Clinicopathological Subtypes Research Articles

The specific DNA methylation landscape in focal cortical dysplasia ILAE type 3D

Focal Cortical Dysplasia (FCD) is a frequent cause of drug-resistant focal epilepsy in children and young adults. The international FCD classifications of 2011 and 2022 have identified several clinico-pathological subtypes, either occurring isolated, i.e., FCD ILAE Type 1 or 2, or in association with a principal cortical lesion, i.e., FCD Type 3. Here, we addressed the DNA methylation signature of a previously described new subtype of FCD 3D occurring in the occipital lobe of very young children and microscopically defined by neuronal cell loss in cortical layer 4. We studied the DNA methylation profile using 850 K BeadChip arrays in a retrospective cohort of 104 patients with FCD 1 A, 2 A, 2B, 3D, TLE without FCD, and 16 postmortem specimens without neurological disorders as controls, operated in China or Germany. DNA was extracted from formalin-fixed paraffin-embedded tissue blocks with microscopically confirmed lesions, and DNA methylation profiles were bioinformatically analyzed with a recently developed deep learning algorithm. Our results revealed a distinct position of FCD 3D in the DNA methylation map of common FCD subtypes, also different from non-FCD epilepsy surgery controls or non-epileptic postmortem controls. Within the FCD 3D cohort, the DNA methylation signature separated three histopathology subtypes, i.e., glial scarring around porencephalic cysts, loss of layer 4, and Rasmussen encephalitis. Differential methylation in FCD 3D with loss of layer 4 mapped explicitly to biological pathways related to neurodegeneration, biogenesis of the extracellular matrix (ECM) components, axon guidance, and regulation of the actin cytoskeleton. Our data suggest that DNA methylation signatures in cortical malformations are not only of diagnostic value but also phenotypically relevant, providing the molecular underpinnings of structural and histopathological features associated with epilepsy. Further studies will be necessary to confirm these results and clarify their functional relevance and epileptogenic potential in these difficult-to-treat children.

Immunohistochemical expression of Hairy and Enhancer of Split 1 (HES1) protein in breast carcinoma

Background Hairy and Enhancer of Split 1 (HES1) is a transcription factor involved in cell differentiation, proliferation, and in various cancer progression. Recently, HES1 was addressed as a potential biomarker that induces stem cell features in breast cancer and stimulates epithelial-mesenchymal transition in triple-negative breast cancer (TNBC). Aim This study aimed to assess HES1 immunohistochemical (IHC) expression in invasive breast carcinoma and correlate it with the clinicopathological variables and different molecular subtypes of the cases. Patients and methods IHC was conducted on 76 paraffin blocks with an anti-HES1 monoclonal antibody, and a final IHC score was calculated based on staining intensity and percentage of positively stained cells. A final IHC of greater than or equal to 4 was considered an HES1 positive expression. Results HES1 expression was positive in 18 (23.7%) cases and was significantly associated with breast cancer HER2-enriched molecular subtype, followed by triple-negative breast cancer (P<0.05). HES1 expression was also significantly associated with estrogen and progesterone receptor negativity and HER2 overexpression (P<0.05). Positive HES1 expression was associated with high tumor grade, advanced stage, high Ki-67 proliferation index, and presence of tumor vascular emboli, although it did not reach statistical significance (P>0.05). Conclusion Our study demonstrated that the HES1 protein showed a significantly higher expression in nonluminal breast cancer subtypes. In addition, it could have a potential role in the growth and spread of breast cancer cells. These findings suggest that HES1 is a possible promising target for therapeutic interventions.

Clinicopathological characteristics and outcome of very young breast cancer patients at a referral center in Iran.

e12568 Background: Although breast cancer (BC) is the most common type of cancer in women worldwide, in women younger than 35 years old is uncommon and only accounts for 2% of breast cancer diagnosed in western countries. However, there is insufficient data on breast cancer in women younger than 35 years old in Iran. The aim of this study was to assess clinicopathological parameters in these very young breast cancer patients. Methods: In this retrospective cohort study, we have collected the demographic, clinical and histopathological data of women younger than 35 years diagnosed with BC who presented to our tertiary center from 2011 to 2017. Patients were followed at least for four years and the diseases-free survival (DFS) and overall survival (OS) were assessed. Chi-square and multivariate regression tests were conducted to assess the association of mentioned variables. A P-value less than 0.05 was considered to be statistically significant. Results: A total of 334 women with Breast Cancer younger than 35 years old were included in this study, of which 219 patients were between 31 to 35. The most common histopathologic type was hormone receptor positive, HER2 negative 41.6 %. HER2 positive (regardless of hormone receptor status) and triple negative were 30.1% and 24.6% of cases respectively. Grade1 was reported in 5% of cases, grade 2 and 3 were 50.9 % and 43.6% respectively. 16.9% of patients were presented in stage I, 44.4% stage II, 30.5% stage III and 8.2% had de novo metastatic disease. Of 68 patients who received neoadjuvant chemotherapy, 29.4% had complete pathological response. Sixty five percent of 199 patients with hormone positive had received Luteinizing hormone-releasing hormone (LHRH) agonist, this type of treatment significantly improved 4-year OS regardless of HER2 expression. Mean follow up was 71.5±26.6 months, 4-year DFS and OS were 66% and 80% respectively. Four-year overall survival was analyzed by stage, it was 100% for stage I, 89% stage II, 79% stage III, and 11% stage IV. The four-year OS corresponding to the subtypes was as follows; HR+/HER2- (89.5%), HR+/HER2+ (76.9%), HR-/HER2+ (73.3%) and TNBC (75.4%). Conclusions: Breast cancer occurring in very young women constituted 9.5% of all breast cancer cases treated at Shohada Hospital, Iran, and this high rate shows a significant correlation with unpublished data by Health ministry in 2016-2017. This high percentage is an alarm not only in breast clinics but also in early detection of breast cancer. In according to other published data, clinicopathological subtypes in our center was similar to other papers. The associations of subtypes with stage and grade, were significant.

