patients who had received multiple lines of therapy. Our results showed pooled ORR and CBR of 25.0% (range, 3.8-72.7%; 95% CI, 18-32%) and 36.0% (range, 8.3-63.0%; 95% CI, 31-42%) for anti-HER2 therapy in HER2-mutated cancers. The pooled median PFS, OS, DOR were 4.89 (95% CI, 4.16-5.62), 12.78 (95% CI, 10.24-15.32), and 8.12 (95% CI, 6.48-9.75) months, respectively. In a subgroup analysis, we analyzed the ORR for different cancers, showing 27.0, 25.0, 23.0, and 16.0% for breast, lung, cervical, and biliary tract cancers, respectively. ORR analyses were performed for different drugs as monotherapy or in combination, showing 60.0% for trastuzumab deruxtecan (T-DXd), 31.0% for pyrotinib, 26.0% for neratinib combined with trastuzumab, 25.0% for neratinib combined with fulvestrant, 19.0% for trastuzumab combined with pertuzumab, and 16.0% for neratinib. In addition, we found that diarrhoea, neutropenia, and thrombocytopenia were the most common grade ≥ 3 AEs associated with anti-HER2 therapeutic agents. In this meta-analysis of heavily pretreated patients with HER2 mutations, anti-HER2 therapies, DS-8201 and trastuzumab emtansine, showed promising efficacy and activity. Anti-HER2 therapies showed different efficacies in different or the same cancer settings and all had a tolerable safety profile.

166P Adjuvant trastuzumab plus pertuzumab (TP) versus trastuzumab (T) alone in patients achieving pathologic complete response after chemotherapy with TP

The APHINITY trial showed that an addition of 1 year pertuzumab (P) to standard chemotherapy with trastuzumab (T) improves invasive disease-free survival in HER2+ breast cancer patient with node-positive. Meanwhile, in patients with pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) with TP, it lacks of evidence whether an addition of P might be omitted in adjuvant treatment. We compared survival outcome according to the type of adjuvant anti-HER2 therapy in patients with pCR after NACT with TP.

Systematic analysis of the expression and prognostic value of ITPR1 and correlation with tumor infiltrating immune cells in breast cancer

BackgroundITPR1 is a key gene for autophagy, but its biological function is still unclear, and there are few studies on the correlation between ITPR1 gene expression and the occurrence and development of breast cancer.MethodsAnalyze the expression of ITPR1 through online databases such as Oncomine and TIMER. Kaplan–Meier plotter and other databases were used to evaluate the impact of ITPR1 on clinical prognosis. The expression of ITPR1 in analysis of 145 cases of breast cancer and 30 cases of adjacent normal tissue was detected by Immunohistochemistry. Statistical analysis was used to evaluate the clinical relevance and prognostic significance of abnormally expressed proteins. And the Western Blot was used to detect the expression of ITPR1 between breast cancer tissues and cells. The TIMER database studied the relationship between ITPR1 and cancer immune infiltration. And used the ROC plotter database to predict the response of ITPR1 to chemotherapy, endocrine therapy and anti-HER2 therapy in patients with breast cancer.ResultsCompared with normal breast samples, ITPR1 was significantly lower in patients with breast cancer. And the increased expression of ITPR1 mRNA was closely related to longer overall survival (OS), distant metastasis free survival (DMFS), disease specific survival (DSS) and relapse free survival (RFS) in breast cancer. And the expression level of ITPR1 was higher in patients treated with chemotherapy than untreated patients. In addition, the expression of ITPR1 was positively correlated with related gene markers of immune cells in different types of breast cancer, especially with BRCA basal tissue breast cancer.ConclusionITPR1 was lower expressed in breast cancer. The higher expression of ITPR1 suggested favorable prognosis for patients. ITPR1 was related to the level of immune infiltration, especially in BRCA-Basal patients. All research results indicated that ITPR1 might affect breast cancer prognosis and participate in immune regulation. In short, ITPR1 might be a potential target for breast cancer therapy.

Targeting lipid metabolism is an emerging strategy to enhance the efficacy of anti-HER2 therapies in HER2-positive breast cancer.

