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The Breast Journal 2022Randomized studies of neoadjuvant (NA) trastuzumab and pertuzumab combined with chemotherapy for HER2-positive breast cancers (BC) have reported pathological complete...
BACKGROUND
Randomized studies of neoadjuvant (NA) trastuzumab and pertuzumab combined with chemotherapy for HER2-positive breast cancers (BC) have reported pathological complete response (pCR) rates of 39 to 61%. This study aimed to determine the real-world efficacy and toxicity of NA trastuzumab and pertuzumab combined with chemotherapy in a UK tertiary referral cancer centre.
METHODS
HER2-positive early BC patients given neoadjuvant chemotherapy with trastuzumab and pertuzumab between October 2016 and February 2018 at our tertiary referral cancer centre were identified via pharmacy records. Clinico-pathological information, treatment regimens, treatment-emergent toxicities, operative details, and pathological responses and outcomes were recorded.
RESULTS
78 female patients were identified; 2 had bilateral diseases and 48 of 78 (62%) were node positive at presentation. 55 of 80 (71%) tumours were ER-positive. PCR occurred in 37 of 78 (46.3%; 95% CI: 35.3-57.2%) patients. 14 of 23 (60.8%) patients with ER-negative tumours achieved pCR; 23 of 55 (41.8%) were ER-positive and 6 of 19 (31.6%) were ER-positive and PgR-positive. No cardiac toxicity was documented. Diarrhoea occurred in 53 of 72 (74%) patients. Grade 3-4 toxicity occurred in ≥2% patients. These were diarrhoea, fatigue, and infection. The Median follow up period was 45.2 months (95% CI 43.8-46.3) with 71 of 78 (91.0%) remaining disease-free and 72 of 78 (92.3%) alive. Estimated OS at 2 years 86% (95% CI: 75-99%).
CONCLUSION
This data confirms the efficacy of neoadjuvant chemotherapy combined with dual HER2 directed therapy. While no cardiac toxicity was observed, diarrhoea occurred frequently. The low pCR rate observed in ER and PgR-positive BCs warrants further investigation and consideration of strategies to increase the pCR rate.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Diarrhea; Female; Humans; Neoadjuvant Therapy; Trastuzumab; Treatment Outcome
PubMed: 35833190
DOI: 10.1155/2022/7146172 -
Breast Cancer (Dove Medical Press) 2021The management of HER2 positive breast cancer has been transformed by the development of targeted therapies. Dual blockade with the monoclonal antibodies, trastuzumab... (Review)
Review
The management of HER2 positive breast cancer has been transformed by the development of targeted therapies. Dual blockade with the monoclonal antibodies, trastuzumab and pertuzumab, added to first-line taxane chemotherapy and second-line therapy with the antibody-drug conjugate, T-DM1, are internationally agreed standards of care for advanced HER2 positive breast cancer, where available. However, until recently, options for patients for third-line therapy and beyond were of modest efficacy or limited by toxicity. In 2019, the results of trials of two exciting new agents for this space were presented. A third-generation HER2 tyrosine kinase inhibitor, tucatinib, combines the efficacy of the second-generation drug, neratinib, with a more manageable toxicity profile and has become a new standard of care after T-DM1, in combination with capecitabine and trastuzumab. The antibody-drug conjugate, trastuzumab deruxtecan, demonstrated remarkable efficacy in heavily pre-treated patients and received accelerated approval in the United States, whilst confirmatory Phase 3 trials are completed. This review will discuss the available data for the post-T-DM1 setting, focusing on tyrosine kinase inhibitors including tucatinib.
PubMed: 34079368
DOI: 10.2147/BCTT.S268451 -
British Journal of Cancer Jul 2023HER2 is overexpressed in 25-30% of breast cancer. Multiple domains targeting of a receptor can have synergistic/additive therapeutic effects.
BACKGROUND
HER2 is overexpressed in 25-30% of breast cancer. Multiple domains targeting of a receptor can have synergistic/additive therapeutic effects.
METHODS
Two domain-specific ADCs trastuzumab-PEG-DM1 (domain IV) and pertuzumab-PEG-DM1 (domain II) were developed, characterised and radiolabeled to obtain [Zr]Zr-trastuzumab-PEG-DM1 and [Cu]Cu-pertuzumab-PEG-DM1 to study their in vitro (binding assay, internalisation and cytotoxicity) and in vivo (pharmacokinetics, biodistribution and immunoPET/SPECT imaging) characteristics.
