Recurrent HER2-positive Breast Cancer Research Articles

Cost of illness of HER2-positive and metastatic and recurrent HER2-positive breast cancer – a Danish register-based study from 2005 to 2016

BackgroundInformation and knowledge about cost of illness and labour productivity in patients with HER2-positive early-stage and metastatic breast cancer treated with trastuzumab is limited. The aim of this study was to estimate the direct and indirect costs associated with treatment of HER2-positive breast cancer among patients with early-stage and metastatic breast cancer, treated with trastuzumab, in a 10-year period after diagnosis.Materials and methodsThis study included all Danish HER2-positive breast cancer patients (≥ 18 years) treated with trastuzumab between 2005 and 2016 identified in The Danish Patient Register and the Danish Cancer Register. Furthermore, we identified patients experiencing metastatic or recurrent breast cancer. For the study populations, we estimated total direct costs and indirect costs for one year prior to the breast cancer diagnosis and up to 10 years after diagnosis compared with a group of matched controls free of breast cancer. In addition to The Danish Patient Register and Cancer Register, we applied patient level data from The Civil Registration System, The National Pathology Register, National Health Service Register for Primary Care, Register of Medicinal Product Statistics, Register of Municipal Services, The DREAM database, and Population’s Education Register.ResultsWe identified 4,153 HER2-positive breast cancer patients, whereof 27% were identified with metastatic or recurrent breast cancer. During the follow-up period of 10 years, we estimated excess direct costs of EUR 115,000 among the total study population compared to controls; EUR 211,000 among patients with metastases or recurrence; and EUR 89,000 among patients without metastases or recurrence. Direct costs were found to be highest in the first year after diagnosis and also peaked in the year after recurrence. Labour productivity was significantly lower among patients with recurrence 10 years after breast cancer diagnosis compared with controls.ConclusionsIn this study, we estimated the direct and indirect cost associated with HER2-positive breast cancer. The costs were significantly higher during the 10 years after diagnosis compared to the control group, specifically among patients experiencing metastases or recurrence of breast cancer.

Abstract PS10-51: TAA013 a trastuzumab antibody drug conjugate phase I dose escalation study in recurrent her2 positive breast cancer

Abstract Background: A phase 1 dose escalation study of TAA013, an antibody drug conjugate linking trastuzumab to a cytotoxic small molecule, DM1, through an SMCC linker, in previously treated recurrent Her2 positive breast cancer patients. Material and Methods: This phase I study follows the traditional 3+3 design, dosing started at 0.6mg/kg, followed by 1.2, 2.4, 3.6, 4.8mg/kg, one intravenous infusion was given every 3 weeks, the initial infusion had to be over 90 minutes, infusion times were later shortened if treatment was well tolerated. The subsequent recommended dose would be expanded to include at least 10 patients. Patients were observed for dose-limiting toxicity (DLT) during a 21-day DLT observation period. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Maximum-tolerated dose (MTD) was defined as the highest dose level that resulted in a DLT in no more than 1 of 6 patients. Study endpoints included safety and tolerability, pharmacokinetic and immunogenicity parameter evaluation, with preliminary evaluation of efficacy. Results: The study enrolled 22 female patients with histologically confirmed Her-2 positive metastatic breast cancer, median age of 50yrs (25-67), median time from initial diagnosis to TAA013 dosing was 39 months (5-99), median prior treatment regimen was 4 (2-10), all had received trastuzumab for a mean of 8.2 months (2-10), alone or in combination with chemotherapy, other prior Her2 targeting drugs given included pertuzumab (2), lapatinib (7), and pyrotinib (8). All patients received at least 2 (median of 6 infusions, range of 1-15) infusions, except for the last 4.8mg/kg patient, but all patients passed the dose limiting toxicity (DLT) observation period of 21 days. There were no dose limiting toxicities, no serious adverse events, nor that resulting in mortality, the maximum tolerated dose was not reached. The most common treatment emergent adverse events (TEAE) included 9 (40.9%) grade 1-2 infusion reactions associated with fever(5) and/or chills(1), the reaction often abated in subsequent cycles. There were no grade 4 TEAE, but there were 3 grade 3 thrombocytopenia, one grade 3 neutropenia, and one grade 3 hyperbilirubinemia which all recovered for the patients to continue treatment, there was also one grade 3 dermatitis in a patient with a history of chronic dermatitis. Antibody drug antibodies were not detected emanating from the TAA013 therapy. Pharmacokinetic studies included evaluation of TAA013, trastuzumab and DM1. Preliminary efficacy evaluation in the 2.4-4.8mg/kg dosing group of heavily pretreated patients resulted in 2 partial responses, including patients who had previously received pyrotinib therapy. Conclusion: TAA013 is a Her2 targeting antibody drug conjugate that is safe and tolerable, with efficacy demonstrated in heavily pretreated Her2 positive breast cancer patients. Keywords: breast cancer, antibody drug conjugates, TAA013. Citation Format: J M Liu, Y M Yin, Hao Wu, W Li, X Huang, XX Li. TAA013 a trastuzumab antibody drug conjugate phase I dose escalation study in recurrent her2 positive breast cancer [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 PS10-51.

