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JCO Global Oncology Feb 2024As the fifth international consensus on advanced breast cancer (ABC5) established guidelines for the management of this disease, the aim of this article was to present...
PURPOSE
As the fifth international consensus on advanced breast cancer (ABC5) established guidelines for the management of this disease, the aim of this article was to present the applicability of the consensus recommendations and to generate knowledge to improve access.
METHODS
Sixty-one recommendation statements were selected and discussed by 15 breast cancer experts from Latin America (LA). After the discussion, the level of consensus was determined through a vote. In addition to this, the level of access to each of the recommendations presented, according to the country and health system, was exposed.
RESULTS
Latin American experts had a high level of agreement with the ABC5 consensus recommendations (range, 83%-100%). Twelve of 61 statements are not available for all patients in LA. Among the limitations to access, the following ones are described: limited access to certain technologies (stereotactic body radiotherapy, positron emission tomography-computed tomography), the high costs of drugs that limits access to treatment with CDK4/6 inhibitors, pertuzumab, or poly(ADP-ribose) polymerase inhibitors, and the lack of molecular tests for access to therapeutic targets, as well as the difficult geography and cultural diversity of our continent.
CONCLUSION
Despite the great relevance of the recommendations of the ABC5 consensus guidelines, we highlight that we still need to improve access for all patients, regardless of the country or health system they are in, for which we call to action to policy makers and patient groups to improve clinical outcomes of patients with advanced breast cancer in our region.
Topics: Humans; Female; Breast Neoplasms; Latin America; Consensus
PubMed: 38301184
DOI: 10.1200/GO.22.00067 -
The Journal of Clinical Investigation Feb 2024BACKGROUNDHER2-targeting therapies have great efficacy in HER2-positive breast cancer, but resistance, in part due to HER2 heterogeneity (HET), is a significant clinical... (Clinical Trial)
Clinical Trial
BACKGROUNDHER2-targeting therapies have great efficacy in HER2-positive breast cancer, but resistance, in part due to HER2 heterogeneity (HET), is a significant clinical challenge. We previously described that in a phase II neoadjuvant trastuzumab emtansine (T-DM1) and pertuzumab (P) clinical trial in early-stage HER2-positive breast cancer, none of the patients with HER2-HET tumors had pathologic complete response (pCR).METHODSTo investigate cellular and molecular differences among tumors according to HER2 heterogeneity and pCR, we performed RNA sequencing and ERBB2 FISH of 285 pretreatment and posttreatment tumors from 129 patients in this T-DM1+P neoadjuvant trial. A subset of cases was also subject to NanoString spatial digital profiling.RESULTSPretreatment tumors from patients with pCR had the highest level of ERBB2 mRNA and ERBB signaling. HER2 heterogeneity was associated with no pCR, basal-like features, and low ERBB2 expression yet high ERBB signaling sustained by activation of downstream pathway components. Residual tumors showed decreased HER2 protein levels and ERBB2 copy number heterogeneity and increased PI3K pathway enrichment and luminal features. HET tumors showed minimal treatment-induced transcriptomic changes compared with non-HET tumors. Immune infiltration correlated with pCR and HER2-HET status.CONCLUSIONResistance mechanisms in HET and non-HET tumors are distinct. HER2-targeting antibodies have limited efficacy in HET tumors. Our results support the stratification of patients based on HET status and the use of agents that target downstream components of the ERBB signaling pathway in patients with HET tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT02326974.FUNDINGThis study was funded by Roche and the National Cancer Institute.
Topics: Female; Humans; Ado-Trastuzumab Emtansine; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Phosphatidylinositol 3-Kinases; Receptor, ErbB-2; Trastuzumab
PubMed: 38300710
DOI: 10.1172/JCI176454 -
Therapeutic Advances in Medical Oncology 2024This study aimed to investigate clinical practices and factors related to the outcomes of T-DM1 use in patients with HER2-positive metastatic breast cancer (mBC).
PURPOSE
This study aimed to investigate clinical practices and factors related to the outcomes of T-DM1 use in patients with HER2-positive metastatic breast cancer (mBC).
METHODS
We included patients with HER2-positive mBC who received T-DM1 as a palliative therapy between August 2017 and December 2018. The safety and outcomes of T-DM1, including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), were evaluated. A Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence interval (CI) for mortality or progression to HER2-positive mBC.