MammaPrint Index as a predictive biomarker for neoadjuvant chemotherapy response and outcome in patients with HR+HER2- breast cancer in NBRST.

521 Background: Hormone receptor positive (HR+), HER2- early stage breast cancer (ESBC) is a heterogeneous disease that has shown lower response to neoadjuvant chemotherapy (NCT) compared with other clinicopathologic subtypes. Genomic profiling may help inform neoadjuvant treatment decisions for ESBC by predicting likelihood of pathological complete response (pCR) or chemosensitivity. The 70-gene MammaPrint (MP) test classifies ESBC patients as having a Low or High Risk of distant metastasis. In the ISPY2 trial, further stratification of MP High Risk into High 1 (H1) or High 2 (H2) improved prediction of chemosensitivity, with significantly higher pCR rates in H2 vs. H1 tumors, particularly in response to immune therapy. Here we evaluate the utility of H1/H2 risk as a biomarker for chemosensitivity and 5 year distant-metastasis free survival (DMFS) in NCT treated patients from the Neoadjuvant Breast Registry Symphony Trial (NBRST). Methods: NBRST (NCT01479101) is an observational prospective study that included 1069 patients with ESBC who received neoadjuvant therapy. Patients with HR+HER2-, MP High Risk tumors who received NCT were included in this analysis (n = 327). Patients were further stratified into H1 (score ≤ 0, > -0.57) or H2 (score ≤ -0.57) groups. Differences in pCR between MP High Risk subcategories were assessed by two-sided proportional z-test. Differences in DMFS was evaluated by Kaplan Meier analysis and log-rank test. Results: MP classified 198 (61%) patients with H1 tumors and 129 (39%) patients with H2 tumors. Age, tumor stage, and lymph node status were comparable between both groups. However, there was a higher proportion of Grade 3 tumors in the H2 group. A significantly higher percentage of pCR was achieved in H2 tumors (30/129; 23%) vs. H1 tumors (12/198; 6.1%) (p < 0.001). Median follow-up was 5.3 years. The 5-year DMFS (% [95% CI]) was significantly worse for patients with H2 tumors (64.8 [55.9 – 75.1]), with most events occurring early ( < 3 years), compared with H1 tumors (77.1 [70.4 – 84.3]; p = 0.012). Patients with H1 tumors that achieved pCR had improved 5-year DMFS (81.8 [61.9 – 100]) compared to H1 tumors that did not achieve pCR (76.8 (69.9 – 84.4; p = 0.009). Patients with H2 tumors that had a pCR demonstrated significantly better 5-year DMFS (80.7 [65.3 – 99.8]) than patients with residual disease (60.2 [50.1 – 72.4]; p = 0.009). Conclusions: These data suggest MammaPrint predicts pCR in HR+HER2- BC patients, with H2 risk tumors exhibiting higher chemosensitivity than H1 tumors. Patients with either H1 or H2 tumors that achieved pCR had similar outcomes, which were significantly improved compared to those with residual disease. Notably, the worst outcomes were observed among patients with H2 risk and residual disease; it should be investigated whether addition of immune therapy to standard NCT would enhance the pCR rates in this patient population. Clinical trial information: NCT01479101 .

Clinical and genomic landscape of RAS pathway mutations in gynecologic cancers.

5611 Background: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic features, subtypes, co-mutations, and implications for therapy. Methods: Patients with gynecologic cancers who had next-generation sequencing at our institution between Feb 2010 and Aug 2022 were included. Clinical, histopathologic, and sequencing data were collected and analyzed. Overall survival was estimated using the Kaplan-Meier model. Results: Of the 3310 gynecologic cancer patients tested, 522 (15.8%) harbored a RAS mutation. For patients with mutation, median age was 56 (18-87) years, with cancer types including ovarian (43.5%), endometrial (43.4%), cervical (9.2%), and vulvovaginal (2.9%). Most patients (92.2%) had recurrence. The most common histology for each cancer included endometrioid in endometrial (60.8%), low grade serous in ovarian (34.4%), adenocarcinoma in cervical (60.4%), and melanoma in vulvovaginal (66.7%). Mucinous and clear cell differentiations were overrepresented (12.5% each). Median overall survival for all RAS-mutated patients was 69 months (95%CI 59-82), which was significantly better than in wildtype control of 56 months (95%CI 52-59, p = 0.022). Mutations observed were in KRAS (85.8%), NRAS (12.8%), and HRAS (3.3%). The most common mutant alleles for each were KRAS G12D (34.5%), KRAS G12V (31.7%), NRAS Q61R (34.3%), and HRAS G12S (17.6%). Of note, the incidence of KRAS G12C was 5.6% (0.8% overall). The most common co-mutations for RAS were PIK3CA (35.7%), PTEN (33.3%), TP53 (32.4%), and ARID1A (20.8%). This trend held for each mutation and cancer type. Of these, 64.7% were potentially actionable alterations, including 91.1% of PIK3CA, 83.7% of PTEN, and 50.0% of ARID1A. RAS pathway targeted therapies were administered to 62 patients (57 MEK, 5 BRAF, 5 KRAS G12C, 4 SHP2). The median overall survival for these patients was significantly improved (101 months, 95%CI 78-160) compared to RAS-mutated patients who did not receive a RAS pathway inhibitor (66 months, 95%CI 53-79, HR 0.7, p = 0.031). Of interest, novel KRAS G12C inhibitors showed durable benefit in 3 ovarian (high grade serous, low grade serous, clear cell) and 2 endometrial (mixed endometrioid, clear cell; mixed endometrioid, serous, mucinous) cancers with a clinical benefit rate of 100%, duration of objective response of 22 months, and ongoing responses at 5 and 16 months. Conclusions: Gynecologic cancers with RAS mutations have distinct histopathologic distribution and portend improved overall survival. The most commonly actionable co-mutations were PIK3CA, PTEN, and ARID1A, which may aid in combination therapy design. RAS pathway targeted therapy is associated with improved overall survival in this cohort and should be considered. [Table: see text]