The efficacy and safety of pertuzumab plus trastuzumab and docetaxel as a first-line therapy in Japanese patients with inoperable or recurrent HER2-positive breast cancer: the COMACHI study

PurposeIn the CLEOPATRA study of patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer, the Japanese patient subgroup did not demonstrate the improved progression-free survival (PFS) of pertuzumab plus trastuzumab and docetaxel vs. placebo that was seen in the overall population. Therefore, COMACHI was conducted to confirm the efficacy and safety of this treatment regimen in this patient subgroup.MethodsThis was a phase IV study of pertuzumab plus trastuzumab and docetaxel in Japanese patients with histologically/cytologically confirmed inoperable or recurrent HER2-positive breast cancer. All patients received pertuzumab, trastuzumab, and docetaxel intravenously every 3 weeks until disease progression/unacceptable toxicity. The primary endpoint was investigator-assessed PFS. Secondary endpoints were overall survival (OS), investigator-assessed objective response rate, and duration of response (DoR). Safety was also assessed.ResultsAt final analysis, median investigator-assessed PFS was 22.8 months (95% CI 16.9–37.5). From first dose, OS rate at 1 year was 97.7%; and at 2 and 3 years were 88.5% and 79.1%, respectively. Of the 118 patients with measurable disease at baseline, response rate was 83.9% (95% CI 77.3–90.5) and median investigator-assessed DoR was 26.3 months (95% CI 17.1–not evaluable). Treatment was well tolerated, with no new safety signals detected.ConclusionsOur results suggest similar efficacy and safety for pertuzumab plus trastuzumab and docetaxel in Japanese patients compared with the overall population of CLEOPATRA, providing further support for this combination therapy as standard of care for Japanese patients with inoperable or recurrent HER2-positive breast cancer.

Resumption of Trastuzumab in Patients With Disease Recurrence After (Neo-) Adjuvant Anti-HER2-therapy in Patients With HER2-positive Breast Cancer.

HER2-positive breast cancers eventually relapse in about one third of patients. Is anti-HER2-directed therapy with Herceptin® (trastuzumab) effective in re-treatment? Between 2008 and 2018, 216 patients with recurrent HER2-positive breast cancer (BC) were re-treated with Herceptin (HER) during first-line therapy. This study assessed the effectiveness and tolerability of re-treatment with HER. After approval from Ethical committee, the NIS was conducted according to German Drug Act. Re-treatment with HER was documented at routine visits starting with a basic observational period of maximum 12 months and a follow-up period of maximum additional four years. HER2-positive BC relapsed after a median of 36.5 months (mos). Patients were re-treated with HER +/- chemotherapy +/- endocrine therapy. HER-containing regimens resulted in median progression-free survival (mPFS) of 12.7 (95%CI=10.5-14.8) mos and overall survival (OS-2) of 31.6 mos (95%CI=28.8-38.4) since recurrence diagnosis. Differentiation of recurrence types (local, visceral, non-visceral) unfolded worst prognosis for patients with visceral metastases. Cardiac monitoring within this non-interventional study (NIS) did not result in new safety concerns. Re-therapy with HER in the first-line setting of advanced HER2-positive breast cancer is effective and without unexpected or intensified adverse events.

Response to Lapatinib-Capecitabine combination in a young patient with recurrent HER2-positive breast cancer refractory to two lines of therapy with anti-HER2 drugs

HER2-positive breast cancer is an aggressive tumour that affects approximately one in five breast cancer women. Clinical studies have shown that HER2-positive cancer have different characteristics from other mammary tumors: a more rapid progression of the disease, an earlier age of onset (women of childbearing age between 30 and 45 are also affected to a large extent), a different response to chemotherapyand, in general, an unfavorable prognosis. Breast cancer with overexpression of the HER2 protein may benefit from the latest generation of target treatments (monoclonal antibodies and anti-HER2 tyrosine kinase inhibitors). Not all HER2-positive tumors, however, respond to therapies, and some responders may later become resistant. We report the case of a young woman with HER2-positive mammary carcinoma who presented resistance to the first two treatment lines with anti-HER2 drugs (trastuzumab-pertuzumab and TDM1) and responded to the combination lapatinib-capecitabine in third line (Oncology).