RESULTS
In total, 824 patients were enrolled during the study period. The mean age of patients was 58 years, and 516 (62.6%) patients relapsed after curative treatment. Excluding a history of endocrine therapy, 341 (41.4%) patients previously received none or first-line chemotherapy, 179 (21.7%) received second-line therapy, and 303 (36.9%) received third-or later-line chemotherapy before T-DM1 therapy. During a median follow-up of 16.8 months, the ORR was 35%, the median PFS was 6.6 months, and the median OS was not reached. The clinical factors associated with the hazard of progression were age (<65 years), poor performance status (⩾2), advanced line of palliative chemotherapy (⩾2), prior pertuzumab use, and treatment duration of palliative trastuzumab (<10 months). Common grade 3-4 adverse events were thrombocytopenia ( = 107, 13.2%), neutropenia ( = 23, 2.8%), anemia ( = 21, 2.6%), and elevated liver enzyme ( = 20, 2.5%). Hypokalemia (⩽3.0 mmol/L) and any-grade bleeding events occurred in 25 (3.1%) and 94 (22.6%) patients, respectively.
CONCLUSION
This is the first nationwide real-world study of T-DM1 use in patients with HER2-positive mBC in Korea. The effectiveness and toxicity profiles of T-DM1 in real-world practice were comparable to those in randomized trials. Moreover, patient factors and previous anti-HER2 therapy could predict the outcomes of T-DM1 therapy.
PubMed: 38288157
DOI: 10.1177/17588359231225029 -
Frontiers in Oncology 2024Inflammatory breast cancer (IBC) is an aggressive and rare form of breast cancer with a poor prognosis. The occurrence of bilateral IBC in a short period of time is...
Inflammatory breast cancer (IBC) is an aggressive and rare form of breast cancer with a poor prognosis. The occurrence of bilateral IBC in a short period of time is extremely rare. In this case report, a 54-year-old woman diagnosed with invasive ductal carcinoma of the left breast underwent lumpectomy, lymph node dissection, chemotherapy, and radiotherapy but opted against trastuzumab treatment. Four years later, she experienced bilateral breast inflammation, skin changes, edema, and heat (calor). Biopsies confirmed breast cancer metastasis to both breasts. Whole-Exome Sequencing revealed genetic mutations, including PIK3CA and C4orf54, in both primary and recurrent tumors, with significant downregulation in the recurrent tumors. KEGG analysis suggested potential enrichment of axon guidance signal pathways in both tumors. The patient showed a partial response after treatment with liposome paclitaxel, along with targeted therapy using trastuzumab and pertuzumab. This case report sheds light on the rare occurrence of bilateral inflammatory breast cancer post-HER-2 treatment and highlights the importance of genetic profiling in understanding the disease. Further research on clinical targets for breast cancer management is warranted.
PubMed: 38283858
DOI: 10.3389/fonc.2024.1276637 -
Journal of Nuclear Medicine : Official... Mar 2024Radioimmunoconjugates targeting human epidermal growth factor receptor 2 (HER2) have shown potential to noninvasively visualize HER2-positive tumors. However, the...
Radioimmunoconjugates targeting human epidermal growth factor receptor 2 (HER2) have shown potential to noninvasively visualize HER2-positive tumors. However, the stochastic approach that has been traditionally used to radiolabel these antibodies yields poorly defined and heterogeneous products with suboptimal in vivo performance. Here, we describe a first-in-human PET study on patients with HER2-positive breast cancer evaluating the safety, biodistribution, and dosimetry of Zr-site-specific (ss)-pertuzumab PET, a site-specifically labeled radioimmunoconjugate designed to circumvent the limitations of random stochastic lysine labeling. Six patients with HER2-positive metastatic breast cancer were enrolled in a prospective clinical trial. Pertuzumab was site-specifically modified with desferrioxamine (DFO) via a novel chemoenzymatic strategy and subsequently labeled with Zr. Patients were administered 74 MBq of Zr-ss-pertuzumab in 20 mg of total antibody intravenously and underwent PET/CT at 1 d, 3-4 d, and 5-8 d after injection. PET imaging, whole-body probe counts, and blood draws were performed to assess the pharmacokinetics, biodistribution, and dosimetry. Zr-ss-pertuzumab PET/CT was used to assess HER2 status and heterogeneity to guide biopsy and decide the next line of treatment at progression. The radioimmunoconjugate was able to detect known sites of malignancy, suggesting that these tumor lesions were HER2-positive. The optimal imaging time point was 5-8 d after administration, and no toxicities were observed. Dosimetry estimates from OLINDA showed that the organs receiving the highest doses (mean ± SD) were kidney (1.8 ± 0.5 mGy/MBq), liver (1.7 ± 0.3 mGy/MBq), and heart wall (1.2 ± 0.1 mGy/MBq). The average effective dose for Zr-ss-pertuzumab was 0.54 ± 0.03 mSv/MBq, which was comparable to both stochastically lysine-labeled Zr-DFO-pertuzumab and Zr-DFO-trastuzumab. One patient underwent PET/CT with both Zr-ss-pertuzumab and Zr-DFO-pertuzumab 1 mo apart, with Zr-ss-pertuzumab demonstrating improved lesion detection and higher tracer avidity. This study demonstrated the safety, dosimetry, and potential clinical applications of Zr-ss-pertuzumab PET/CT. Zr-ss-pertuzumab may detect more lesions than Zr-DFO-pertuzumab. Potential clinical applications include real-time evaluation of HER2 status to guide biopsy and assist in treatment decisions.