De novo or acquired resistance of cancer cells to currently available Human Epidermal Growth Factor Receptor 2 (HER2) inhibitors represents a clinical challenge. Several resistance mechanisms have been identified in recent years, with lipid metabolism reprogramming, a well-established hallmark of cancer, representing the last frontier of preclinical and clinical research in this field. Fatty Acid Synthase (FASN), the key enzyme required for fatty acids (FAs) biosynthesis, is frequently overexpressed/activated in HER2-positive (HER2+) breast cancer (BC), and it crucially sustains HER2+ BC cell growth, proliferation and survival. After the synthesis of new, selective and well tolerated FASN inhibitors, clinical trials have been initiated to test if these compounds are able to re-sensitize cancer cells with acquired resistance to HER2 inhibition. More recently, the upregulation of FA uptake by cancer cells has emerged as a potentially new and targetable mechanism of resistance to anti-HER2 therapies in HER2+ BC, thus opening a new era in the field of targeting metabolic reprogramming in clinical setting. Here, we review the available preclinical and clinical evidence supporting the inhibition of FA biosynthesis and uptake in combination with anti-HER2 therapies in patients with HER2+ BC, and we discuss ongoing clinical trials that are investigating these combination approaches.

A 10-Gene Signature for Predicting the Response to Neoadjuvant Trastuzumab Therapy in HER2-Positive Breast Cancer

Background and PurposeDual-target therapy may increase the incidence of adverse events and cause economic burden to patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. It is necessary to identify the patients who could benefit greatly from a single-target neoadjuvant therapy in order to avoid overtreatment of patients. Patients and MethodsThe baseline transcriptome data and clinical characteristics of patients with HER2-positive breast cancer who received neoadjuvant trastuzumab therapy were obtained from the Gene Expression Omnibus database. Least absolute shrinkage and selection operator (LASSO) regression analyses were used to construct the predictive model for pathologic complete response (pCR). ResultsA 10-gene signature model for predicting pCR rate after neoadjuvant trastuzumab therapy was constructed by LASSO regression. The areas under the receiver operating characteristics (ROC) curves in the training set and validation set were 0.896 (95% confidence interval [CI], 0.8165-0.9758) and 0.775 (95% CI, 0.5402-1), respectively. The result of logistic regression analysis showed that the risk score calculated by the 10-gene signature model was a potential predictor for pCR. Among the 10-gene signature, TFAP2B, SUSD2, AQP3, MUCL1, and ANKRD30A were found to be predictors for worse relapse-free survival (RFS) in patients with HER2-positive breast cancer, whereas MGP, YIF1B, ANKRD36BP2, and FBXO6 were found to be predictors for favorable RFS. ConclusionA novel 10-gene signature that could predict the response of neoadjuvant anti-HER2 therapy in patients with HER2-positive breast cancer was developed, and the risk score of the 10-gene signature could be calculated to guide the selection of anti-HER2 therapy regimens.

Abstract PS10-42: Clinical outcomes with neoadjuvant chemotherapy plus dual anti-HER2 therapy in patients with operable/locally advanced breast cancer: Single institution experience

