Current Landscape of Anti-HER2 Targeted Therapy in Breast Cancer: Challenges and Future Perspectives

Tucatinib approval by EMA expands options for HER2-positive locally advanced or metastatic breast cancer

Background: Amphiregulin is a ligand for the epidermal growth factor receptor (EGFR). Human epidermal growth factor receptor 2 (HER2) shares common signal pathways and forms a heterodimer with EGFR. In this study, we investigated the effect of amphiregulin on trastuzumab therapy in HER2-positive breast cancer. Methods: We analyzed serum amphiregulin levels by enzyme-linked immunosorbent assay (ELISA) from baseline serum samples obtained from HER2-positive metastatic breast cancer patients who received first-line trastuzumab plus taxane chemotherapy. In addition, in vitro experiments were performed to elucidate the biologic mechanism of clinical findings related to amphiregulin using SK-BR-3 and BT-474 cell lines. Results: Between October 2004 and July 2009, a total of 50 women with HER2-positive metastatic breast cancer were consecutively enrolled. The median age was 47 years (range, 27-72 years). Eighteen patients (36.0%) received weekly paclitaxel plus trastuzumab, 24 patients (48.0%) tri-weekly paclitaxel plus trastuzumab, and 8 patients (16.0%) tri-weekly docetaxel plus trastuzumab. Among 43 patients with measurable lesions, the response rate (RR) was 76.7%. The median follow-up duration was 29.2 months (range, 0.7-63.3 months). The median progression-free survival (PFS) was 17.6 months (95% confidence interval (CI), 13.4-21.9 months). The median overall survival (OS) was 47.0 months (95% CI, 35.3-58.6 months). The median serum amphiregulin level was 1.0 ng/mL with a maximum level of 4.4 ng/mL. Patients with high serum amphiregulin levels (≥0.5 ng/mL) had significantly shorter PFS (p=0.018) along with a tendency toward lower RR (p=0.237) and shorter OS (p=0.529) than the others. The in vitro colony forming assay demonstrated that the addition of amphiregulin resulted in increased proliferation of both SK-BR-3 and BT-474 cells. In addition, the anti-proliferative effect of trastuzumab was decreased in the presence of amphiregulin in both SK-BR-3 and BT-474 cells. The Western blot analysis showed that amphiregulin increased the phosphorylation of Akt and its downstream molecules in both SK-BR-3 and BT-474 cells. In addition, in the presence of amphiregulin, sustained phosphorylation of Akt and its downstream molecules was observed after trastuzumab treatment in both SK-BR-3 and BT-474 cells. Conclusions: High serum amphiregulin levels (≥0.5 ng/mL) predicted disease progression after first-line trastuzumab plus taxane chemotherapy in patients with HER2-positive metastatic breast cancer. Amphiregulin promoted the proliferation of HER2-positive breast cancer cells in vitro and induced trastuzumab resistance by activating PI3K/Akt pathway. Our results suggest that the measurement of serum amphiregulin levels by ELISA may provide additional information for the clinical outcome of trastuzumab-based chemotherapy in patients with HER2-positive breast cancer. Citation Format: Ji-Won Kim, Young Seok Joung, Ahrum Min, Hyun-Jin Nam, Jee Hyun Kim, Seock-Ah Im, Kyung-Hun Lee, Jin-Soo Kim, Tae-Yong Kim, Sae-Won Han, Yoon Kyung Jeon, Do-Youn Oh, Tae-You Kim, In Ae Park. Amphiregulin confers trastuzumab resistance by activating PI3K/Akt pathway in HER2-positive breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2386. doi:10.1158/1538-7445.AM2013-2386

Trastuzumab Beyond Progression in Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: UK Practice now and in the Future