Primary efficacy analyses of NeoRHEA, neoadjuvant biomarker research study of palbociclib combined with endocrine therapy in estrogen receptor positive/HER2 negative breast cancer.

522 Background: CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) are standard of care in the treatment of estrogen receptor (ER) positive, HER2-negative (ER+/HER2-) advanced breast cancer (BC). We tested palbociclib + ET as neoadjuvant therapy to identify baseline biomarkers of no response. Methods: NeoRHEA (NCT03065621) was a phase II, single arm trial evaluating 4 months of neoadjuvant palbociclib and ET in pre- or post-menopausal women with ER+/HER2- early BC. The primary objective was to identify biomarkers of no response by locally-assessed ultrasound (US) using RNA-seq on baseline (pretreatment) tumor biopsies. No response to treatment was defined as stable or progressive disease (SD or PD) at post-treatment US based on WHO criteria. Secondary endpoints included residual cancer burden (RCB) of 3 and absence of complete cell cycle arrest (CCCA) defined as Ki67 by immunohistochemistry (IHC) > 2.7% at surgery. We evaluated baseline clinicopathological characteristics, RNA-seq derived PAM50 subtypes and mRNA expression of ESR1, Ki67, CCNE1, RB1 and CDK6 single genes according to US response and CCCA. We also performed gene set enrichment analysis (GSEA) for 50 gene sets related to cancer hallmarks according to US response and CCCA. Results: 73 of 100 patients enrolled had baseline frozen tumors with enough cellularity and successful RNA-sequencing performed. Among the 73 patients, 70% were post-menopausal, 84% had cT2 and 70% cN0 tumors, 75% had invasive ductal carcinoma and 66% had histological grade 2 tumors. RNA-seq derived PAM50 subtypes were Luminal A, Luminal B, and non-Luminal in 56%, 36% and 8% of patients, respectively. Among the 73 patients, 31 (42%) had absence of US response (28 and 3 patients had stable and progressive disease by US, respectively) and 23 (31%) had RCB 3 tumors. Fifty-three of 73 patients had Ki67 by IHC available at surgery out of whom, 14 (26%) had absence of CCCA. Neither baseline clinicopathological characteristics nor PAM50 subtypes nor expression of ESR1, Ki67, CCNE1 and RB1 were associated with absence of US response or absence of CCCA. Interestingly, we observed higher baseline mRNA expression of CDK6 in patients with absence of US response (p = 0.039) or those with no CCCA (p = 0.004). We observed an enrichment in inflammatory / IFN-γ response and proliferation-related, G2M checkpoint gene sets in patients with US response (NES: 2.06, 2.30, 1.47; FDR: 7.04e-9, 5.48e-17, 0.0193 respectively) and an enrichment in early estrogen response gene set in patients with absence of US response (NES: -1.78, FDR: 0.0006). No signaling pathway was enriched in patients without CCCA. Conclusions: High pre-treatment mRNA expression of the CDK6 gene was associated with no US response or absence of CCCA in patients treated with neoadjuvant palbociclib and ET. Independent validation is needed. Clinical trial information: NCT03065621 .

Case report of a patient with unclassified tauopathy with molecular and neuropathological features of both progressive supranuclear palsy and corticobasal degeneration

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are distinct clinicopathological subtypes of frontotemporal lobar degeneration. They both have atypical parkinsonism, and they usually have distinct clinical features. The most common clinical presentation of PSP is Richardson syndrome, and the most common presentation of CBD is corticobasal syndrome. In this report, we describe a patient with a five-year history of Richardson syndrome and a family history of PSP in her mother and sister. A tau PET scan (18F-APN-1607) revealed low-to-moderate uptake in the substantia nigra, globus pallidus, thalamus and posterior cortical areas, including temporal, parietal and occipital cortices. Neuropathological evaluation revealed widespread neuronal and glial tau pathology in cortical and subcortical structures, including tufted astrocytes in the motor cortex, striatum and midbrain tegmentum. The subthalamic nucleus had mild-to-moderate neuronal loss with globose neurofibrillary tangles, consistent with PSP. On the other hand, there were also astrocytic plaques, a pathological hallmark of CBD, in the neocortex and striatum. To further characterize the mixed pathology, we applied two machine learning-based diagnostic pipelines. These models suggested diagnoses of PSP and CBD depending on the brain region – PSP in the motor cortex and superior frontal gyrus and CBD in caudate nucleus. Western blots of insoluble tau from motor cortex showed a banding pattern consistent with mixed features of PSP and CBD, whereas tau from the superior frontal gyrus showed a pattern consistent with CBD. Real-time quaking-induced conversion (RT-QuIC) using brain homogenates from the motor cortex and superior frontal gyrus showed ThT maxima consistent with PSP, while reaction kinetics were consistent with CBD. There were no pathogenic variants in MAPT with whole genome sequencing. We conclude that this patient had an unclassified tauopathy and features of both PSP and CBD. The different pathologies in specific brain regions suggests caution in diagnosis of tauopathies with limited sampling.