Abstract Background: Pertuzumab, a monoclonal antibody targeting subdomain II of HER2 and blocking dimerization, was approved by the FDA in 2013 as neoadjuvant therapy in combination with trastuzumab + chemotherapy for HER2+ locally advanced or early-stage breast cancer patients (pts). TCHP (Docetaxel/Carboplatin/Trastuzumab/Pertuzumab) is a popular, non-anthracycline neoadjuvant therapy. In the TRYPHAENA trial, pathologic complete response (pCR) rate was 63.6% with 6 cycles of neoadjuvant TCHP (47.5% in ER+/PR+ and 81.1% in ER-/PR- tumors). We previously reported (SABCS 2015) our institutional experience with neoadjuvant TCHP in 75 pts with operable/locally advanced HER2+ breast cancer (10/2013 - 12/2015). Now we report our updated experience of 230 pts (10/2013 - 12/2019) with neoadjuvant chemotherapy + dual anti-HER2 therapy. Patients &amp; Methods: Medical record search identified HER2+ pts (T1c-T3/N0-3 or Tany/N1-3) treated with neoadjuvant chemotherapy + dual anti-HER2 therapy from 10/2013 to 12/2019. Collected information included pt and tumor characteristics at diagnosis, details of neoadjuvant therapy, clinical, radiologic, &amp; pathologic assessment of tumor response, type of breast and axillary nodal surgery, and long-term disease outcomes. Results: 230 pts (229 female, 1 male) met the inclusion criteria; median age: 52 yrs (range 25-79); Clinical stage: I (2%), II (78%) , III (20%); ER+ and/or PR+ 70% ; ER-/PR- 30%. 228 pts received TCHP and 2 pts AC then THP. 170 pts (74%) received 6 cycles of TCHP without dose reduction; 49 pts (21%) received 6 cycles, but with dose reduction (most commonly due to diarrhea, nausea, neutropenia, and anemia); 11 pts (5%) received &amp;lt; 6 cycles (7 of those also needed dose reduction). Mean left ventricular ejection fraction was 62.0% pre-treatment, and 60.9% post-treatment. Of the 230 pts who underwent breast surgery (1 had no breast primary at presentation), 86 pts (38%) had breast conserving surgery, 19 (8%) unilateral mastectomy, and 124 (54%) bilateral mastectomy. Axillary assessment was by SLNB in 75% and ALND in 25% (with/without SLNB). Among 138 pts with cN0 and axillary assessment, 124 had SLNB (4 had + nodes), 14 had ALND (11 had + nodes). Among 91 pts with cN1-3, 47 had SLNB (1 had + nodes) and 44 had ALND (27 had + nodes). Overall pCR rate (ypT0/Tis, ypN0) was 59%. pCR rate was 50% for ER+ and/or PR+, and 79% for ER-/PR-. pCR by Stage: I (50%), II (60%), III (55%). At median follow-up of 2.9 years, 221 pts (96%) were alive with no evidence of disease; 8 pts (3.5%) have experienced recurrence (6 distant, 1 locoregional, 1 unknown site), and 1 pt died after developing AML as the only event. The table below presents details on the 8 pts who suffered recurrence: 4 had clinical stage II disease, and 4 clinical stage III. All pts had hormone receptor + tumors at diagnosis. 7 of 8 pts (88%) with recurrence did not have pCR at surgery. Most common sites of distant metastases as first event were liver and bone. Of the 8 pts with recurrence, 6 are alive with disease (median follow-up 2.8 years). There was 1 death due to disease progression, and 1 pt was lost to follow-up. Conclusions: Our updated results continue to demonstrate the clinical safety and efficacy of neoadjuvant therapy with TCHP for operable/locally advanced HER2+ breast cancer. Our pCR rates are similar to those observed in the TRYPHAENA trial. Longer follow-up is required to evaluate the long-term clinical outcomes with this regimen. Recurrence DataPatient NumberAge at DiagnosisDate of DiagnosisHormone Receptor at DiagnosisClinical Stage at DiagnosisType of Breast SurgerypCRPathologic Stage at SurgeryDate of RecurrenceTime to Metastases (Years)Site of Recurrence16511/19/14PositivecT2N1 (IIB)Left MastectomyYesypT0N0 (0)4/6/172.4Liver, Bone2366/15/15PositivecT2N0 (IIA)Bilateral MastectomyNoypT3N0 (IIB)3/19/182.8Liver3546/29/15PositivecT2N3 (IIIC)Left MastectomyNoypT1bN1a (IIA)10/2/194.3Bone4577/1/15PositivecT2N3 (IIIC)Left LumpectomyNoypT1cN1a (IIA)2/4/193.6Bone, Soft Tissue5568/20/15PositivecT2N0 (IIA)Left LumpectomyNoypT1aN0 (IA)6/28/182.8Lymph Node6264/29/16PositivecT4N0 (IIIB)Bilateral MastectomyNoypT2N1 (IIB)12/13/171.6Liver7539/27/16PositivecT3N3 (IIIC)Bilateral MastectomyNoypT3N3 (IIIC)Not KnownNot KnownNot Known8319/3/17PositivecT2N1 (IIB)Bilateral MastectomyNo (clinical progression)ypT3N2a (IIIC)6/25/180.8Lungs Citation Format: Nirja Shah, Nikita Shah, Said Baidas, Ana Cuesta-Fernandez, Marc Demers, Maria Demori, Tomas Dvorak, Rachel Eisenberg, Terrence Gross, Danielle Henry, Michael Kahky, Patrick Kelly, Swathy Kolli, Regan Rostorfer, Jeffrey Smith, Cameron Swanick, Eleftherios Mamounas. Clinical outcomes with neoadjuvant chemotherapy plus dual anti-HER2 therapy in patients with operable/locally advanced breast cancer: Single institution experience [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-42.

Recent advances in the treatment of hormone receptor-positive/human epidermal growth factor 2-positive advanced breast cancer.

Hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-positive (HR+/HER2+) advanced breast cancer is a special subtype of cancer with unique features. Major guidelines recommend that combination therapy containing anti-HER2 therapy (e.g., trastuzumab and pertuzumab) should be applied as the first-line treatment for HER2+ advanced breast cancer, regardless of HR status. Endocrine therapy could be relegated to patients who cannot tolerate chemotherapy or as a post-chemotherapy empirical maintenance strategy. Previous studies have shown that the HR pathway interacts with the HER2 pathway, and the HR and HER2 pathways of endocrine therapy combined with targeted therapy can effectively avoid tumor resistance. Therefore, the combination of endocrine and targeted therapies is the preferred treatment plan for HR+/HER2+ patients to replace chemotherapy. In this review, we will discuss research progress regarding endocrine therapy combined with anti-HER2 therapy in patients with advanced breast cancer, to provide more evidence for clinical practice and broader perspectives for related research. In the future, we hope there will be more studies on HR+/HER2+ advanced breast cancer to elucidate the optimal and appropriate treatment for these patients.

Combination treatment with a PI3K/Akt/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells

Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) are observed in 15–20% of breast cancers (HER2+ breast cancers), and anti-HER2 therapies have significantly improved prognosis of patients with HER2+ breast cancer. One resistance mechanism to anti-HER2 therapies is constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway. Combination therapy with small-molecule inhibitors of AKT and HER2 was conducted in HER2+ breast cancer cell lines with or without PIK3CA mutations, which lead to constitutive activation of the PI3K pathway. PIK3CA mutations played important roles in resistance to single-agent anti-HER2 therapy in breast cancer cell lines. Combination therapy of a HER2 inhibitor and an AKT inhibitor, as well as other PI3K pathway inhibitors, could overcome the therapeutic limitations associated with single-agent anti-HER2 treatment in PIK3CA-mutant HER2+ breast cancer cell lines. Furthermore, expression of phosphorylated 4E-binding protein 1 (p4EBP1) following the treatment correlated with the antiproliferative activities of the combination, suggesting that p4EBP1 may have potential as a prognostic and/or efficacy-linking biomarkers for these combination therapies in patients with HER2+ breast cancer. These findings highlight potential clinical strategies using combination therapy to overcome the limitations associated with single-agent anti-HER2 therapies in patients with HER2+ breast cancer.

Abstract P4-10-22: Loss of androgen receptor after neoadjuvant anti-HER2 therapy in patients with locally advanced HER2-positive breast cancer

Abstract Background.Androgen receptor (AR) is widely expressed in different breast cancer subtypes. AR plays an important role in promoting the growth of HER2 + breast cancer through cross-talk with HER2 signaling, including WNT7B upregulation, beta-catenin activation, stimulation of HER3 gene transcription, and promotion of HER2/HER3 heterodimerization. Preclinical data have shown that inhibiting AR with enzalutamide results in decreased HER2 phosphorylation and activation of ERK and AKT, without affecting HER2 and HER3 expression; however, the role that inhibiting HER2 with anti-HER2 therapy plays in AR expression and regulation is still unknown. In this study, we sought to identify the influence of anti-HER2 therapy on AR and estrogen receptor (ER) expression after neoadjuvant treatment in patients with locally advanced HER2+ breast cancer. Methods.We retrospectively collected data from 68 patients with locally advanced HER2+ breast cancer who received neoadjuvant treatment with trastuzumab and chemotherapy. AR and ER levels were determined by immunohistochemistry in available initial biopsy specimens and in surgical specimens of all patients with residual disease after neoadjuvant therapy. AR was assessed by Immunohistochemistry (IHC) staining using AR441 antibody from DAKO. Expression in &amp;gt;10% of cells was considered positive. Pathological complete response (pCR) was defined as ypT0/is, ypN0. ROC curve analysis was performed to identify the correlation between AR score and pCR. Results.Twenty-five patients had pretreatment tissue available. Eighteen (72%) were positive for AR staining and 20 (80%) for ER staining. Of the 25 cases, 10 (40%) achieved a pCR and 15 (60%) did not. The median AR score for those with a pCR was higher, 20 (range 0, 80) vs 10 (range 0, 70). The area under the ROC curve was 0.59 (95% confidence interval 0.35, 0.83); we found no statistically significant relationship between AR score and pCR (p = 0.47). All nine cases positive for AR before neoadjuvant therapy who had residual tissue for staining after therapy had negative AR staining after neoadjuvant anti-HER2 therapy. Of 18 cases positive for ER before neoadjuvant therapy who had residual tissue for staining after therapy, only 6 (33%) had negative ER staining after neoadjuvant anti-HER2 therapy. Further, all patients initially positive for AR and ER remained ER positive but were AR negative after therapy. Conclusions. We found that in 100% of cases AR positivity disappeared after anti-HER2 neoadjuvant therapy in patients with residual disease, whereas ER positivity disappeared in only 33% of cases, suggesting that blocking HER2 may inhibit positive feedback with AR; however, both AR and ER receptors have independent biological interactions with HER2 that need to be explored. We plan to confirm our results with a larger sample size, and we will continue to monitor our patients to determine the influence of AR negativity after neoadjuvant anti-HER2 therapy on disease-free and overall survival. Citation Format: Jose Rodrigo Espinosa Fernandez, Aysegul A. Sahin, Kenneth R. Hess, Raul Gerardo Ramirez Medina, Paula Anel Cabrera Galeana, Alejandro Javier España Ferrufino, Nereida Esparza Arias, Juan Enrique Bargallo Rocha, José Antonio García Gordillo, Gerardo Emmanuel Lopez Muñiz, Naoto T Ueno. Loss of androgen receptor after neoadjuvant anti-HER2 therapy in patients with locally advanced HER2-positive 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 P4-10-22.

