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Anthracycline-based and gemcitabine-based chemotherapy in the adjuvant setting for stage I uterine leiomyosarcoma: a retrospective analysis at two reference centers.

ABSTRACT: Background:Radically resected early uterine leiomyosarcoma (eULMS) is still marked by a poor prognosis. Adjuvant strategies investigated up to now have not been corroborated by controlled studies. We retrospectively reviewed the clinical outcome of eULMS patients treated with adjuvant anthracycline-based or gemcitabine-based chemotherapy at two Italian reference centers. Methods:In this explorative, retrospective, cohort analysis, we included all the consecutive patients with radically resected eULMS treated at two centers between 1997 and 2017. Results:A total of 109 consecutive patients were included. Sixty-six (60%) received an anthracycline-based regimen, whereas 43 (40%) received a gemcitabine-based regimen. Median disease-free survival (DFS) was 41.3 months with anthracycline-based regimens compared to 20.9 months with gemcitabine-based regimens (HR: 0.49; 95% CI: 0.30-0.80; P?=?0.004). In the multivariable model, anthracycline-based regimens were independently associated with a better DFS. No difference in terms of overall survival was observed. Conclusions:DFS was not the same by using an anthracycline-based or a gemcitabine-based adjuvant chemotherapy for patients with radically resected eULMS. The results of our study are in line with recent prospective controlled evidence in limb and superficial trunk soft tissue sarcomas. The role of anthracycline-based adjuvant chemotherapy should still be viewed as a research issue in eULMS.

SUBMITTER: Fuca G

PROVIDER: S-EPMC7456084 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Anthracycline-based and gemcitabine-based chemotherapy in the adjuvant setting for stage I uterine leiomyosarcoma: a retrospective analysis at two reference centers.

Fucà Giovanni G Fabbroni Chiara C Mancari Rosanna R Manglaviti Sara S Bogani Giorgio G Fumagalli Elena E Bertulli Rossella R Morosi Carlo C Collini Paola P Raspagliesi Francesco F Colombo Nicoletta N Casali Paolo G PG Sanfilippo Roberta R

Clinical sarcoma research 20200828

<h4>Background</h4>Radically resected early uterine leiomyosarcoma (eULMS) is still marked by a poor prognosis. Adjuvant strategies investigated up to now have not been corroborated by controlled studies. We retrospectively reviewed the clinical outcome of eULMS patients treated with adjuvant anthracycline-based or gemcitabine-based chemotherapy at two Italian reference centers.<h4>Methods</h4>In this explorative, retrospective, cohort analysis, we included all the consecutive patients with radi ...[more]

PMID: 32874547

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Project description:The morphologic assessment of uterine leiomyosarcoma (LMS) may be challenging, and diagnostic immunohistochemical (IHC) analysis is currently lacking. We evaluated the genomic landscape of 167 uterine LMS by targeted next-generation sequencing (NGS) to identify common genomic alterations. IHC analyses corresponding to these genomic landmarks were applied to a test cohort of 16 uterine LMS, 6 smooth muscle tumors of uncertain malignant potential (STUMP), and 6 leiomyomas with NGS data and a validation cohort of 8 uterine LMS, 12 STUMP, 21 leiomyomas and leiomyoma variants, 7 low-grade endometrial stromal sarcomas, and 2 diagnostically challenging uterine smooth muscle tumors. IHC results were individually interpreted by 3 pathologists blinded to NGS data. Overall, 94% of LMS showed ≥1 genomic alteration involving TP53, RB1, ATRX, PTEN, CDKN2A, or MDM2, with 80% showing alterations in ≥2 of these genes. In the test cohort, an initial panel of p53, Rb, PTEN, and ATRX was applied, followed by a panel of DAXX, MTAP, and MDM2 in cases without abnormalities. Abnormal p53, Rb, PTEN, and ATRX IHC expression was seen in 75%, 88%, 44%, and 38% of LMS, respectively, in the test cohort. Two or more abnormal IHC results among these markers were seen in 81% of LMS. STUMPs demonstrated only 1 IHC abnormality involving these markers. No IHC abnormalities were seen in leiomyomas. In the validation cohort, abnormal p53, Rb, and PTEN IHC results were seen in LMS, whereas rare STUMP or leiomyomas with bizarre nuclei showed IHC abnormalities involving only 1 of the markers. Abnormalities in ≥2 markers were present in both diagnostically challenging smooth muscle tumors, confirming LMS. Concordance was excellent among pathologists in the interpretation of IHC (κ = 0.97) and between IHC and NGS results (κ = 0.941). Uterine LMS exhibit genomic landmark alterations for which IHC surrogates exist, and a diagnostic algorithm involving molecular-based IHC may aid in the evaluation of unusual uterine smooth muscle tumors.

