Second-Line Treatment of HER2-Positive Salivary Gland Tumor: Ado-Trastuzumab Emtansine (T-DM1) after Progression on Trastuzumab

Correa, Tatiana; Matos, Gustavo Duarte Ramos; Segura, M. Soriano; Anjos, Carlos Henrique dos

doi:10.1159/000488669

Cited by 27 publications

(24 citation statements)

References 16 publications

(25 reference statements)

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“…Several characteristic findings in SDC have been exploited in the development of targeted therapy including the overexpression of HER2/ neu ( ERBB2 ) found in 37% of SDC ERBB2 gene amplification is found in 72% of overexpressing cases . Clinical responses to HER2‐targeted agents, alone or in combination with chemotherapy, have been reported in individual patients with HER2 + SDC . Additionally, androgen receptor (AR) expression which is a defining feature of SDC, is found in up to 98% of cases .…”

Section: Introductionmentioning

confidence: 99%

“…2 Clinical responses to HER2-targeted agents, alone or in combination with chemotherapy, have been reported in individual patients with HER2 + SDC. [4][5][6][7] Additionally, androgen receptor (AR) expression which is a defining feature of SDC, is found in up to 98% of cases. 1,8 Some argue that AR-negative SDC is virtually non-existent, as many such cases are either AR-positive after repeat immunohistochemistry (IHC) testing, or are subsequently reclassified as a different entity with morphologic similarities to SDC.…”

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confidence: 99%

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Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling

et al. 2019

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Salivary duct carcinoma (SDC) is a rare, aggressive salivary gland malignancy, which often presents at an advanced stage. A proportion of SDC are characterized by HER2 amplification and/or overexpression of androgen receptor (AR), which could be targeted in a subset of patients, but the presence of AR splice variant‐7 (AR‐V7) in some SDC cases could result in resistance to anti‐androgen therapy. We evaluated a cohort of 28 cases of SDC for potentially targetable biomarkers and pathways using immunohistochemistry (IHC) and next‐generation sequencing (DNA and RNA) assays. Pathogenic genetic aberrations were found in all but 1 case and affected TP53 (n = 19), HRAS (n = 7), PIK3CA, ERBB2 (HER2), and NF1 (n = 5 each); KMT2C (MLL3) and PTEN (n = 3 each); BRAF (p.V600E), KDM5C and NOTCH1 (n = 2 each). Androgen receptor was expressed in all cases and 13 of 27 harbored the AR‐V7 splice variant (including a case without any other detectable genetic alteration). HER2 IHC was expressed in 11 of 28 cases. The majority of SDC cases had no biomarkers predictive of immunotherapy response: 5 cases exhibited low (1%‐8%) programmed death ligand 1 (PD‐L1) expression in tumor cells, 2 cases exhibited elevated TMB, and no samples exhibited microsatellite instability. Notably, the pre‐treatment biopsies from 2 patients with metastatic disease, who demonstrated clinical responses to anti‐androgen therapy, showed AR expression and no AR splice variants. We conclude that comprehensive molecular profiling of SDCs can guide the selection of patients for targeted therapies involving AR, HER2, PD‐L1, mitogen‐activated protein kinase, and PIK3CA pathways.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling

et al. 2019

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“…In the case of ERBB2 (HER2) gene amplification (29.4–46.4%), patients can be treated with docetaxel plus trastuzumab, showing an overall response rate of 70.2% and median PFS of 8.9 months . Double HER2 blockade with docetaxel–trastuzumab–pertuzumab or in second‐line with the antibody‐drug conjugate trastuzumab‐emtansine also showed promising results . Finally, the high frequency (61.3%) of oncogenic driver gene mutations offers personalized treatment options …”

Section: Introductionmentioning

confidence: 99%

“…8 Double HER2 blockade with docetaxel-trastuzumab-pertuzumab or in second-line with the antibody-drug conjugate trastuzumab-emtansine also showed promising results. [9][10][11] Finally, the high frequency (61.3%) of oncogenic driver gene mutations offers personalized treatment options. 12 Despite the efficacy of ADT in the palliative and adjuvant setting, ADT is only effective in a subgroup of patients and little is known about primary resistance mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Prediction of clinical benefit from androgen deprivation therapy in salivary duct carcinoma patients