The prognostic value of HER2 status and efficacy of anti-HER2 therapy in patients with HR-positive mucinous breast cancer: a nationwide study from the Korean Breast Cancer Society.

The effect of human epidermal growth factor receptor 2 (HER2) status on mucinous carcinoma (MC) of the breast is unknown due to the rarity of HER2-positive cases. We evaluated the prognostic value of HER2 status and the efficacy of anti-HER2 therapy in patients with hormone receptor (HR)-positive MC. From the data of 154,661 patients recorded in the Korean Breast Cancer Registry between January 1990 and August 2016, 3076 (2.0%) were diagnosed with MC. Overall survival (OS) according to HER2 status and anti-HER2 therapy was analyzed using Kaplan-Meier estimates. Multivariate analysis was performed using the Cox proportional hazards model to estimate the adjusted hazards ratio (HR) for clinicopathologic factors. A total of 2716 HR-positive MC patients were enrolled and followed up for a median 100.1months. Of these, 2094 (77.1%) were HER2-negative and 228 (8.4%) were HER2-positive. HR-positive, HER2-positive MC patients had more advanced pathologic tumor stages (T3 or T4) (p = 0.001), more axillary lymph node involvement (p < 0.001), higher nuclear grade (p < 0.001), and more lymphovascular invasion (p = 0.012) than HER2-negative patients. Subgroup analysis of HR-positive, node-positive MC showed that HER2-positive MC was an independent prognostic factor for OS (HR = 2.657; 95% CI, 1.665-4.241; p < 0.001). HR-positive, node-positive, and HER2-negative MC had significantly longer OS than HER2-positive MBC (p = 0.017). The node-positive subgroup that received anti-HER2 therapy had increased OS, although not significantly (p = 0.224). Our nationwide database study revealed that HER2-positive status was associated with worse prognosis in HR-positive and node-positive MC. Anti-HER2 therapy might be beneficial in HR-positive, node-positive, and HER2-positive MC.

An updated evaluation of serum sHER2, CA15.3, and CEA levels as biomarkers for the response of patients with metastatic breast cancer to trastuzumab-based therapies

BackgroundThe transmembrane receptor tyrosine kinase HER2 is overexpressed in approximately 15% of breast tumors and correlates with poor clinical prognosis. Several treatments that target HER2 are approved for treatment of HER2-positive metastatic breast cancer. The serum biomarkers most widely used to monitor anti-HER2 therapies in patients with HER2-positive metastatic breast cancer currently are CA15.3 and CEA. Nevertheless, their clinical utility in patients with breast cancer remains a subject of discussion and controversy; thus, additional markers may prove useful in monitoring the therapeutic responses of these patients. The extracellular domain of HER2 can be shed by proteolytic cleavage into the circulation and this shed form, sHER2, is reported to be augmented during metastasis of HER2-positive breast tumors. Here, we studied the clinical usefulness of sHER2, CA15.3, and CEA for monitoring treatment for breast cancer.MethodsWe measured prospectively pretreatment and post-treatment serum levels (day 1, 30, 60 and 90) of these three biomarkers in 47 HER2-positive, metastatic breast cancer patients treated with trastuzumab in combination with paclitaxel. Evaluation of the disease was performed according to the Response Evaluation Criteria in Solid Tumor (RECIST) at day 90.ResultsPatients with progressive disease at day 90 had smaller relative changes between day 1 and day 30 than those with complete, partial or stable responses at day 90: -9% versus -38% for sHER2 (P = 0.02), +23% versus -17% for CA15.3 (P = 0.005) and +29% versus -26% for CEA (P = 0.02). Patients with progressive disease at day 90 were less likely than the other patients to have a relative decrease of > 20% in their biomarker levels at day 30: 6% vs 33% for sHER2 (P = 0.03), 0% vs 27% for CA15.3 (P = 0.03), 4% vs 29% for CEA (P = 0.04). No patient with progressive disease at day 90 had > 20% reduction of the average combined biomarker levels at day 30 whereas 63% of the other patients had (P = 0.003). Moreover, when we analyzed a > 10% reduction of the average biomarker levels no patient with progressive disease at day 90 had a decrease > 10% at day 30 whereas 78% of other patients had (P<0.001, Se = 100%, Sp = 78%).ConclusionWe show that regular measurement of sHER2, CA15.3, and CEA levels is useful for predicting the therapeutic response and for monitoring HER2-targeted therapy in patients with HER2-positive metastatic breast cancer. The average decrease of the three biomarkers with a threshold of > 10% appears to be the best parameter to distinguish patients who go on to have progressive disease from those who will have a complete, partial or stable response.

