Surgeons’ preferences for using sentinel lymph node biopsy in patients with ductal carcinoma in situ

BACKGROUND: There is a large variation between Dutch hospitals in the use of Sentinel Lymph Node Biopsy (SLNB) in patients with a biopsy diagnosis of Ductal Carcinoma in Situ. The aim of our study was to investigate whether this variation might be explained by preferences of surgeons, organisational factors or the influence of patients preferences. METHODS: A cross-sectional web survey was conducted among 260 Dutch oncological/breast surgeons. Preferences of surgeons and the influence of the patients’ preferences were determined by means of best-worst scaling (BWS) of profile case scenarios and by ranking risk factors. The survey also explored organisational questions, the reported use of diagnostic techniques and influences on the decision. RESULTS: The BWS scenarios were completed by 57 surgeons. The most important reasons for performing SLNB were a suspected invasive component and DCIS grade 3. In the ranking, these were also the first and second most important factor, followed by the size of the lesion and a mass on mammogram. In 58% to 70% of the scenarios, the surgeons would not change their decisions on the use of SLNB if the patient’s chose differed. No organisational factor was significantly associated with the reported use of SLNB. CONCLUSION: The inter-hospital variation in the use of SLNB could not be attributed to organisational factors or surgeons’ preferences for risk factors. The risk factors that most surgeons reported as reasons for performing SLNB are consistent with the factors described in the Dutch treatment guideline for the use of SLNB

Trends in incidence, treatment, survival and subsequent breast cancer in lobular carcinoma in situ in the Netherlands:A population-based analysis

Purpose: We analysed incidence, treatment, survival, occurrence of ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC) after lobular carcinoma in situ (LCIS) in the Netherlands. Methods: All women diagnosed with classic LCIS between 1989 and 2017 were identified from the Netherlands Cancer Registry. We calculated overall (OS), relative survival (RS) and cumulative incidence functions (CIF, accounting for competing risks) of mortality, DCIS and IBC. For IBC, standardised incidence ratios (SIR) of IBC were calculated. Analyses were stratified for surgical treatment. Results: We included 1890 patients. Median age was 51 years. Median follow-up was 8.5 years. In 1989–2017, LCIS incidence increased from 41 to 124, surgical treatment decreased from 100% to 41.1 % – mostly BCS. 10-year OS and 20-year RS exceeded 90 % in all subgroups. Overall, 48 (2.5 %) and 270 (14.3 %) patients were diagnosed with DCIS and IBC. IBCs were mostly early-stage. After mastectomy, 13 of 14 IBCs presented contralaterally. In the other groups, 64.8–70.9 % of IBCs presented ipsilaterally, 34.5–53.9 % of these were lobular. The SIR of ipsilateral IBC was highest after no surgery (6.9, 95%CI:4.9–9.4), lowest after mastectomy (0.2, 95%CI:0.4–0.8). Conclusion: LCIS incidence increased, surgical treatment decreased. The low mortality risks support consideration of active surveillance. However, the increased IBC incidence suggests careful monitoring

Transcriptomic properties of her2+ ductal carcinoma in situ of the breast associate with absence of immune cells