Boxtel¹,

Verhaegh

Grunsven

et al. 2019

Intl Journal of Cancer

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Androgen deprivation therapy (ADT) is first‐line palliative treatment in androgen receptor‐positive (AR+) salivary duct carcinoma (SDC), and response rates are 17.6–50.0%. We investigated potential primary ADT resistance mechanisms for their predictive value of clinical benefit from ADT in a cohort of recurrent/metastatic SDC patients receiving palliative ADT (n = 30). We examined mRNA expression of androgen receptor (AR), AR splice variant‐7, intratumoral androgen synthesis enzyme‐encoding genes AKR1C3, CYP17A1, SRD5A1 and SRD5A2, AR protein expression, ERBB2 (HER2) gene amplification and DNA mutations in driver genes. Furthermore, functional AR pathway activity was determined using a previously reported Bayesian model which infers pathway activity from AR target gene expression levels. SRD5A1 expression levels and AR pathway activity scores were significantly higher in patients with clinical benefit from ADT compared to those without benefit. Survival analysis showed a trend toward a longer median progression‐free survival for patients with high SRD5A1 expression levels and high AR pathway activity scores. The AR pathway activity analysis, and not SRD5A1 expression, also showed a trend toward better disease‐free survival in an independent cohort of locally advanced SDC patients receiving adjuvant ADT (n = 14) after surgical tumor resection, and in most cases a neck dissection (13/14 patients) and postoperative radiotherapy (13/14 patients). In conclusion, we are the first to describe that AR pathway activity may predict clinical benefit from ADT in SDC patients, but validation in a prospective study is needed.

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“…In addition, potential targetable amplifications were detected, i.e. high level amplifications of ERBB2 [45][46][47] (colorectal carcinoma, salivary duct carcinoma, prostate cancer, ovarian cancer), MET [48,49] (lung cancer, esophageal carcinoma), and FGFR1 [50] (lung cancer, colorectal carcinoma).…”

Section: Analysis In Routine Diagnosticsmentioning

confidence: 99%

Comprehensive routine diagnostic screening to identify predictive mutations, gene amplifications, and microsatellite instability in FFPE tumor material

et al. 2020

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Background: Sensitive and reliable molecular diagnostics is needed to guide therapeutic decisions for cancer patients. Although less material becomes available for testing, genetic markers are rapidly expanding. Simultaneous detection of predictive markers, including mutations, gene amplifications and MSI, will save valuable material, time and costs. Methods: Using a single-molecule molecular inversion probe (smMIP)-based targeted next-generation sequencing (NGS) approach, we developed an NGS panel allowing detection of predictive mutations in 33 genes, gene amplifications of 13 genes and microsatellite instability (MSI) by the evaluation of 55 microsatellite markers. The panel was designed to target all clinically relevant single and multiple nucleotide mutations in routinely available lung cancer, colorectal cancer, melanoma, and gastro-intestinal stromal tumor samples, but is useful for a broader set of tumor types. Results: The smMIP-based NGS panel was successfully validated and cutoff values were established for reliable gene amplification analysis (i.e. relative coverage ≥3) and MSI detection (≥30% unstable loci). After validation, 728 routine diagnostic tumor samples including a broad range of tumor types were sequenced with sufficient sensitivity (2.4% dropout), including samples with low DNA input (< 10 ng; 88% successful), low tumor purity (5-10%; 77% successful), and cytological material (90% successful). 75% of these tumor samples showed ≥1 (likely) pathogenic mutation, including targetable mutations (e.g. EGFR, BRAF, MET, ERBB2, KIT, PDGFRA). Amplifications were observed in 5.5% of the samples, comprising clinically relevant amplifications (e.g. MET, ERBB2, FGFR1). 1.5% of the tumor samples were classified as MSIhigh, including both MSI-prone and non-MSI-prone tumors.

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Second-Line Treatment of HER2-Positive Salivary Gland Tumor: Ado-Trastuzumab Emtansine (T-DM1) after Progression on Trastuzumab

Cited by 27 publications

References 16 publications

Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling

Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling

Prediction of clinical benefit from androgen deprivation therapy in salivary duct carcinoma patients

Comprehensive routine diagnostic screening to identify predictive mutations, gene amplifications, and microsatellite instability in FFPE tumor material

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