Efficacy and safety of trastuzumab emtansine (T-DM1) in the treatment of HER2-positive metastatic breast cancer (MBC): a meta-analysis of randomized controlled trial.

AimsTrastuzumab emtansine (T-DM1), an antibody-drug conjugate against human epidermal growth factor receptor 2 (HER2), has been used in the treatment of patients with HER2-positive metastatic breast cancer (MBC). We conducted a meta-analysis to evaluate the efficacy and toxicity of T-DM1 for the treatment of patients with HER2-positive MBC.Materials and MethodsRandomized controlled trials (RCTs), published in Pubmed, Embase, and Web of Science were systematically reviewed to assess the survival benefits and toxicity profile of HER2-positive patients with MBC who were treated with T-DM1. Outcomes included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and toxicities. Results were expressed as the hazard ratio (HR) with 95% confidence intervals (CIs).ResultsA total of 5 RCTs involving 3,720 patients met the inclusion criteria and were included in this meta-analysis. T-DM1 significantly prolonged PFS (HR = 0.73, 95% CI: 0.61, 0.86; P < 0.05), OS (HR = 0.68, 95% CI: 0.62, 0.74; P < 0.05), but it did not increase ORR (RR = 1.25, 95% CI: 0.94, 1.66; P = 0.148). Subgroup analysis indicated that T-DM1 significantly improved PFS when it was used as first-line (HR = 0.86, 95% CI: 0.74, 1.00; P < 0.05) or non-first-line treatment (HR = 0.65, 95% CI: 0.53, 0.81; P < 0.05). T-DM1 was associated with more frequent adverse events, including fatigue, elevated ALT, elevated AST, and thrombocytopenia, than other anti-HER2 therapies.ConclusionsBased on the current evidence, T-DM1 significantly prolonged PFS and OS with a tolerated toxicity than other anti-HER2 therapies in patients with HER2-positive MBC. These findings confirm the use of T-DM1 for the treatment of patients with HER2-positive MBC. Further well-designed, multi-center RCTs needed to identify these findings.

Anti-HER-2 therapy following severe trastuzumab-induced cardiac toxicity

The human epidermal growth factor receptor 2 (HER2) is overexpressed in 25%–30% of breast cancer patients. Anti-HER2 therapies have changed the aggressive course of HER2+ breast cancer. In spite of the therapeutic benefits, their cardiotoxicities are major concerns, especially when used concurrently with anthracyclines.Here we present an elderly patient with relapsed HER2+ breast cancer. Her presentation for relapsed disease was unusual for the physical finding as well as the history of trastuzumab-induced severe cardiotoxicity while requiring additional anti-HER2 therapy. She received neoadjuvant anti-HER2 treatment for stage III breast caner. Due to severe reduction of cardiac ejection fraction (EF), she only received five doses of adjuvant transtuzumab. Unfortunately her disease relapsed one year later with chest wall lesions and a persistent low EF. We treated the patient with lapatinib combined with capecitabine which resulted rapid resolution of her chest wall lesion. More importantly, the patient had one year of disease control without deterioration in her ejection fraction. We discussed the management of recurrent HER2+ breast cancer with chest wall disease and the choice of anti-HER2 therapy in patients with a history of transtuzumab-induced cardiac dysfunction.