312P - Phase II clinical trial of first-line eribulin plus trastuzumab for advanced or recurrent HER2-positive breast cancer

312P - Phase II clinical trial of first-line eribulin plus trastuzumab for advanced or recurrent HER2-positive breast cancer

Long-term survival in a young woman with recurrent HER2-positive breast cancer.

We report the case of a patient with HER2-positive breast cancer relapsing after 7 years from diagnosis with a HER2-positive tumor recurrence, treated with anti-HER2 drugs (pertuzumab, trastuzumab and lapatinib) associated to radiotherapy and/or chemotherapy. These therapeutic strategies allowed satisfactory disease control after about 4 years from recurrence (Oncology).

Phase II clinical trial of the 1st line combination therapy of eribulin and trastuzumab for advanced or recurrent HER2-positive breast cancer.

e13016Background: Eribulin mesylate is approved to treat patients with advanced or reccurent breast cancer who have received at least two previous chemotherapy regimens. CLEOPTRA demonstrated the e...

Abstract OT3-01-13: MetaPHER: A phase IIIb multicenter, open-label, single-arm safety study of subcutaneous trastuzumab, in combination with pertuzumab and docetaxel in patients with HER2-positive advanced breast cancer

Abstract Background: In patients (pts) with HER2-positive metastatic breast cancer (BC), the phase III CLEOPATRA study (NCT00567190) demonstrated significant improvement in progression-free (PFS) and overall survival (OS) from first-line treatment with intravenous (IV) pertuzumab (PERJETA® [P IV]) plus trastuzumab (Herceptin® [H IV]) plus docetaxel (D IV). HannaH (NCT00950300), a phase III trial in pts with HER2-positive early BC demonstrated that fixed-dose trastuzumab subcutaneous (Herceptin® [H SC]) is non-inferior to weight-based H IV infusion in the co-primary endpoints of serum trough concentration and pathologic complete response, which was supported by the long-term efficacy endpoints of event-free survival (EFS) and OS. The safety profile of H SC was consistent with the known safety profile of H IV. H SC is comprised of 600 mg trastuzumab and recombinant human hyaluronidase (rHuPH20) as an excipient, allowing a significantly reduced administration time compared with H IV (5 mins versus 30–90 mins, respectively). The MetaPHER study is designed to investigate the safety and efficacy of H SC in combination with P IV and D IV in pts with HER2-positive advanced BC. Trial design: MetaPHER is a phase IIIb multicenter, open-label, single-arm study, with eligible pts receiving H SC 600 mg/5 mL q3w, P IV (840 mg loading dose, then 420 mg at each subsequent cycle q3w), and D IV (at least 6 cycles at 75 mg/m2 q3w with possible escalation to 100 mg/m2 q3w; after Cycle 6, continuation of docetaxel is at the investigator's discretion). Study treatment is administered until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end, whichever occurs first. Pts will receive post-treatment follow-up for safety and survival. Eligibility: Women aged ≥18 years with metastatic or locally recurrent HER2-positive BC, ECOG performance status 0 or 1, and a left ventricular ejection fraction ≥50% are eligible. Exclusion criteria include disease-free interval of <6 months from completion of adjuvant or neoadjuvant non-hormonal treatment to disease recurrence; previous systemic non-hormonal therapy for metastatic or locally recurrent BC; history of persistent grade ≥2 hematological toxicity; current grade ≥3 peripheral neuropathy; or clinically significant cardiovascular disease. Aims: The primary objective is to evaluate the safety and tolerability of H SC in combination with P IV and D IV in pts with HER2-positive advanced BC. Secondary endpoints include PFS, OS, objective response rate and incidence of anti-trastuzumab and anti-rHuPH20 antibody formation. Statistical methods: Safety and efficacy results will be summarized descriptively to include all enrolled pts who received at least one dose of any study drug; the study is not designed for formal hypothesis testing. A sample size of 400 pts provides reasonable precision for the estimation of grade ≥3 AEs and cardiac AEs. Accrual: MetaPHER is enrolling, FPI was May 2015, and target enrollment is 400 pts; clinicaltrials.gov ID: NCT02402712. Contact information: For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Citation Format: Kümmel S, Crepelle-Fléchais A, Schlegel M, Hillenbach C, Swat A, Franz M, Girase P, Schneider A, Heinzmann D, Shing M. MetaPHER: A phase IIIb multicenter, open-label, single-arm safety study of subcutaneous trastuzumab, in combination with pertuzumab and docetaxel in patients with HER2-positive advanced breast cancer. [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 OT3-01-13.