Brain metastases from HER2-positive breast cancer

HER2-positive breast cancer

HER2 is overexpressed in approximately 20-25% of breast cancers and defines an aggressive sub-type of the disease. Fortunately for patients with HER2 positive breast cancer, the prognosis has improved in the last 10 years due to the development of HER2 targeted therapies, in particular trastuzumab, the HER2-directed monoclonal antibody. Recent data show that approximately 9.5% of patients with HER2 positive metastatic breast cancer achieve a durable complete response (> 5 years) following trastuzumab-based therapy. However, 90% of these patients still continue to develop progressive disease. These data highlight the need to develop novel therapeutic strategies to overcome both innate and acquired resistance to HER2 directed therapeutics. Lapatinib, a small molecule tyrosine kinase inhibitor of HER2 and EGFR, has efficacy in trastuzumab resistant breast cancer and is approved for the treatment of patients with trastuzumab-refractory HER2 positive metastatic breast cancer. However, in metastatic disease, therapeutic action is often short-lived with most patients developing progressive disease. Thus, HER2 positive tumors can be innately resistant, or acquire resistance, to both trastuzumab and lapatinib. Over the past 2 years, two new HER2 targeted therapies, pertuzumab and T-DM1 have received approval for the treatment of HER2 positive metastatic breast cancer. The pertuzumab monoclonal antibody blocks dimerization of HER2 with other members of the HER family and clinically has been shown to improve overall survival when used in combination with trastuzumab and docetaxel. The novel antibody drug conjugate, T-DM1, which links trastuzumab to the cytotoxic agent emtansine, improves the response of patients with trastuzumab-refractory metastatic breast cancer, compared to the standard of care lapatinib plus capecitabine regimen. A number of second generation irreversible pan-HER tyrosine kinase inhibitors are currently in clinical development, including neratinib, afatinib and dacomitinib. More recently, the utility of HER2-directly therapeutics has been expanded into nonbreast tumors such as gastric cancers that carry the HER2-alteration. Data from ongoing clinical trials will determine if targeting HER2 can also improve the prognosis of these cancer patients.

The use of trastuzumab-based chemotherapy has dramatically improved outcome for patients with early stage HER2-positive breast cancer. Given the excellent outcomes seen to date and the toxicities associated with therapy, it is critical to establish whether additional therapies can further improve outcome, and conversely if there are patients who would have a favorable outcome with less therapy. The addition of pertuzumab to trastuzumab-based chemotherapy results in improved survival for patients with metastatic HER2-positive breast cancer and higher response rates in the pre-operative setting. Although results of the AFFINITY trial demonstrated improved outcome for adding pertuzumab to trastuzumab-based chemotherapy, the benefit was largely restricted to patients with node-positive breast cancer. Additionally, it is unclear if patients treated pre-operatively require the continued addition of pertuzumab to trastuzumab. Neratinib, a pan-HER tyrosine kinase inhibitor, reduces recurrence rate when used following adjuvant trastuzumab, but the benefit appears restricted to hormone receptor-positive breast cancers and diarrhea is a significant issue with this agent. In contrast, de-escalating treatment for patients with stage 1 HER2-positive breast cancer with the use of paclitaxel and trastuzumab is associated with extremely favorable outcomes. To date, the treatment of HER2-positive early stage breast cancer has not taken hormone receptor status into account when selecting HER2-directed therapies. Breast cancers that express both hormone receptors and HER2 are heterogeneous and a significant proportion have a luminal A phenotype, suggesting the possibility that combined estrogen receptor and HER2 inhibition may be especially important, given the crosstalk between these pathways. Further evaluation of non-chemotherapeutic approaches in triple positive breast cancers is justified. Citation Format: O'Regan RM. Adjuvant therapy for HER2-positive breast cancers: is less more? [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES4-2.

Breast cancer targeted therapy: successes and challenges

Prognosis of Her2-positive breast cancer has changed since the introduction of trastuzumab for treatment in metastatic and early breast cancer. It was described to be even better compared to prognosis of Her2-negative metastatic breast cancer. The purpose of this study was to evaluate the effect of trastuzumab in our cohort. Besides the effect of adjuvant pretreatment with trastuzumab on survival of patients with metastatic Her2-positive breast cancer was analyzed. All patients with primary breast cancer of the Regional Breast Cancer Center Dresden diagnosed during the years 2001-2013 were analyzed for treatment with or without trastuzumab in the adjuvant and in the metastatic treatment setting using Kaplan-Meier survival estimation and Cox regression. Age and tumor stage at time of first diagnosis of breast cancer as well as hormone receptor status, grading, time, and site of metastasis at first diagnosis of distant metastatic disease were analyzed. Of 4.481 female patients with primary breast cancer, 643 presented with metastatic disease. Her2-positive status was documented in 465 patients, including 116 patients with primary or secondary metastases. Median survival of patients with Her2-positive primary metastatic disease was 3.0years (95% CI 2.3-4.0). After adjustment for other factors, survival was better in patients with Her2-positive breast cancer with trastuzumab therapy compared to Her2-negative metastatic disease (HR 2.10; 95% CI 1.58-2.79). Analysis of influence of adjuvant therapy with and without trastuzumab by Kaplan-Meier showed a trend for better survival in not pretreated patients. Median survival was highest in hormone receptor-positive Her2-positive (triple-positive) primary metastatic breast cancer patients with 3.3years (95% CI 2.3-4.6). Prognosis of patients with Her2-positive metastatic breast cancer after trastuzumab treatment is more favorable than for Her2-negative breast cancer. The role of adjuvant chemotherapy with or without trastuzumab warrants further research. Survival is best in triple-positive metastatic breast cancer. This will effect counseling at the time of first diagnosis of metastatic breast cancer.