RESULTS
The ADCs had an average drug-to-antibody ratio of 3. Trastuzumab did not compete with [Cu]Cu-pertuzumab-PEG-DM1 for binding to HER2. The highest antibody internalisation was observed with the combination of ADCs in BT-474 cells compared with single antibodies or ADCs. The combination of the two ADCs had the lowest IC compared with treatment using the single ADCs or controls. Pharmacokinetics showed biphasic half-lives with fast distribution and slow elimination, and an AUC that was five-fold higher for [Zr]Zr-trastuzumab-PEG-DM1 compared with [Cu]Cu-pertuzumab-PEG-DM1. Tumour uptake of [Zr]Zr-trastuzumab-PEG-DM1 was 51.3 ± 17.3% IA/g (BT-474), and 12.9 ± 2.1% IA/g (JIMT-1) which was similarly to [Cu]Cu-pertuzumab-PEG-DM1. Mice pre-blocked with pertuzumab had [Zr]Zr-trastuzumab-PEG-DM1 tumour uptakes of 66.3 ± 33.9% IA/g (BT-474) and 25.3 ± 4.9% IA/g (JIMT-1) at 120 h p.i.
CONCLUSION
Using these biologics simultaneously as biparatopic theranostic agents has additive benefits.
Topics: Animals; Mice; Tissue Distribution; Precision Medicine; Receptor, ErbB-2; Trastuzumab; Neoplasms
PubMed: 37095184
DOI: 10.1038/s41416-023-02272-4 -
Cureus Jun 2023Increasingly complex and constantly emerging cancer treatment protocols are associated with kidney toxicities. Data clearly demonstrate that when patients with cancer...
Increasingly complex and constantly emerging cancer treatment protocols are associated with kidney toxicities. Data clearly demonstrate that when patients with cancer develop acute or chronic kidney disease, severe fluid and electrolyte abnormalities, outcomes are inferior, and the promise of curative therapeutic regimens is lessened. We present a case of a 74-year-old woman with metastatic, recurrent ER+/PR-/HER2+ invasive ductal carcinoma of the right breast, status post bilateral mastectomies, chemotherapy, radiation therapy, and hormonal therapies, who were clinically stable on Trastuzumab/Pertuzumab maintenance for about a year. She then experienced disease progression. She was started on Trastuzumab+Deruxtecan (T-Dxt). However, due to worsening diarrhea of more than 12 episodes per day, decreased oral intake, weakness and weight loss, she got admitted to the hospital. Laboratory data showed hyponatremia, hypokalemia, non-anion gap metabolic acidosis, hypomagnesemia, and hypophosphatemia. These laboratory abnormalities were initially attributed to diarrhea. Renal losses were suspected when the electrolyte abnormalities did not correct despite improving diarrhea. Urine electrolytes were hence tested. There was evidence of Fanconi syndrome with glucosuria, proteinuria, and renal potassium and phosphorus wasting. Fanconi syndrome was attributed to the Deruxtecan component of the combination chemotherapy, as she was previously on Trastuzumab with no such abnormalities. The electrolyte abnormalities resolved over the course of a few months. To our knowledge, this is the first case of Fanconi syndrome due to T-Dxt.
PubMed: 37492824
DOI: 10.7759/cureus.40890 -
Breast Cancer Research and Treatment Jul 2021Immediate and proper implementation of a new and more potent therapy is important to ensure that the patient achieves the best possible outcome. This study aimed to...
PURPOSE
Immediate and proper implementation of a new and more potent therapy is important to ensure that the patient achieves the best possible outcome. This study aimed to examine whether the real-world overall survival (OS) has improved in patients with human epidermal growth factor receptor 2-positive (HER2 +) advanced breast cancer (ABC) since the market release of pertuzumab and T-DM1. Furthermore, we aimed to assess the implementation and survival rates per hormone receptor (HR) subtype.
PATIENTS AND METHODS
We included 493 systemically treated patients consecutively diagnosed with HER2 + ABC in 2008-2017 from the SOutheast Netherlands Advanced BREast cancer (SONABRE) Registry. Median OS was obtained using the Kaplan-Meier method and differences between periods (2008-2012 versus 2013-2017) were tested using multivariable Cox proportional hazards regression modeling. The 3-year implementation rates were estimated for any HER2-targeted therapy, pertuzumab, and T-DM1 by using the competing risk method and calculated from the date of diagnosis of ABC to start of HER2-targeted therapy of interest.