Topics: Humans; Female; Breast Neoplasms; Lysine; Positron Emission Tomography Computed Tomography; Prospective Studies; Tissue Distribution; Antibodies, Monoclonal, Humanized; Immunoconjugates
PubMed: 38272704
DOI: 10.2967/jnumed.123.266392 -
European Journal of Cancer (Oxford,... Mar 2024Biliary tract cancers (BTCs) encompass a heterogeneous group of rare tumors, including intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA),... (Review)
Review
Biliary tract cancers (BTCs) encompass a heterogeneous group of rare tumors, including intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), gallbladder cancer (GBC) and ampullary cancer (AC). The present first-line palliative treatment regimen comprises gemcitabine and cisplatin in combination with immunotherapy based on two randomized controlled studies. Despite the thorough investigation of these palliative treatments, long-term survival remains low. Moving beyond conventional chemotherapies and immunotherapies, the realm of precision medicine has demonstrated remarkable efficacy in malignancies such as breast and gastric cancers, characterized by notable HER2 overexpression rates. In the context of biliary tract cancer, significant HER2 alterations are observed, particularly within eCCA and GBC, heightening the interest in precision medicine. Various anti-HER2 therapies, including trastuzumab, pertuzumab, trastuzumab-deruxtecan, zanidatamab and neratinib, have undergone investigation. The objective of this review is to summarize the current evidence and outline future directions of targeted HER2 treatment therapy in patients with biliary tract tumors, specially extrahepatic cholangiocarcinoma and gallbladder cancer.
Topics: Humans; Gallbladder Neoplasms; Ampulla of Vater; Common Bile Duct Neoplasms; Cholangiocarcinoma; Biliary Tract Neoplasms; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Trastuzumab; Antibodies, Bispecific
PubMed: 38266541
DOI: 10.1016/j.ejca.2024.113564 -
Frontiers in Oncology 2023The surgical treatment of the primary site has been a subject of controversy in patients with de novo metastatic breast cancer. In recent years, studies using large...
OBJECTIVE
The surgical treatment of the primary site has been a subject of controversy in patients with de novo metastatic breast cancer. In recent years, studies using large databases and retrospective analyses have provided evidence of the survival benefits of localized surgery for these patients. However, due to the improved prognosis associated with novel antitumor agents and the widespread use of anti-HER2 therapy, it is important to investigate the role of primary site surgery in the context of new drug treatments for stage IV HER2-positive breast cancer.
METHODS
This retrospective analysis included patients with metastatic breast cancer at diagnosis who were consulted at the First Hospital of Jilin University between 2016 and 2022. We compared the patients' clinical and pathological characteristics, treatment regimens, and prognosis between the surgery and non-surgery groups.
RESULTS
A total of 96 patients with stage IV HER2-positive breast cancer were included in the study, with 24 patients (25%) undergoing surgery for the primary lesion. Patients with lower Eastern Cooperative Oncology Group (ECOG) scores, earlier T-stage, metastases confined to one organ/site, and fewer metastases were more likely to undergo surgery. Patients in the surgical group had longer progression-free survival (median 25.7 . 15.9 months, p=0.073) and overall survival (median 79.1 . 48 months, p=0.073) compared to patients in the non-surgical group, however, there was no statistical difference. Univariate and multivariate Cox regression analysis suggested that the choice of first-line targeted therapy regimens rather than surgical treatment influenced the patients' prognoses. In the subgroup of patients receiving first-line targeted therapy with trastuzumab plus pertuzumab, the decision to undergo surgery on the primary site did not have a statistically significant effect on prognosis.
CONCLUSION
Primary site surgery does not improve the prognosis of de novo stage IV HER2-positive breast cancer. In the era of anti-HER2 therapy, primary surgery is not recommended, except in exceptional circumstances.
PubMed: 38264738
DOI: 10.3389/fonc.2023.1308854 -
Cancer Science Mar 2024Molecular testing to determine optimal therapies is essential for managing patients with colorectal cancer (CRC). In October 2022, the Japanese Society of Medical...