HER2 is a member of the epidermal growth factor receptor (EGFR) family of tyrosine kinases and is involved in the growth, invasion, metastasis, and prognosis of breast cancer. The rationale for prospective trials evaluating the role of anti-HER2 monoclonal antibody therapy for patients with high-risk HER2-positive resected breast cancer is based on several factors. These include 1) the relative and absolute poor prognosis of patients with node-positive, HER2-positive breast cancer; 2) the emerging data of potential importance concerning anthracyclines as a component of adjuvant therapy for patients with HER2-positive breast cancer; 3) the role of taxanes in the management of patients with HER2-positive metastatic breast cancer; and 4) the feasibility and efficacy of molecularly targeted anti-HER2 monoclonal antibody treatment alone or in combination with chemotherapy for patients with advanced breast cancer.

Pertuzumab: New therapy for late-stage breast cancer

Since the introduction of trastuzumab in the late 1990s, the treatment landscape for patients with metastatic human epidermal growth factor receptor 2 (HER2) –positive breast cancer has changed dramatically. In addition to trastuzumab, a series of novel HER2directed therapies has gained regulatory approval, including lapatinib, pertuzumab, and ado-trastuzumab-emtansine (T-DM1). The result is that for many patients, the disease has been transformed from a rapidly lethal illness to one in which episodes of disease progression are punctuated by long periods of tumor control. Despite these advances, HER2-positive metastatic breast cancer is still not generally curable, and the vast majority of patients will eventually succumb to their disease. Furthermore, over time, up to half of patients will develop CNS metastases, and these can be a source of both substantial morbidity and mortality. The two articles that accompany this editorial directly address several related questions. First, is there a preferred anti-HER2 therapy for use in the first-line setting? Second, does the choice of anti-HER2 therapy affect the incidence of brain metastases? In addition, these studies raise important considerations regarding trial design moving forward. In the NCIC Clinical Trials Group MA.31 trial, Gelmon et al directly compared first-line trastuzumab versus lapatinib, each paired with a taxane, in patients with HER2-positive metastatic breast cancer. Among the 652 patients in the intent-to-treat population, although the objective response rates were similar, progression-free survival (PFS) was inferior in the lapatinib arm (median, 9.0 v 11.3 months; hazard ratio [HR], 1.37; P .001), and there was a trend for overall survival (OS) in favor of trastuzumab, which reached significance in the centrally confirmed HER2-positive subset (n 537; HR, 1.47; P .03). Patient-reported global quality of life, as assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (QLQ-C30), was similar between arms, although expected differences were seen that favored trastuzumab for outcomes such as diarrhea and rash. Rates of therapy discontinuation for reasons other than progression or death were similar between arms. The CEREBEL trial, as reported by Pivot et al, also compared trastuzumab versus lapatinib, this time with a capecitabine backbone. In contrast with MA.31, patients could be enrolled either in the firstline setting or in a subsequent line of therapy. Just under half of patients who were included in CEREBEL had not received any previous therapy for metastatic breast cancer. As with MA.31, although objective response rates were similar between arms, patients who were randomly assigned to the trastuzumab-containing arm experienced longer PFS and OS compared with patients who were randomly assigned to the lapatinib-containing arm (median PFS, 6.6 v 8.1 months; HR, 1.30; 95% CI, 1.04 to 1.64; median OS, 22.7 v 27.3 months; HR, 1.34, 95% CI, 0.95 to 1.90). In placing these data into context, at least two issues come to mind: the patient populations enrolled, and data regarding other anti-HER2 agents that have been developed since these trials were initiated. The patient populations in both studies were notable: in MA.31, less than 20% of patients had received previous adjuvant or neoadjuvant trastuzumab, and 43% of patients presented with de novo metastatic disease. In CEREBEL, the patient population included 18% with de novo disease; only 28% of patients had received adjuvant trastuzumab, and only 35% had previously received trastuzumab for metastatic disease. Results of the studies are generally consistent with preoperative data from several studies, including CALGB (Cancer and Leukemia Group B) study 40601, in which lapatinibtaxane was inferior to trastuzumab-taxane with respect to the primary end point of pathologic complete response in newly diagnosed, trastuzumab-naive patients with clinical stage II to III, HER2positive breast cancer. To what extent MA.31 and CEREBEL can be generalized to a population of first-line patients with metastatic disease who have relapsed despite adjuvant trastuzumab is somewhat unclear. Indeed, in a hypothesis-generating subset analysis of CEREBEL, the benefit of trastuzumab-capecitabine compared with lapatinib-capecitabine was restricted to patients without previous exposure to trastuzumab or chemotherapy. PFS did not differ by arm among patients with previous trastuzumab exposure or those treated in the second-line setting or beyond. Since these trials were initiated, two new agents have gained regulatory approval for HER2-positive metastatic breast cancer: pertuzumab and T-DM1. Given the superiority of trastuzumab-taxane compared with lapatinib-taxane in MA.31, and the superiority of pertuzumab-trastuzumab-taxane compared with trastuzumab-taxane in CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 14 MAY 1