Safety and effectiveness of anti-HER2 therapy in patients with advanced metastatic tissue HER2-negative breast cancer with elevated serum HER2 and/or HER2 overexpressing circulating tumor cells

Safety and effectiveness of anti-HER2 therapy in patients with advanced metastatic tissue HER2-negative breast cancer with elevated serum HER2 and/or HER2 overexpressing circulating tumor cells

Abstract P4-13-11: Everolimus, letrozole and trastuzumab in estrogen receptor and HER2-positive patients with metastatic breast cancer and other solid tumors: Evaluating synergy and overcoming resistance

Abstract Background Combining anti-estrogen therapy with HER2 and mTOR inhibitors may be synergistic and overcome resistance to hormonal and anti-HER2 therapies in patients with estrogen receptor (ER)-positive and HER2 receptor amplified and/or mutant advanced cancers. Patients and Methods We evaluated the mTOR inhibitor everolimus, aromatase inhibitor letrozole and anti-HER2 antibody trastuzumab in patients with ER-positive, HER2-positive and/or mutant, solid tumors (confirmed by IHC, FISH, and/or HER2 sequencing). The primary objectives were to determine maximum tolerated dose (MTD) and toxicity and to evaluate response. Secondary objectives were to correlate activity with genomic and proteomic signatures. Next-generation sequencing (NGS) was performed either using a 50-gene panel or externally by Foundation Medicine (Cambridge, MA, USA). Results Nine of 10 patients enrolled are currently evaluable for toxicity and response including 7 patients with breast cancer, one patient with ovarian cancer, and one patient with cervical cancer. The median age was 57 years (range, 33-66 years) and the median number of prior therapies in the metastatic setting was 5 (range, 2-7). Of these nine patients, six were HER2+ (by IHC and/or FISH) and three had HER2 mutations (in the absence of HER2 overexpression or amplification). Dose Level (DL) 1 consisted of trastuzumab loading dose of 4mg/kg IV and maintenance dose of 2 mg/kg IV every 21 days, everolimus 5 mg PO daily and letrozole 2.5 mg PO daily. DL2 consisted of trastuzumab loading dose of 6mg/kg IV and maintenance dose of 4 mg/kg IV every 21 days, everolimus 5 mg PO daily and letrozole 2.5 mg PO daily. DL3 consists of trastuzumab loading dose of 6 mg/kg IV and maintenance dose of 4 mg/kg IV every 21 days, everolimus 7.5 mg PO daily and letrozole 2.5 mg PO daily. Currently patients are being enrolled in DL3 and no DLTs have been observed. Additional dose levels are planned with increased trastuzumab and everolimus to the FDA approved doses or until MTD is reached. The most common grade 1 and 2 treatment-related toxicities were fatigue (6 patients), anemia and constipation (2 patients each). No grade 3 or 4 toxicities have been reported. Median time to treatment failure (TTF) was 7.4 months (95% CI 5.2-9.6). One patient with breast cancer and a HER2 mutation experienced a partial response (PR) with a 32% decrease in measurable disease. This patient had no prior HER2-targeted therapy and previously progressed while on letrozole and while on exemestane and everolimus. Six additional patients experienced stable disease (SD) ≥ 6 months, 5 with breast cancer and 1 with cervical cancer. Of these 6 patients, 1 had a HER2 mutation and another had a PIK3CA mutation. Conclusions Combination treatment with everolimus, letrozole and trastuzumab is well tolerated and active in ER+, HER2+ and/or mutant solid tumors, including breast and cervical cancer. Clinical benefit (PR/SD≥6 months) was seen in 7 of 9 patients (78%), including patients with HER2 mutations in the absence of overexpression and/or amplification and patients with no genomic alterations in the PI3K/AKT/mTOR pathway. Enrollment is ongoing. Citation Format: Janku F, Hong DS, Atkins JT, Karp DD, Tsimberidou AM, Piha-Paul SA, Subbiah V, Naing A, Fu S, Moulder SL, Tripathy D, Meric-Bernstam F, Wheler JJ. Everolimus, letrozole and trastuzumab in estrogen receptor and HER2-positive patients with metastatic breast cancer and other solid tumors: Evaluating synergy and overcoming resistance. [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 P4-13-11.