Abstract 726: Constitutive NF-kB-activation loop enhances resistance to trastuzumab in HER2 positive luminal B breast cancer

Abstract [Purpose] Luminal B breast cancer patients are significantly at the risk of relapse with in 5 years. Acquired resistance to the receptor tyrosine kinase HER2 targeting antibody trastuzumab is a major clinical problem in the treatment of recurrent HER2-positive breast cancer. The molecular mechanisms leading to trastuzumab resistance (TZR) remain unclear in luminal B breast cancer. Here, we investigated the mechanism of TZR in HER2-positive luminal B breast cancer cells with acquired resistance. [Methods and Results] We generated trastuzumab resistant breast cancer cell line (BT-474-R) by treating BT-474 cells with trastuzumab for over long-term. Initial validation showed that HER2 overexpression in the BT-474-R cells remained unaltered suggesting that probably HER2 independent signaling pathway is involved in the development of TZR. We demonstrated that NF-κB is constitutively activated in the BT-474-R cells by quantitative realtime RT-PCR, western blotting and immunofluorescent microscopy. Expression of pro-inflammatory cytokines were also demonstrated. Pharmacologic inhibition of NF-κB improved sensitivity to trastuzumab in BT-474-R cells. We identified both IKK-α and IKK-β as the major determinants of the activation of the NF-κB signaling in the resistant cells. [Conclusion] Our study suggests by activating NF-κB pathway, luminal B cells may facilitate acquiring basal-like, Her2+ phenotype a notion consistent with “progression through grade” hypothesis. Finally, our study suggests that blocking NF-κB will provide a new treatment option to limit relapse in HER2 positive breast cancer patients treated with trastuzumab. Citation Format: Hirotaka Kanzaki, Nishit Makhopadhya, Xiaojiang Cui, Krishnan V. Ramanujan, Tatsuaki Takeda, Yoshihisa Kitamura, Toshiaki Sendo, Ramachandran Murali. Constitutive NF-kB-activation loop enhances resistance to trastuzumab in HER2 positive luminal B breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 726. doi:10.1158/1538-7445.AM2015-726

Abstract OT3-1-04: A phase 2 study of eribulin in combination with pertuzumab and trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 (HER2)-positive breast cancer (SONG-02)

Abstract Background: Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and the combination of pertuzumab plus trastuzumab plus taxanes, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival (PFS). However, in the second and later line treatment of HER2-positive advanced or recurrent breast cancer, it has not settled whether it should be treated with pertuzumab plus trastuzumab plus chemotherapy or with trastuzumab plus chemotherapy. Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that has been proved to prolong the overall survival of advanced or recurrent breast cancer patients compared with the treatment of physician's choice. The benefit of eribulin in combination with trastuzumab for patients with locally recurrent or metastatic HER2-positive breast cancer has been reported. However, the efficacy and safety of eribulin in combination with pertuzumab and trastuzumab for advanced or recurrent HER2-positive breast cancer patients has not been reported. The purpose of this study is to evaluate the efficacy and safety of eribulin in combination with pertuzumab and trastuzumab as second and later line therapy for patients with advanced or recurrent HER2-positive breast cancer. Trial Design: This is a multicenter single arm phase 2 study for advanced or recurrent HER2-positive breast cancer patients who have experienced progression with anti-HER2 therapy. Patients received eribulin mesylate 1.4mg/m2 administered via intravenous (IV) infusion over 2 to 5 minutes on Days 1 and 8 each 21-day cycle and pertuzumab 840mg/kg IV and trastuzumab 8mg/kg IV over 90 minutes on Day 1 of Cycle 1. Thereafter eribulin mesylate 1.4mg/m2 and pertuzumab 420mg/kg and trastuzumab 6mg/kg was infused each 21-day cycle until disease progression or the appearance of toxic effects that could not be effectively managed. The primary endpoint is PFS of the combination therapy, based on local assessment of response using RECIST 1.1 criteria. Secondary endpoints are overall response rate (ORR), safety and tolerability. In addition, we examine PFS and safety according to the most recent treatment regimen. The study was conducted in accordance with the Declaration of Helsinki (2008), and the protocol and informed consent forms were submitted for approval to institutional review boards by the primary investigators. All patients provided written informed consent before undergoing any study-related procedures Statistical Method: All efficacy analyses were based primarily on the full analysis set (FAS), which included all patients who received over 1 dose(s) of study treatment. The PFS and ORR were calculated 95% confidence intervals (CIs). Treatment of 39 evaluable patients with the identified phase 2 doses will detect this difference with a power of 80% and alpha=5% (one-sided test). Accounting for a 10% invaluable rate and lead-in patients, a total of 43 patients will be enrolled on the study. Clinical trial information UMIN000014107. Citation Format: Hajime Abe, Shunji Kamigaki, Yoshifumi Komoike, Nobuki Matsunami, Yoshiaki Nakano, Kenji Tezuka, Junji Tsurutani, Jun Yamamura, Keiichi Yamazaki. A phase 2 study of eribulin in combination with pertuzumab and trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 (HER2)-positive breast cancer (SONG-02) [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 OT3-1-04.