T-Cells Subsets in Castleman Disease: Analysis of 28 Cases Including Unicentric, Multicentric and HHV8-Related Clinical Forms.

Castleman disease (CD) is a rare lymphoproliferative disorder that includes various clinico-pathological subtypes. According to clinical course, CD is divided into unicentric CD (UCD) and multicentric CD (MCD). MCD is further distinguished based on the etiological driver in herpes virus-8-related MCD (that can occur in the setting of HIV); in MCD associated with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes); and idiopathic MCD (iMCD). The latter can also be divided in iMCD-TAFRO (thrombocytopenia, anasarca, fever, myelofibrosis, organomegaly) and iMCD not otherwise specified. To date, CD pathogenesis is still uncertain, but CD may represent the histological and clinical result of heterogeneous pathomechanisms. Transcriptome investigations in CD lymph nodes have documented the expression and up-regulation of different cytokines; furthermore, few recent studies have shown alterations of different T-cell subsets in CD patients, suggesting a possible role of the nodal microenvironment in CD development. On this basis, our study aimed to investigate the distribution of T-cell subsets in the clinico-pathological spectrum of CD. We evaluated the CD4/CD8 ratio and the number of T-regulatory (T-reg) FOXP3+ cells in 28 CD cases. In total, 32% of cases showed a decreased CD4/CD8 ratio due to increased CD8+ T-cells, including both UCD, iMCD, and HHV8+ MCD cases. The T-reg subset analysis revealed a statistically significant (p < 0.0001) lower mean number of FOXP3+ T-reg cells in CD cases when compared with non-specific reactive lymph nodes. We did not find statistically significant differences in T-reg numbers between the different CD subtypes. These findings may suggest that alterations in T-cell subpopulations that can lead to disruption of immune system control may contribute to the numerous changes in different cellular compartments that characterize CD.

Abstract P2-11-17: Prognostic value of Trop2 expression levels in non-metastatic triple-negative breast cancer and correlation with other biomarkers

Abstract Background: Since the development of anti Trop2 antibody-drug conjugates (ADC), Trop2 has been validated as a major therapeutic target for antibody-drug conjugates in metastatic triple-negative breast cancer (TNBC). However, very few data have been reported regarding the prognostic implication, or clinicopathological variables, associated with Trop2 expression levels in early TNBC. Our aim was to evaluate Trop2 expression and its prognostic value in a retrospective series of patients with non-metastatic TNBC and a long follow-up, characterized for Basal-like (BL) or molecular apocrine-like (MA) IHC profiles as well as TILs infiltrate, PDL1 expression and PIK3CA/PTEN mutations. Patients and methods: The analysis was performed in a series of 228 patients with non-metastatic TNBC treated in our center between 2002 and 2012 arrayed on 6 TMA. BL and MA profiles were defined as IHC CK5/6 and/or EGFR expression, and Androgen-receptor and FOXA1 IHC expression, respectively. Trop2 expression levels were tested for their association with baseline clinicopathological variables, and for Relapse-Free Survival (RFS) and Overall survival (OS). Trop2 IHC level of expression was evaluated using the ENZ-ABS380 mouse monoclonal antibody and the methodology described by Bardia et al. (Annals of Oncology, 2021) to quantify the membrane signal. First, we established a score grid, according to staining intensity (no labeling: 0; weak labeling: 1; moderate labeling: 2; strong labeling: 3). Then, for each sampled core, the percentage of labeled invasive tumor cells in each intensity was reported. The overall membrane expression was then calculated using the H-Score method (3 x % of cells with labeling intensity 3 + 2 x % of cells with intensity 2 + 1 x % of cells with intensity 1). The scores obtained ranged from 0 to 300. Results: Median age was 58.2 years (range 28.5-89.1). 43.9% of tumors were classified pT1 and 63.5% pN0. 83.8% of patients had ductal carcinomas. Histological grade 1-2 represented 22.7% of all tumors. A BL phenotype was observed in 68.1% of cases, and an MA profile in 39.4% of the cases. Adjuvant chemotherapy (ACT) was delivered in 74% of patients. We observed low Trop2 expression (H-Score &amp;lt; 100) in 12.3% of the cases (28/228 samples), moderate Trop2 expression (H-Score 100-200) in 28.9% of the cases (66/228 samples), and strong Trop2 expression (H-Score &amp;gt;200) in 58.8% of the cases (134/228 samples). We only identified 3 tumors without any Trop2 expression. Regarding baseline clinicopathological correlations, Trop2 levels were only found significantly associated with pT stage, pT1 tumors displaying more frequently high Trop2 scores compared to tumors &amp;gt;= pT2 (p=0.002). No significant correlation was found between Trop2 expression levels and HER2 levels (0 vs. 1+/2+), BL or MA status. With a median follow-up of 9.7 years, Trop2 levels were not associated with RFS nor OS in univariate analysis. In multivariate analysis, poor RFS was associated with classical variables in the early TNBC setting: tumors &amp;gt;=T2 stage (Hazard Ratio (HR) 2.13, p=0.02), N+ status (HR 3.51, p&amp;lt; 0.001), while high (&amp;gt;5%) TILs infiltration levels (HR 0.54, p=0.03) and adjuvant chemotherapy use (HR 0.49, p=0.007) were associated with improved RFS. Conclusions: Trop2 is expressed in nearly all early TNBC cases, and Trop2 levels of expression, while associated with T stage, did not impact survival in this population. These results are consistent with the ones reported in the metastatic setting in the ASCENT trial. Trop2 level of expression appearing homogeneous distributed in all the clinicopathological subtypes of TNBC, advocating for the evaluation of combined treatments with anti-Trop2 ADCs and dedicated targeted therapies in specific TNBC subgroups. Citation Format: William Jacot, Marie-Christine Chateau, Simon Thezenas, Séverine Guiu, Nelly Firmin, Florence Boissière-Michot. Prognostic value of Trop2 expression levels in non-metastatic triple-negative breast cancer and correlation with other biomarkers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-17.