Project description:Triple-negative breast cancer (TNBC) constitutes a heterogeneous breast cancer subgroup with poor prognosis; survival rates are likely to be lower with TNBC compared to other breast cancer subgroups. For this disease, systemic adjuvant chemotherapy regimens often yield suboptimal clinical results. To improve treatment regimens in TNBC, identification of molecular biomarkers may help to select patients for individualized adjuvant therapy. Evidence has accumulated that determination of the methylation status of the PITX2 gene provides a predictive value in various breast cancer subgroups, either treated with endocrine-based therapy or anthracycline-containing chemotherapy. To further explore the validity of this novel predictive candidate biomarker, in the present exploratory retrospective study, determination of the PITX2 DNA-methylation status was assessed for non-metastatic TNBC patients treated with adjuvant anthracycline-based chemotherapy by molecular analysis of breast cancer tissues. The PITX2 DNA-methylation status was determined in fresh-frozen tumor tissue specimens (n=56) by methylation-specific qRT-PCR (qMSP) and the data related to disease-free and overall survival, applying an optimized DNA-methylation score of 6.35%. For non-metastatic TNBC patients treated with adjuvant systemic anthracycline-based chemotherapy, a low PITX2 DNA-methylation status (<6.35) defines TNBC patients with poor disease-free and overall survival. Univariate and multivariate analyses demonstrate the statistically independent predictive value of PITX2 DNA-methylation. For non-metastatic TNBC patients, selective determination of the PITX2 DNA-methylation status may serve as a cancer biomarker for predicting response to anthracycline-based adjuvant chemotherapy. The assay based on methylation of the PIXT2 gene can be applied to frozen and routinely available formalin-fixed, paraffin-embedded (FFPE) breast cancer tumor tissues that will not only define those TNBC patients who may benefit from anthracycline-based chemotherapy but also those who should be spared the necessity of such potentially toxic treatment. Such patients should be allocated to alternative treatment options.

Project description:BackgroundThe aim of the present study was to investigate the efficacy of adjuvant dose-dense sequential chemotherapy with epirubicin, paclitaxel, and CMF in subgroups of patients with high-risk operable breast cancer, according to tumor subtypes defined by immunohistochemistry (IHC).Materials and methodsFormalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 1,039 patients participating in two adjuvant dose-dense sequential chemotherapy phase III trials were centrally assessed in tissue micro-arrays by IHC for 6 biological markers, that is, estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki67, cytokeratin 5 (CK5), and EGFR. The majority of the cases were further evaluated for HER2 amplification by FISH. Patients were classified as: luminal A (ER/PgR-positive, HER2-negative, Ki67(low)); luminal B (ER/PgR-positive, HER2-negative, Ki67(high)); luminal-HER2 (ER/PgR-positive, HER2-positive); HER2-enriched (ER-negative, PgR-negative, HER2-positive); triple-negative (TNBC) (ER-negative, PgR-negative, HER2-negative); and basal core phenotype (BCP) (TNBC, CK5-positive and/or EGFR-positive).ResultsAfter a median follow-up time of 105.4 months the 5-year disease-free survival (DFS) and overall survival (OS) rates were 73.1% and 86.1%, respectively. Among patients with HER2-enriched tumors there was a significant benefit in both DFS and OS (log-rank test; p = 0.021 and p = 0.006, respectively) for those treated with paclitaxel. The subtype classification was found to be of both predictive and prognostic value. Setting luminal A as the referent category, the adjusted for prognostic factors HR for relapse for patients with TNBC was 1.91 (95% CI: 1.31-2.80, Wald's p = 0.001) and for death 2.53 (95% CI: 1.62-3.60, p<0.001). Site of and time to first relapse differed according to subtype. Locoregional relapses and brain metastases were more frequent in patients with TNBC, while liver metastases were more often seen in patients with HER2-enriched tumors.ConclusionsTriple-negative phenotype is of adverse prognostic value for DFS and OS in patients treated with adjuvant dose-dense sequential chemotherapy. In the pre-trastuzumab era, the HER2-enriched subtype predicts favorable outcome following paclitaxel-containing treatment.

Dataset Information

Anthracycline-based and gemcitabine-based chemotherapy in the adjuvant setting for stage I uterine leiomyosarcoma: a retrospective analysis at two reference centers.

Publications

Anthracycline-based and gemcitabine-based chemotherapy in the adjuvant setting for stage I uterine leiomyosarcoma: a retrospective analysis at two reference centers.

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