The sarcomatoid variant of anaplastic large cell lymphoma is one of the rarest histologic variants of this neoplasm. Due to its sarcomatoid features, it is frequently misdiagnosed as a poorly ...differentiated sarcoma, anaplastic carcinoma, or melanoma. We report the case of a 92-year-old woman with a sarcomatoid anaplastic large cell lymphoma mimicking a primary breast neoplasm. The patient presented with a rapidly enlarging lump in the left breast and nodules in the right axilla. The immunohistochemical profile showed reactivity for leukocyte common antigen, UCHL-1, vimentin, and CD30, but immunoexpression of anaplastic lymphoma kinase was lacking. Anaplastic large cell lymphomas are lymphoid neoplasms of T-cell/null-cell lineage that consistently express the activation marker CD30 and usually carry a gene rearrangement of the anaplastic lymphoma kinase gene. To the best of our knowledge, this is the first reported case of sarcomatoid anaplastic large cell lymphoma presenting as a primary breast neoplasm in which anaplastic lymphoma kinase expression was assessed.
Amplification of and oncogenic mutations in
, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and ...internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody-drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with
-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy. SIGNIFICANCE: T-DM1 is clinically effective in lung cancers with amplification of or mutations in
. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.
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AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary ...tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for
and
somatic mutations. Metastases were enriched in
, and
mutations;
and
amplifications; and
deletions. An increase in clonality was observed in driver genes such as
and
. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with
and/or
mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR
/HER2
cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC. SIGNIFICANCE: The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic samples from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients.
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P53 is considered one of the most important tumor suppressor genes and is mutated in up to 50% of all neoplasms. Well-differentiated thyroid carcinomas (WDTCs) only infrequently harbor p53 mutations. ...In contrast, these genetic alterations have been described in approximately 85% of anaplastic thyroid carcinomas and are considered a fundamental event in the malignant progression of WDTCs. However, alternative mechanisms to overcome p53 tumor suppressing properties in WDTCs and anaplastic carcinomas (ACs) have not been clarified to date. p63, a p53-homologue, has been recently characterized. In contrast to p53, p63 gene encodes six isoforms, three with transactivating and three with dominant negative (ΔN-p63) activities on p53 reporter genes. We hypothesized that overexpression of ΔN-p63 isoforms might constitute an alternative mechanism to overcome p53 tumor suppressing properties in WDTCs and ACs lacking p53 alterations. We semiquantitatively evaluated p53 and p63 immunoexpression in 12 papillary carcinomas (PC) and 11 anaplastic carcinomas. Only nuclear expression was considered specific. All PCs lacked p53 expression; at variance, nine ACs showed p53 immunoreactivity (+: 1 case; ++: 6 cases; +++: 2 cases). In PCs, p63 expression was restricted to scattered neoplastic cells juxtaposed to the basement membrane of papillary projections and to foci of squamous metaplasia. In ACs, p63 expression was observed in three cases, one of which lacked concurrent p53 immunoexpression. Our results do not support the hypothesis that p63 might constitute an alternative mechanism to overcome p53 tumor suppressing properties in thyroid neoplasms.
Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We ...prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74-2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52-0.76; P < 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.
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