The Association Between Age Groups with Clinicopathologic and Molecular Subtypes of Breast Cancer Patients

&lt;p align="center"&gt; &lt;/p&gt;&lt;p&gt;&lt;strong&gt;Introduction:&lt;/strong&gt; The increase in incidence proportion of breast cancer disease among young patients &amp;lt; 40 years old is exceeding that of older patients. The purpose of the research is to know the differences between clinicopathologic and molecular subtypes between patients &amp;lt; 40 years old and ≥ 40 years old.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods:&lt;/strong&gt; The conducting research on Medical Records (MR) was an observational analytic method with a cross-sectional design. The independent variable was age. Dependent variables were histopathological type, stage of disease, grade of tumor, and molecular subtype of cancer. Univariate analyses to describe the samples. The differences between those variables according to age groups were analyzed by a bivariate statistic and the odds ratio with a confident interval (CI) of 95% of each variable would be displayed by binary logistic regression statistic. &lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The most prevalent age of breast cancer patients was in the range of 50-59 years (47%), the mean age of 53.66 ± 0.977 years, in the range of 29 years old to 86 years old, and patients aged &amp;lt; 40 years was 12%. Ductal carcinoma type (89.7%), stage III tumor (40.2%), poor differentiation grade III (60.7%), and luminal A subtype (42.7%) were the most prevalent clinicopathologic and molecular subtypes. There weren’t differences between histopathologic type, stage of disease, and molecular subtype with age. The histopathologic grade was different from the age variable (p=0.015). Old age had worse histopathologic differentiation than young age (OR 2.166; 95% CI 0.973-4.823).&lt;/p&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; There weren’t significant differences between stage and molecular subtypes of breast cancer between age groups. There was poorer histopathologic differentiation in patients ≥ 40 years. &lt;p align="center"&gt; &lt;/p&gt;

Comparative Study on Clinicopathological Characteristics of Breast Cancer in Vietnam and Italy

Background: In Vietnam and Italy, breast cancer (BC) occurs in women more frequently than any other cancer. Vietnam has a substantially lower incidence of breast cancer than Italy, but a higher mortality rate. Most Vietnamese patients present to the hospital with severe tumors at the late stages of diagnosis. The purpose of this study was to compare clinicopathologic features, biomarkers, and subtypes of BC between Vietnamese women and Italian ones. Methods: The sample was collected from all Vietnamese patients undergoing surgery with the diagnosis of primary invasive breast carcinoma in Hue Central Hospital as well as Hue University Hospital in Vietnam during 1 year from April 2016 to April 2017, and from the same category of women in Sassari University Hospital, Italy during the year 2016. The study parameters in both groups consisted of age at diagnosis, tumor size, histologic grade, histologic type, axillary node status, stages of diagnosis, biomarkers (Estrogen Receptor - ER, Progesterone Receptor - PR, Ki-67 cell proliferation marker - Ki-67, Human epidermal growth factor receptor 2 - HER2), and molecular subtypes of BC. Results: 323 patients were collected in total (235 from Sassari, Italy, and 88 from Thua Thien - Hue province, Vietnam). Vietnamese patients were diagnosed at a younger age than Italian patients, at just 52.5 on average, while the figure for Italian was 62. The Vietnamese BC patients also had a bigger tumor in size, higher grade, more axillary node positivity as well as a later stage of disease in comparison with Italian ones. The proportion of ER-positive was higher in the Italian group than that in Vietnam (88.1 vs 55.7%). The high Ki-67 expression prevalence was significantly higher in Vietnamese patients compared with Italian (81.8 vs 45.1%). The HER2-positive rate in Vietnam was 33%, higher than that in Italy (8.1%). Histologic grade and cell proliferation index Ki-67 were significantly correlated with HER2 positivity in both groups. Conclusions: Vietnamese patients demonstrated more aggressive tumor features and worse prognostic biomarkers than Italian patients. The prevalence of HER2 positive and high Ki-67 expression in Vietnamese patients was considerably higher than in Italian patients. The remarkable differences in clinicopathological characteristics between the two populations suggest the diversity of biological tumor, ethnicity, and environment as well as the effectiveness of the screening program.

Management of Early-Stage Vulvar Cancer.