RESULTS
The median OS in 2008-2012 versus 2013-2017 was 28.3 versus 39.7 months in all patients (adjusted hazard ratio (adjHR) 0.85, 95%CI 0.66-1.08), 29.9 versus 36.3 months in patients with HR + /HER2 + disease (adjHR 0.97, 95%CI 0.72-1.32), and 22.7 versus 40.9 months in patients with HR-/HER2 + disease (adjHR 0.59, 95%CI 0.38-0.92). Any HER2-targeted therapy was used in 79% of patients in 2008-2012 and in 84% in 2013-2017. The use of pertuzumab and T-DM1 in 2013-2017 was 48% and 29%, respectively. For patients diagnosed with HR + /HER2 + and HR-/HER2 + disease, implementation rates in 2013-2017 were , respectively, 77% and 99% for any HER2-targeted therapy, 38% and 69% for pertuzumab, and 24% and 40% for T-DM1.
CONCLUSION
The survival of patients with HER2 + ABC improved since the introduction of pertuzumab and T-DM1. There is room for improvement in implementation of these HER2-targeted therapies, especially in patients with HR + /HER2 + disease.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Netherlands; Receptor, ErbB-2; Registries; Trastuzumab
PubMed: 33743103
DOI: 10.1007/s10549-021-06178-8 -
Molecular Cancer Sep 2020Triple negative breast cancer (TNBC) remains the most challenging breast cancer subtype so far. Specific therapeutic approaches have rarely achieved clinical...
BACKGROUND
Triple negative breast cancer (TNBC) remains the most challenging breast cancer subtype so far. Specific therapeutic approaches have rarely achieved clinical improvements in treatment of TNBC patients and effective molecular biomarkers are largely unknown.
METHODS
We used paired TNBC samples and high throughput RNA sequencing to identify differentially expressed circRNAs. Sucrose gradient polysome fractionation assay, antibody and Mass spectra were used to validate active circRNA translation. The novel protein function was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by immunoprecipitation analyses and kinase activity assay.
RESULTS
Circular HER2 RNA (circ-HER2) encoded a novel protein, HER2-103. Unexpectedly, while HER2 mRNA and protein were barely detected, circ-HER2/HER2-103 was expressed in ~ 30% TNBC clinical samples. Circ-HER2/HER2-103 positive TNBC patients harbored worse overall prognosis than circ-HER2/HER2-103 negative patients. Knockdown circ-HER2 inhibited TNBC cells proliferation, invasion and tumorigenesis in vitro and in vivo, suggesting the critical role of circ-HER2/HER2-103 in TNBC tumorigenicity. Mechanistically, HER2-103 promoted homo/hetero dimerization of epidermal growth factor receptor (EGFR)/HER3, sustained AKT phosphorylation and downstream malignant phenotypes. Furthermore, HER2-103 shared most of the same amino acid sequences as HER2 CR1 domain which could be antagonized by Pertuzumab, a clinical used HER2 antibody. Pertuzumab markedly attenuated in vivo tumorigenicity of circ-HER2/HER2-103 expressing TNBC cells but showed no effects in circ-HER2/HER2-103 negative TNBC cells.
CONCLUSION
Our results not only demonstrated that certain TNBCs were not truly 'HER2 negative' but also highlighted the clinical implications of Pertuzumab in circ-HER2/HER2-103 expressing TNBC patients.
Topics: Animals; Antibodies, Monoclonal, Humanized; Apoptosis; Carcinogenesis; Cell Proliferation; ErbB Receptors; Female; Gene Expression Regulation, Neoplastic; Heterografts; Humans; MCF-7 Cells; Mice; Middle Aged; RNA, Circular; Receptor, ErbB-2; Triple Negative Breast Neoplasms
PubMed: 32917240
DOI: 10.1186/s12943-020-01259-6 -
Appraisal of Systemic Treatment Strategies in Early HER2-Positive Breast Cancer-A Literature Review.Cancers Aug 2023The overexpression of the human epidermal growth factor receptor 2 (HER2+) accounts for 15-20% of all breast cancer phenotypes. Even after the completion of the standard... (Review)
Review
BACKGROUND
The overexpression of the human epidermal growth factor receptor 2 (HER2+) accounts for 15-20% of all breast cancer phenotypes. Even after the completion of the standard combination of chemotherapy and trastuzumab, relapse events occur in approximately 15% of cases. The neoadjuvant approach has multiple benefits that include the potential to downgrade staging and convert previously unresectable tumors to operable tumors. In addition, achieving a pathologic complete response (pCR) following preoperative systemic treatment is prognostic of enhanced survival outcomes. Thus, optimal evaluation among the suitable strategies is crucial in deciding which patients should be selected for the neoadjuvant approach.
METHODS
A literature search was conducted in the Embase, Medline, and Cochrane electronic libraries.