Abstract P4-12-20: Clinical outcomes of patients with recurrent HER2-positive breast cancer after exposure to adjuvant trastuzumab

Abstract Background: Trastuzumab has become the cornerstone of adjuvant therapy for patients with HER2-positive breast cancer, as it has significantly impacted on overall survival for these patients. Unfortunately, not all patients are cured, and recurrences occur in up to 13% of patients. In the post-trastuzumab era, long-term outcomes for HER2-positive breast cancer patients who develop recurrent disease after exposure to adjuvant trastuzumab is unknown. Methods: We retrospectively identified patients with stage I-III HER2-positive breast cancer treated at The Ohio State University Medical Center from 1995-2011. Patients were divided into two groups: those exposed to adjuvant trastuzumab, and those who never received adjuvant trastuzumab. Medical records were reviewed to obtain demographic data, disease status at diagnosis, adjuvant and metastatic therapeutic regimens, date and location of recurrent disease, date of last follow-up and vital status. Time-dependent analyses were carried out using Kaplan-Meier estimates. Results: Six hundred and sixty-two patients were initially identified and included in the analysis. Of the 374 patients who did not receive adjuvant trastuzumab, 96 patients had recurrence (26%). There were 288 patients who received adjuvant trastuzumab, with 33 patients developing relapse (11%). In the patients who received adjuvant trastuzumab and subsequently recurred, there was a higher incidence of CNS recurrence (n = 8; 24%) than those who did not receive adjuvant trastuzumab (n = 10; 10%). Those that received adjuvant trastuzumab also had fewer bone metastases (n = 3; 9%) than the patients who did not receive adjuvant trastuzumab (n = 29; 30%). There was no difference in overall survival in patients with metastatic progression after exposure to adjuvant trastuzumab compared to patients with metastatic HER2-positive breast cancer without prior adjuvant trastuzumab (p = 0.41). Of the 33 patients who relapsed after adjuvant trastuzumab, the majority received HER2-targeted therapy in the form of trastuzumab or lapatinib (n = 22; 67%). Eleven patients received trastuzumab-based therapy and 9 received lapatinib-based therapy. Two patients received the combination of trastuzumab and lapatinib. The remainder received cytotoxic therapy alone (n = 3; 9%), endocrine therapy (n = 1; 3%) or local therapy (surgery or radiation) (n = 4; 12%). Three patients received no therapy. Conclusion: There was no difference in overall survival for HER2-positive breast cancer patients who recur after adjuvant trastuzumab compared to metastatic patients without exposure to adjuvant trastuzumab. CNS disease as the first site of recurrence occured more frequently in patients who had received adjuvant trastuzumab than in those who were not previously exposed to trastuzumab. Continued HER2-targeted therapy after relapse on adjuvant trastuzumab was the regimen of choice in the first-line metastatic setting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-20.

Long term disease-free survival after stopping trastuzumab in trastuzumab-sensitive metastatic breast cancer patients treated with local-regional therapy

11542 Background: The standard of care when treating patients with metastatic or locally recurrent HER2-positive breast cancer includes using T alone or in combination with chemotherapy. Patients whose disease responds to trastuzumab generally continue therapy until disease progression. Little is known about women with limited disease volume who respond to T and receive definitive local-regional treatment. Can T be stopped in these patients? At a cost upwards of $40,000/year and an FDA recommended weekly dosing interval, any information on this topic would be valuable. Methods: Case series of women seen by a single medical oncologist. Patients had HER2-positive metastatic or locally recurrent breast cancer whose disease was resectable or could be encompassed within a radiation therapy (RT) port. This is not a clinical trial. Patients were treated according to the best medical judgment of the physicians involved. Results: Six patients are described. Two patients had chest wall recurrence (skin) in a previo...