Simple SummaryVulvar cancer is a rare gynecological malignancy that affects mainly postmenopausal women. Recently, however, an alarming increase in the rates among young women has been observed due to human papillomavirus infection. The standard treatment for vulvar cancer is surgery with or without radiotherapy as adjuvant treatment. In recent decades, sentinel lymph node biopsy has been included as part of the surgical treatment. Thus, our objective was to review and discuss the advances found in the literature about early-stage vulvar cancer. For this, we searched PubMed for publications in the English language. Relevant articles, such as the GROINS-V studies, and the GOG protocols, are presented in this review exhibiting the evolution of early-stage vulvar cancer treatment and the decrease in surgical morbidity rates.Vulvar cancer is a rare gynecological malignancy since it represents 4% of all cancers of the female genital tract. The most common histological type is squamous cell carcinoma (90%). This type can be classified into two clinicopathological subtypes according to the etiology. The first subtype is associated with persistent human papillomavirus infection and is usually diagnosed in younger women. The second subtype is associated with lichen sclerosus condition, and in most cases is diagnosed in postmenopausal women. Currently, an increase in first subtype cases has been observed, which raised the concern about associated mortality and treatment morbidity among young women. Vulvar cancer treatment depends on histopathology grade and staging, but surgery with or without radiotherapy as adjuvant treatment is considered the gold standard. In recent decades, sentinel lymph node biopsy has been incorporated as part of the treatment. Therefore, we sought to review and discuss the advances documented in the literature about vulvar cancer focusing on the treatment of early-stage disease. Relevant articles, such as the GROINS-V studies and the GOG protocols, are presented in this review. Additionally, we discuss key points such as the evolution of treatment from invasive surgery with high morbidity, to more conservative approaches without compromising oncologic safety; the role of sentinel lymph node mapping in the initial staging, since it reduces the complications caused by inguinofemoral lymphadenectomy; the recurrences rates, since local recurrence is common and curable, however, groin-associated, or distant recurrences have a poor prognosis; and, finally, the long-term follow-up that is essential for all patients.

Does ethnicity matter? A two-statewide population based analysis of outcomes of primary mediastinal B-cell lymphoma in Hispanics.

e19568 Background: Primary mediastinal B-cell lymphoma (PMBCL) is considered a rare distinct clinicopathological and molecular subtype of diffuse large B-cell lymphoma (DLBCL), mainly affecting females in their 4th and 5th decades [1,2,3]. Since the 1960s, there has been a significant increase in the number of immigrants to the US; and the states of Florida (FL) and Texas (TX) are well known for their Hispanic (HI) enriched population. Since there is scarce data of PMBCL in HI; we researched demographics, treatment patterns and outcomes in H compared to Non-Hispanics (NH) from FL and TX. Methods: This is a retrospective study of patients diagnosed with PMBCL from the Texas Cancer Registry (TCR) and the Florida Cancer Data System (FCDS), with years of analysis 2006-2017. Patients were identified by the International Classification of Diseases for Oncology Third Edition (ICD-O-3). Key variables collected included gender, race, ethnicity, dates at diagnosis and death, primary payer at diagnosis, stage, type of treatment, poverty index, and vitality status. The significance of variation in the distribution of categorical outcomes with ethnicity (H, NH) was assessed with Fisher’s Exact tests or Pearson’s Chi-square tests as appropriate. Survival distributions were described with Kaplan-Meier curves, and the significance of variation in median survival with ethnicity was assessed with log-rank testing. All statistical testing was two-sided with a significance level of 5%. Results: We had 2 cohorts; cohort A (A) includes 19 H vs. 89 NH from TX, cohort B (B), 27 H vs. 121 NH from FL. The median age at diagnosis in A was 33 years (y) in H vs 40 y in NH ( p-value = 0.091); while median age in B was 36 y in H vs 46 y in NH ( p-value = 0.005). Regarding poverty index; in A, most of H were in the 10-20% bracket, and most NH were in the 5-10% bracket. On the contrary, in B, most of H were in the 5-10%, and most NH were in the 10-20% bracket. Lack of insurance was more prevalent in H in A vs. NH, 42% vs. 12%, respectively, where it was less prevalent in H vs. NH in B, 8% vs. 5%. Multiple agents of chemotherapy were delivered to 74% of H, 70% of NH vs. 82% of H and 65% of NH with p-value = 0.292 and 0.635 in A and B, respectively. In A, the NH had better median survival (m) than H, not reached vs. 10.3 y, respectively. In B, H had better m than the NH, 10.7 y vs. not reached, respectively. The 5 y survival probability in A was even among H and NH; 0.702 [95% CI 0.49-1] and 0.732 [95% CI 0.578 - 0.9280], respectively. While 5 y survival probability in B was higher in H compared to NH, 0.923 [95% CI 0.675 -0.869] and 0.766 [95% CI 0.434 - 0.615], respectively. The overall survival (OS) difference in A and B, H vs. NH was not statistically significant. Conclusions: Despite some identified demographic differences in patients diagnosed with PMBCL, comparing H vs. NH on each cohort, there was no statistically significant difference in the overall survival probability.

A novel HNRNPH1::ERG rearrangement in aggressive acute myeloid leukemia.

FUS::ERG rearrangement is a recurrent abnormality seen in a subgroup of acute myeloid leukemia (AML) with a poor prognosis. We described here a novel HNRNPH1::ERG rearrangement in a de novo AML. The patient was unresponsive to routine chemotherapy and succumbed to the disease just 3 months after diagnosis. Two additional cases of AML with HNRNPH1::ERG rearrangement were discovered by searching a publicly available sequencing database. The three patients share several clinical phenotypes with the FUS::ERG rearranged AML, including high blast count at diagnosis, pediatric or young adult-onset, and poor overall survival. In addition, hnRNPH1 and FUS are both hnRNP family members, a group of RNA-binding proteins functioning in RNA metabolism and transport. Therefore, we suggest that patients with HNRNPH1::ERG or FUS::ERG rearrangement belong to the same distinct clinicopathologic subtype of AML, that is, AML with ERG rearrangement. Based on a previous study showing that FUS::ERG binds to the retinoic acid-responsive elements and that all-trans retinoic acid-induced cell differentiation of AML cells, we support the clinical evaluation of an APL-like therapeutic regimen for AML with ERG rearrangement.