Abstract P3-06-32: Genetic heterogeneity for Her2 accounts for a significant percentage of breast cancers changing Her2 status following implementation of the 2013 CAP/ASCO HER2 reporting guidelines

Abstract Background: Current evidence indicates that patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive Breast Cancer (BC) benefit from HER2-targeted therapies. Accurate determination of HER2 status is critical to ensure that the correct patients are offered targeted treatment while patients with HER2-negative tumors–who are unlikely to benefit from anti-HER2 therapy– are spared from the adverse effects of these costly drugs. Guidelines for performance and reporting of HER2 testing, first published in 2007 by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP), were updated in October 2013. The new reporting criteria are based on a combination of HER2:CEP17 ratio and average HER2 copy number. Methods: We retrospectively reviewed HER2 dual probe FISH test results sequentially performed by the Cytogenetics Laboratory at Vanderbilt University from January to May 2014 since implementation of the updated guidelines. The cases were then rescored using the 2007 guidelines. The clinicopathologic features of cases with a change in Her2 status after scoring with the 2013 guidelines were examined for statistical significance. Results: If the 266 performed HER2 FISH tests had been scored using the 2007 guidelines the results would have been the following: amplified (n = 44, 16%), equivocal (n = 28, 10%) and not amplified (n = 194, 70%). However, using the 2013 guidelines the cases were actually reported as follows: amplified (n=57, 21%), equivocal (n=22, 8.3%) and not amplified (n=187, 68%). Additionally, 18 cases demonstrated genetic heterogeneity in &amp;gt;25% of cells. The updated guidelines resulted in a change in Her2 status in 12% of tests (32/266; p less than 0.0001); 13 changed from equivocal to amplified, 13 cases changed from not amplified to equivocal and 6 cases changed from equivocal to not amplified. Cases with a change in Her2 status following implementation of the new guidelines were more likely to demonstrate genetic heterogeneity (28% [9/32] vs. 4% [9/234]; p less than 0.0001). Furthermore, hormone receptor (HR)-negative tumors scored as not amplified by the 2007 guidelines were more likely to undergo an upgrade in HER2 status under the 2013 guidelines than HR-positive tumors (26% [11/41] vs. 7% [11/153], p less than 0.0001). Conclusions: The 2013 reporting criteria, based on a combination of HER2:CEP17 ratio and average HER2 copy number, increase the number of patients eligible for HER2-targeted therapies while decreasing equivocal results. Tumors that demonstrate genetic heterogeneity for Her2 or are HR-negative account for a significant percentage of these newly eligible cases. Correlation with clinical response is required to confirm the proposed improved analytical validity of the updated guidelines. Clinical trials to evaluate the benefit of anti-Her2 therapy in patients with genetic heterogeneity are in the planning phase. Citation Format: Monica V Estrada, Jena M Giltnane, Ferrin C Wheeler, Ashwini Yenamandra, Vandana Abramson, Ingrid A Mayer, Julie Means, Brent Rexer, Ingrid M Meszoely, Melinda E Sanders. Genetic heterogeneity for Her2 accounts for a significant percentage of breast cancers changing Her2 status following implementation of the 2013 CAP/ASCO HER2 reporting guidelines [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-32.

High HER2 expression correlates with response to the combination of lapatinib and trastuzumab.

Expression of p95HER2 has been associated with resistance to trastuzumab-based therapy in patients with metastatic breast cancer. Conversely, high levels of HER2 have been linked with increased clinical benefit from anti-HER2 therapy. In this work, we aimed to investigate whether the levels of p95HER2 and HER2 can predict response to anti-HER2 therapy in patients with breast cancer. We measured p95HER2 and HER2 by VeraTag and HERmark, respectively, in primary tumors of patients enrolled in the neoadjuvant phase III study NeoALTTO and correlated these variables with pathologic complete response (pCR) and progression-free survival (PFS) following lapatinib (L), trastuzumab (T), or the combination of both agents (L+T). A positive correlation between p95HER2 and HER2 levels was found in the 274 cases (60%) in which quantification of both markers was possible. High levels of these markers were predictive for pCR, especially in the hormone receptor (HR)-positive subset of patients. High HER2 expression was associated with increased pCR rate upon L+T irrespective of the HR status. To examine whether the levels of either p95HER2 or HER2 could predict for PFS in patients treated with lapatinib, trastuzumab or L+T, we fit to the PFS data in Cox models containing log2(p95HER2) or log2(HER2). Both variables correlated with longer PFS. Increasing HER2 protein expression correlated with increased benefit of adding lapatinib to trastuzumab. HER2 expression is a stronger predictor of pCR and PFS than p95HER2 for response to lapatinib, trastuzumab and, more significantly, L+T.