CONCLUSION
The evaluation of tumor and LN staging and, hence, stratifying BC recurrence risk are decisive factors in guiding clinicians to optimize treatment decisions between the neoadjuvant versus adjuvant approaches. For each individual case, it is important to consider the most likely postsurgical outcome, since, if the patient does not obtain pCR following neoadjuvant treatment, they are eligible for adjuvant T-DM1 in the case of residual disease. This review of HER2-positive female BC outlines suitable neoadjuvant and adjuvant systemic treatment strategies for guiding clinical decision making around the selection of an appropriate therapy.
PubMed: 37686612
DOI: 10.3390/cancers15174336 -
Advances in Therapy Feb 2022Health technology assessments and value frameworks are becoming increasingly important for clinical decision-making. Most of these frameworks, however, focus on value to... (Review)
Review
White Paper on the Value of Time Savings for Patients and Healthcare Providers of Breast Cancer Therapy: The Fixed-Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Injection as an Example.
Health technology assessments and value frameworks are becoming increasingly important for clinical decision-making. Most of these frameworks, however, focus on value to payers rather than patients and healthcare providers and may ignore other sources of economic value such as patient and physician time cost, impact on productivity, and direct health system costs. This article focusses on fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) in the treatment of HER2-positive breast cancer. We review relevant clinical evidence, examine data on time and resource use of the subcutaneous administration of trastuzumab compared with intravenous treatment and how it can be extrapolated to PH FDC SC, and discuss the value PH FDC SC can bring to patients and healthcare providers. We will also provide our own experiences of PH FDC SC from the healthcare (oncologist, healthcare economist, pharmacist) and patient point of view. The data, combined with our personal experiences, suggest that switching from intravenous pertuzumab and trastuzumab to PH FDC SC could reduce non-drug costs for healthcare providers treating patients with HER2-positive breast cancer through time savings and other economic benefits. Furthermore, PH FDC SC could also save patient time given its shorter administration and post-injection observation time versus intravenous infusions, potentially resulting in reduced productivity loss. These benefits could be applied to other subcutaneous formulations, either currently available or in development.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Health Personnel; Humans; Injections, Subcutaneous; Receptor, ErbB-2; Trastuzumab
PubMed: 34988876
DOI: 10.1007/s12325-021-01996-0 -
Breast Care (Basel, Switzerland) Dec 2021The addition of trastuzumab to standard chemotherapy has improved survival in patients with HER2-positive breast cancer in neoadjuvant, adjuvant, and metastatic...
BACKGROUND
The addition of trastuzumab to standard chemotherapy has improved survival in patients with HER2-positive breast cancer in neoadjuvant, adjuvant, and metastatic settings. In higher tumor stages, the addition of pertuzumab is now a standard of care and associated with a favorable toxicity profile. We evaluated the safety and efficacy of the trastuzumab biosimilar SB3 in combination with pertuzumab in HER2-positive breast cancer patients.
METHODS
Seventy-eight patients with HER2-positive breast cancer treated at the Division of Oncology at the Medical University of Graz were included. Summary measures are reported as medians (25th to 75th percentile) for continuous variables and as absolute frequencies (%) for count data.
RESULTS
Thirty-five patients received a median of 4 (3-7) cycles of trastuzumab biosimilar SB3 plus pertuzumab. All patients had a normal baseline left ventricular ejection fraction (LVEF; >50%) prior to the initiation of SB3 plus pertuzumab treatment with a median LVEF of 60% (60-65). Twenty-one patients had a median absolute LVEF decline of 1% (-5 to 0). Two patients (5.7%) had a LVEF reduction ≤50%, but none ≥10%. There were no unexpected adverse events. Twenty-two of 35 patients (63%) were treated with trastuzumab biosimilar SB3 and pertuzumab in the neoadjuvant setting and 11 patients (50%) achieved a pathological complete response. The safety and the efficacy in this setting was comparable to the trastuzumab plus pertuzumab combination in neoadjuvantly treated matched samples.
CONCLUSION
In this series of HER2-positive breast cancer patients, the combination of SB3 plus pertuzumab was consistent with the known safety and efficacy profile of trastuzumab and pertuzumab combination.
PubMed: 35082570
DOI: 10.1159/000513766 -
Breast Cancer Research and Treatment Jan 2021In the CLEOPATRA study of patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer, the Japanese patient subgroup did...
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.
PURPOSE
In 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.
METHODS
This 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.
RESULTS
At 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.
CONCLUSIONS
Our 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.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Female; Humans; Japan; Receptor, ErbB-2; Trastuzumab; Treatment Outcome
PubMed: 32920732
DOI: 10.1007/s10549-020-05921-x