Abstract P4-05-09: Clinicopathologic characteristics and molecular profiling of HER2-low breast cancer: A single academic institution experience

Abstract Objectives: Recently-published phase I clinical trials have demonstrated promising efficacy of novel HER2-targeted therapy in advanced breast cancers with a HER2 immunohistochemistry (IHC) score of 1+, or 2+ with a non-amplified in-situ hybridization (ISH). This has raised the possibility for changing the categories for clinical interpretation of HER2 in breast cancers into: 1) HER2-negative (HER2 IHC score of 0+), 2) HER2-low (IHC score of 1+, or 2+ with a non-amplified ISH), and 3) HER2-positive (HER2 IHC score of 3+ and IHC score of 2+ with amplified ISH). Earlier studies on low HER2-expressing breast cancers focused on differences between HER2 2+ with negative ISH and HER2 0/1+. The aims of this study are to investigate the clinical, pathologic and molecular features of HER2-low breast cancers, in comparison to HER2-negative breast cancers. Methods: 281 breast cancers with HER2 IHC were diagnosed between 04/2020 and 12/2020 at our institution, including 164 HER2-negative, 87 HER2-low, and 30 HER2-positve cases. The clinicopathologic information and molecular subtyping (Agendia BluePrint) results of HER2-low breast cancers were retrospectively collected, and compared to those of HER2-negative cases. A p-value of &amp;lt; 0.05 was considered statistically significant. Results: HER2-low breast cancers accounted for 31% (87/281) of breast cancers in our study population. The majority of these HER2-low cases were clinical stage I-II, with 6 cases (6.9%) being stage IV. Most of the HER2-low cancers had a HER2 IHC score of 1+ (87%, 76/87), a ductal phenotype (82%, 71/87), histologic grades of 1 or 2 (94%, 82/87), were ER positive (94%, 81/86), PR positive (86%, 74/86), and had luminal molecular subtypes (96%, 83/87). Four patients received neoadjuvant chemotherapy and none of them achieved pathologic complete response. Compared to HER2-negative cancers, HER2-low breast cancers showed a lower Ki-67 (p&amp;lt;0.05), a higher ER positivity (p&amp;lt;0.05), a higher pathologic stage (p&amp;lt;0.05), and were more likely to be of the luminal molecular subtype (p&amp;lt;0.05). There was no significant difference in age, tumor size, histologic type, histologic grade, presence of lymphovascular invasion, PR status, or pathologic nodal stage (Table 1). Conclusions: HER-2 low breast cancers represent a heterogeneous group, and the majority are lower grade, early-stage, hormonal receptor positive, have a HER2 IHC score of 1+, and have a luminal molecular phenotype. This study provides the baseline clinicopathologic and molecular features of HER2-low breast cancers. Additional studies are needed to further elucidate the biology of HER2-low breast cancers. Table 1. Comparison of clinicopathologic parameters and molecular subtypes between HER2-low and HER2-negative breast cancersHER2-Low (n=87)HER2-Negative (n=164)P valueAge (year)66.6264.380.22Tumor size (mm)21.4919.290.49Histologic typeDuctal711390.57Lobular1524Mixed11Histologic grade143640.156239813519pT Stage142880.0452817362Unknown2735PN stage036760.351613210300Unknown2353ER positivity94.2 % (81/86)82.9% (136/64)0.01PR positivity86% (74/86)76.8% (126/164)0.09Ki-67 (%)12.8118.290.03Molecular subtypeLuminal A571050.003Luminal B2630HER210Basal328 Citation Format: Huina Zhang, Hani Katerji, Bradley M Turner, David G Hicks. Clinicopathologic characteristics and molecular profiling of HER2-low breast cancer: A single academic institution experience [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-05-09.

Diffuse large B-cell lymphoma and new insights into its pathobiology and implication in treatment.

The most common non-Hodgkin lymphoma (NHL) subtype is diffuse large B-cell lymphoma (DLBCL). It accounts for roughly 30% of all cases of NHL affecting both nodal and extra nodal sites. There are molecular subtypes of DLBCL, germinal centre subtype (GCB), and activated B-cell (ABC), based on gene expression profiling (GEP), in accumulation to distinct morphological and clinicopathological subtypes. To prognosticate patients, the International Prognostication Index (IPI) and its variants are used. In ABC type DLBCL, limited stage disease is treated with a combination of abbreviated systemic chemotherapy (three cycles) and field radiation therapy. Although advanced stage disease is treated with a full course of chemotherapy as well as novel agents (Bortezomib, Ibrutinib, Lenalidomide). In this review study, we looked at the role of multiple aspects of genetic and microenvironment changes which have effects in DLBCL tumours.