Molecular testing to determine optimal therapies is essential for managing patients with colorectal cancer (CRC). In October 2022, the Japanese Society of Medical Oncology published the 5th edition of the Molecular Testing Guideline for Colorectal Cancer Treatment. In this guideline, in patients with unresectable CRC, RAS/BRAF V600E mutational and mismatch repair tests are strongly recommended prior to first-line chemotherapy to select optimal first- and second-line therapies. In addition, HER2 testing is strongly recommended because the pertuzumab plus trastuzumab combination is insured after fluoropyrimidine, oxaliplatin, and irinotecan in Japan. Circulating tumor DNA (ctDNA)-based RAS testing is also strongly recommended to assess the indications for the readministration of anti-EGFR antibodies. Both tissue- and ctDNA-based comprehensive genomic profiling tests are strongly recommended to assess the indications for targeted molecular drugs, although they are currently insured in patients with disease progression after receiving standard chemotherapy (or in whom disease progression is expected in the near future). Mutational and mismatch repair testing is strongly recommended for patients with resectable CRC, and RAS/BRAF V600E mutation testing is recommended to estimate the risk of recurrence. Mutational and mismatch repair and BRAF testing are also strongly recommended for screening for Lynch syndrome. Circulating tumor DNA-based minimal residual disease (MRD) testing is strongly recommended for estimating the risk of recurrence based on clinical evidence, although MRD testing was not approved in Japan at the time of the publication of this guideline.
Topics: Humans; Japan; Circulating Tumor DNA; Proto-Oncogene Proteins B-raf; Colorectal Neoplasms; Mutation; Molecular Diagnostic Techniques; Disease Progression; Medical Oncology
PubMed: 38263580
DOI: 10.1111/cas.16039 -
Biomedicines Jan 2024Pertuzumab and trastuzumab have been shown to improve the outcomes of patients with metastatic breast cancer, with a rate of left ventricular dysfunction of...
Pertuzumab and trastuzumab have been shown to improve the outcomes of patients with metastatic breast cancer, with a rate of left ventricular dysfunction of approximately 6%. We report the case of a postmenopausal woman who presented with Takotsubo syndrome during maintenance therapy with pertuzumab and trastuzumab, in association with fulvestrant (an anti-estrogen) and denosumab. After normalization of cardiac function, therapy with pertuzumab and trastuzumab was resumed in the absence of new cardiac toxicity. We report the first clinical case of Takotsubo syndrome during double anti-HER2 blockade in association with an antiestrogen. Furthermore, we show how anti-HER2 therapy can be safely resumed after the detection of Takotsubo syndrome.
PubMed: 38255284
DOI: 10.3390/biomedicines12010179 -
Biomolecules Dec 2023Intact Transition Epitope Mapping-One-step Non-covalent force Exploitation (ITEM-ONE) analysis reveals an assembled epitope on the surface of Pertuzumab, which is...
Intact Transition Epitope Mapping-One-step Non-covalent force Exploitation (ITEM-ONE) analysis reveals an assembled epitope on the surface of Pertuzumab, which is recognized by the anti-Pertuzumab affimer 00557_709097. It encompasses amino acid residues NSGGSIYNQRFKGR, which are part of CDR2, as well as residues FTLSVDR, which are located on the variable region of Pertuzumab's heavy chain and together form a surface area of 1381.46 Å. Despite not being part of Pertuzumab's CDR2, the partial sequence FTLSVDR marks a unique proteotypic Pertuzumab peptide. Binding between intact Pertuzumab and the anti-Pertuzumab affimer was further investigated using the Intact Transition Epitope Mapping-Thermodynamic Weak-force Order (ITEM-TWO) approach. Quantitative analysis of the complex dissociation reaction in the gas phase afforded a quasi-equilibrium constant (KD m0g#) of 3.07 × 10. The experimentally determined apparent enthalpy (ΔHm0g#) and apparent free energy (ΔGm0g#) of the complex dissociation reaction indicate that the opposite reaction-complex formation-is spontaneous at room temperature. Due to strong binding to Pertuzumab and because of recognizing Pertuzumab's unique partial amino acid sequences, the anti-Pertuzumab affimer 00557_709097 is considered excellently suitable for implementation in Pertuzumab quantitation assays as well as for the accurate therapeutic drug monitoring of Pertuzumab in biological fluids.
Topics: Epitope Mapping; Epitopes; Antibodies, Monoclonal, Humanized; Thermodynamics
PubMed: 38254624
DOI: 10.3390/biom14010024