Introduction: Metastatic HER2-positive breast cancer is treated with regimens such as taxane with trastuzumab and pertuzumab followed by trastuzumab deruxtecan (T-DXd). The third line options are ado-trastuzumab emtansine (T-DM1), tucatinib with capecitabine, and trastuzumab. Mutations in the PIK3CA gene encoding PI3Kα have been reported in 12%-39% of HER2-positive breast cancers and are associated with worse prognosis. Alpelisib is an oral, α-specific PI3K inhibitor that is approved in combination with fulvestrant in hormone receptor positive, HER2-negative, PIK3CA-mutated advanced breast cancer following progression on or after endocrine therapy. Activating mutations in the PIK3CA gene are associated with resistance to anti-HER2 therapies. Combined inhibition of HER2 and PI3K overcomes this mechanism preclinically. We present a patient with estrogen and progesterone receptor (ER/PR) negative, HER2-positive, PIK3CA-mutated multidrug resistant refractory breast cancer who had a complete response to alpelisib and trastuzumab. Case Presentation: A 63-year-old female patient underwent left mastectomy for a stage I (T1aN0M0) ER/PR-negative, HER2-positive breast cancer in 2014. Four years later, she developed a HER2-positive right axillary breast cancer which was treated with neoadjuvant chemotherapy followed by axillary nodal dissection and regional radiation therapy. Since 2018, right axillary nodal and chest wall metastases progressed on several lines of systemic therapy including lapatinib and capecitabine, trastuzumab and paclitaxel, trastuzumab and vinorelbine, fam-trastuzumab-deruxtecan-nhki (Enhertu), T-DM1, margetuximab with eribulin, and finally trastuzumab with capecitabine. A right chest wall biopsy demonstrated a high grade invasive ductal carcinoma that was ER/PR-negative and HER2-positive. Next generation sequencing revealed a PIK3CA mutation (p.H1047R). Treatment was changed to alpelisib and trastuzumab. After four months of treatment, she developed a complete response of cutaneous metastases with adverse effect of grade 2 mucositis. She continues to be under treatment and is doing well. Conclusions: Alpelisib and trastuzumab can be a viable treatment option for patients with HER2-positive and PIK3CA-mutated metastatic breast cancer. Our case demonstrates the importance of obtaining next generation sequencing in patients with refractory breast cancer. Integrating precision medicine can elucidate mechanisms of resistance and allow treatment with combination and targeted therapies that can improve patient outcomes, similar to our patient presented in this vignette. Citation Format: Farah Shah, Nejina Rijal, Erin H. Lin, Sayeh M. Lavasani, Rita S. Mehta, Ritesh Parajuli. Complete response with Alpelisib and Trastuzumab in a patient with ER/PR-negative, HER2-positive refractory metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-05-19.