The significance of StAR-related lipid transfer protein-3 expression in breast cancer

StAR-related lipid transfer domain containing proteins (STARD3) are agroup of proteins that contain asteroidogenic acute regulatory protein-related lipid transfer domain. Breast cancer (BC) has been linked to the STARD3 gene. In this study, we sought to confirm the relationship of STARD3 protein expression with clinicopathological characteristics and BC molecular subtypes. Using tissue microarray, we examined the STARD3 protein expression in 200 BC tissues and 20 normal breast tissues. Higher protein expression of STARD3 was found in tumor tissues than normal tissues. One hundred and fifty-two (69.1%) of the 200 cases tested positive for STARD3 (high H-score), while seventy (30.9%) had alow STARD3 H-score. When STARD3 is present, its expression ranges from mild to strong. STARD3 H-score was strongly linked to human epidermal growth factor receptor 2 (HER2)-positive (p < 0.001) and estrogen receptor (ER)-positive (p < 0.009) patients, but not to triple-negative BC patients. STARD3 high H-score was associated with histological grade and tumor size. No significant associations were found with stage of the disease, pathological stage or node status. Our research revealed that STARD3 levels were higher in tissues from malignant BC, and it was associated with HER2 and ER, suggesting that it might be utilized as amarker for BC.

Castleman disease and mimickers: Clinicopathological findings of atypical lymphoproliferative disorders associated with autoimmune disease.

Atypical lymphoproliferative disorders (LPDs) related with autoimmune disease (AID) show marked clinicopathological diversity, which are defined as three distinct clinicopathological subtypes such as those resembling Castleman disease (CD), atypical paracortical hyperplasia with lymphoid follicles (APHLF), and atypical lymphoplasmacytic and immunoblastic proliferation (ALPIB). We studied excisional biopsy specimens from 31 patients with atypical LPDs associated with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren syndrome (SjS). The lesions in these 31 cases were classified into 6 (19.4%) cases resembling CD, 14 (45.2%) cases of APHLF, and 11 (35.5%) cases of ALPIB. Five cases (83.3%) resembling CD were in the active stage with systemic symptoms and multicentric lymphadenopathy. Thirteen cases (92.9%) of APHLF showed systemic symptoms, multicentric lymphadenopathy and abnormal laboratory findings. Histologic findings for cases resembling CD were rare in patients with RA and SjS. In AID patients, histologic findings for cases resembling CD or APHLF findings correlated with disease activity and multicentric lymphadenopathy. Six cases (54.5%) of ALPIB were in the active phase with systemic symptoms and multicentric lymphadenopathy. ALPIB tended to be unrelated to AID activity, especially in the majority of patients with no abnormal laboratory findings. Atypical LPDs associated with AID is a group of diseases that may be overdiagnosed and overtreated. The diagnosis of atypical LPDs associated with AID requires an understanding of the histological findings as well as a comprehensive assessment of the presence of systemic symptoms, the distribution of lymphadenopathy, and abnormal laboratory findings.

Mucinous adenocarcinoma: A unique clinicopathological subtype in colorectal cancer.

Mucinous adenocarcinoma (MAC) is a unique clinicopathological subtype of colorectal cancer, which is characterized by extracellular mucinous components that comprise at least 50% of the tumor tissue. The clinical characteristics, molecular features, response to chemo-/radiotherapy, and prognosis of MAC are different from that of non-MAC (NMAC). MAC is more common in the proximal colon, with larger volume, higher T-stage, a higher proportion of positive lymph nodes, poorer tumor differentiation, and a higher proportion of peritoneal implants compared to NMAC. Although biopsy is the main diagnostic method for MAC, magnetic resonance imaging is superior in accuracy, especially for rectal carcinoma. The aberrant expression of mucins, including MUC1, MUC2 and MUC5AC, is a notable feature of MAC, which may be related to tumor invasion, metastasis, inhibition of apoptosis, and chemo-/radiotherapy resistance. The genetic origin of MAC is mainly related to BRAF mutation, microsatellite instability, and the CpG island methylator phenotype pathway. In addition, the poor prognosis of rectal MAC has been confirmed by various studies, and that of colonic MAC is still controversial. In this review, we summarize the epidemiology, clinicopathological characteristics, molecular features, methods of diagnosis, and treatments of MAC in order to provide references for further fundamental and clinical research.

Advances in the Treatment of RET Fusion-positive Advanced Non-small Cell Lung Cancer

转染重排（rearranged during transfection, RET）融合阳性发生于0.7%-2%的非小细胞肺癌（non-small cell lung cancer, NSCLC）。RET基因与其他结构域之间的融合代表了NSCLC独特的生物学和临床病理学亚型。近些年以来，RET融合阳性晚期NSCLC治疗领域取得了重要进展。传统化疗能够带来一定的临床获益。在靶向药物临床应用之前或不适用的情况下，以铂类为基础的系统性化疗方案是患者初始治疗选择。免疫治疗在RET融合阳性人群中的报告数据较少且通常结果较差，不推荐免疫单药或免疫联合化疗方案作为这类患者的系统性治疗。多靶点激酶抑制剂在这类人群中的重新应用能够取得一定的治疗反应，目前仅卡博替尼和凡德他尼推荐在有限条件下作为初始或后续治疗。然而，依然存在不能满足的临床需求。普拉替尼（Pralsetinib）和塞尔帕替尼（Selpercatinib）作为RET选择性酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI），显著改善了RET融合阳性NSCLC患者生存及预后。普拉替尼和塞尔帕替尼已确立成为这类患者一线或后续治疗的首选方案。与其他TKI治疗时观察到的类似，RET靶向抑制治疗也会导致耐药问题，而获得性耐药的出现将影响治疗的远期有效性，并限制后续的药物选择。因此，本文将围绕RET融合阳性晚期NSCLC治疗进展进行综述。