Purpose: This analysis describes comprehensive real-world data concerning the use of anti-HER2 therapies in HER2 positive metastatic breast cancer (MBC). Specifically, it describes the therapy patterns of treatments with trastuzumab (TZM), pertuzumab+trastuzumab (PTZ/TZM), lapatinib (LAP) and trastuzumab emtansine (T-DM1). Methods: The PRAEGNANT study is a real-time, real-world registry for patients with MBC. Patients can be registered for PRAEGNANT at any time during the course of their metastatic disease and are followed up until death. All therapy lines are documented. This analysis presents the utilization of anti-HER2 therapies as well as therapy sequences. Results: Of 1936 patients within PRAEGNANT at the time of database closure 451 were HER2 positive (23.3%). Within the analysis set (417 patients after an unilateral breast cancer diagnosis), of which 53% were included in PRAEGNANT in the 1stline setting, 241 were treated with TZM (58%), 237 with PTZ (57%), 85 with LAP (20%) and 125 with T-DM1 (30%) during the course of their therapies. The sequence PTZ/TZMàT-DM1 was given to 51 patients (12%). Worse ECOG, negative hormone receptor status, and visceral or brain metastases were associated with a more frequent use of this therapy sequence. Most patients received T-DM1 after a therapy with pertuzumab. Conclusions: Both novel therapies (PTZ/TZM and T-DM1) are utilized in a high proportion of HER2 positive breast cancer patients. As most patients receive T-DM1 after pertuzumab real world data might help to understand whether this sequence has similar efficacy like in the approval study. Citation Format: Lux MP, Hartkopf AD, Huober J, Volz B, Taran F-A, Overkamp F, Hadji P, Tesch H, Haeberle L, Ettl J, Lueftner DI, Wallwiener M, Müller V, Beckmann MW, Belleville E, Wimberger P, Hielscher C, Geberth M, Lermann J, Abenhardt W, Kurbacher C, Wuerstlein R, Thomssen C, Untch M, Fasching PA, Janni W, Fehm TN, Wallwiener D, Brucker SY, Schneeweiss A, Kolberg H-C. Therapy landscape of patients with metastatic, HER2 positive breast cancer - Data from the real world breast cancer registry PRAEGNANT (NCT02338167) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-37.

Background: SYD985 is a HER2-targeting antibody-drug conjugate (ADC) based on trastuzumab and a cleavable linker-duocarmycin (vc-seco-DUBA) payload. Following proteolytic cleavage the synthetic duocarmycin prodrug is activated, binds to the minor groove of DNA, and subsequently causes irreversible DNA-alkylation. SYD985 has demonstrated unprecedented anti-tumor activity in preclinical breast cancer models with high (HER2 3+) or moderate/low expression of HER2 (HER2 2+ and HER2 1+). Clinical data of patients with HER2-positive and HER2-negative breast cancer treated with SYD985 in an ongoing first-in-human phase I trial (NCT02277717) in patients with locally advanced or metastatic solid tumors are presented. Trial design: Main inclusion criteria are ECOG performance status 0-1, left ventricular ejection fraction ≥ 55%, and adequate organ function. Patients are treated with SYD985 every three weeks until tumor progression or unacceptable toxicity. Thirty nine patients, including 26 breast cancer patients, were enrolled in the dose-escalation part and treated with doses varying from 0.3 mg/kg to 2.4 mg/kg SYD985. Patients enrolling in the first expanded cohort will be treated with 1.2 mg/kg SYD985. In this cohort a total of 48 patients with HER2-positive breast cancer (IHC 3+ or ISH positive) will be enrolled from May 2016 onwards. HER2 status was determined locally in the dose-escalation part but will be done centrally in the expanded cohort part of the trial. Tumor evaluation (RECIST 1.1) is performed every 6 weeks. Results: Enrolled breast cancer patients were heavily pretreated with a median of 7 systemic therapies. All patients with HER2-positive breast cancer were previously treated with trastuzumab and ado-trastuzumab emtansine (T-DM1). As of 16 May 2016, tumor evaluation data were available for 19 of the 26 enrolled breast cancer patients. In total, 8 partial responses were observed of which 6 were confirmed by a second CT-scan. The number of cycles administered ranged from 1 to 11. Ten of the 26 patients are still on treatment. Best overall response HER2 statusN EvaluablePRSDPDORR All dosesORR Doses ≥1.2 mg/kgHER2-positive (all T-DM1 pretreated)1458136%42%HER2-negative (IHC 1+/2+ and ISH neg)531160%75%Overall1989242%50% One dose-limiting toxicity occurred at 2.4 mg/kg SYD985, i.e. pneumonitis (grade 5). Overall, SYD985 is well tolerated up to doses of 1.8 mg/kg every 3 weeks. The most frequently reported drug-related AEs were conjunctivitis, stomatitis, fatigue, and decreased appetite. The majority of drug-related AEs were of mild or moderate intensity. Conclusion: SYD985 shows promising efficacy in both HER2-positive and HER2-negative metastatic breast cancer patients with an acceptable safety profile. SYD985 may offer a new targeted treatment option for patients who have become refractory to the available HER2-targeting therapies, and potentially for breast cancer patients who are not indicated for HER2-targeting therapies. Updated data, including additional results of up to 48 HER2-positive breast cancer patients, will be presented during the meeting. Citation Format: Aftimos PG, van Herpen CM, Mommers EC, Koper NP, Goedings P, Oesterholt M, Awada A, Desar IM, Lim J, Dean E, Rolfo C, Macpherson I, Banerji U. SYD985, a novel anti-HER2 ADC, shows promising activity in patients with HER2-positive and HER2-negative metastatic 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 P6-12-02.