SIMPLE SUMMARY: Tumor-infiltrating lymphocytes (TILs) are likely to play a role in the biological behavior of HER2+ ductal carcinoma in situ (DCIS). To prevent invasiveness, the potential of targeted immune-modulating treatment of HER2+ DCIS has been explored. We identified a 29-gene expression profile that was associated with the density of TILs. These genes included CCND3, DUSP10 and RAP1GAP, which may guide towards more rationalized choices with respect to immune-mediated therapy in HER2+ DCIS, such as targeted vaccine therapy. ABSTRACT: The identification of transcriptomic alterations of HER2+ ductal carcinoma in situ (DCIS) that are associated with the density of tumor-infiltrating lymphocytes (TILs) could contribute to optimizing choices regarding the potential benefit of immune therapy. We compared the gene expression profile of TIL-poor HER2+ DCIS to that of TIL-rich HER2+ DCIS. Tumor cells from 11 TIL-rich and 12 TIL-poor DCIS cases were micro-dissected for RNA isolation. The Ion AmpliSeq Transcriptome Human Gene Expression Kit was used for RNA sequencing. After normalization, a Mann–Whitney rank sum test was used to analyze differentially expressed genes between TIL-poor and TIL-rich HER2+ DCIS. Whole tissue sections were immunostained for validation of protein expression. We identified a 29-gene expression profile that differentiated TIL-rich from TIL-poor HER2+ DCIS. These genes included CCND3, DUSP10 and RAP1GAP, which were previously described in breast cancer and cancer immunity and were more highly expressed in TIL-rich DCIS. Using immunohistochemistry, we found lower protein expression in TIL-rich DCIS. This suggests regulation of protein expression at the posttranslational level. We identified a gene expression profile of HER2+ DCIS cells that was associated with the density of TILs. This classifier may guide towards more rationalized choices regarding immune-mediated therapy in HER2+ DCIS, such as targeted vaccine therapy

A solitary Peutz-Jeghers type polyp in the jejunum of a 19 year-old male

A 19-year old male presented with melena and anemia. A duodenoscopy revealed no abnormalities, but a small bowel X-ray series demonstrated a large jejunal polyp. This 4 cm large polyp was visualised during peroperative small bowel endoscopy and was subsequently surgically removed. The polyp had the characteristic histologic appearance of a Peutz-Jeghers type polyp, but the patient had no other signs of Peutz-Jeghers syndrome, such as the characteristic mucocutaneous pigmentation, the presence of multiple polyps or a positive family history. After removal of the polyp, melena did not recur and his hemoglobin concentration normalized. Altogether, the patient does not fulfill the diagnostic criteria for Peutz-Jeghers syndrome and appears to have a solitary jejunal Peutz-Jeghers type polyp. All previously reported patients with such polyps were older than this patient

Expression and Localization of Ferritin-Heavy Chain Predicts Recurrence for Breast Cancer Patients with a <i>BRCA1/2</i> Mutation

The ferritin-heavy chain (FTH1) is the catalytic subunit of the ferroxidase ferritin, which prevents oxidative DNA damage via intracellular iron storage. FTH1 was shown to be a prognostic marker for triple-negative breast cancer (BC) patients and associated with an enrichment of CD8+ effector T cells. However, whether the expression and localization of FTH1 are also associated with clinical outcome in other BC subtypes is unknown. Here, we investigated the association of FTH1 with time to survival in BCs from 222 BRCA1/2 mutation carriers by immunohistochemistry on tissue microarrays. In addition, for 51 of these patients, the association between FTH1 and specific subsets of T cells was evaluated on whole slides using automatic scoring algorithms. We revealed that nuclear FTH1 (nFTH1) expression, in multivariable analyses, was associated with a shorter disease-free (HR = 2.71, 95% CI = 1.49–4.92, p = 0.001) and metastasis-free survival (HR = 3.54, 95% CI = 1.45–8.66, p = 0.006) in patients carrying a BRCA1/2 mutation. However, we found no relation between cytoplasmic FTH1 expression and survival of BRCA1/2 mutation carriers. Moreover, we did not detect an association between FTH1 expression and the amount of CD45+ (p = 0.13), CD8+ (p = 0.18), CD4+ (p = 0.20) or FOXP3+ cells (p = 0.17). Consequently, the mechanism underlying the worse recurrence-free survival of nFTH1 expression in BRCA1/2 mutation carriers needs further investigation.</p

Interobserver Agreement of PD-L1/SP142 Immunohistochemistry and Tumor-Infiltrating Lymphocytes (TILs) in Distant Metastases of Triple-Negative Breast Cancer: A Proof-of-Concept Study. A Report on Behalf of the International Immuno-Oncology Biomarker Working Group

Patients with advanced triple-negative breast cancer (TNBC) benefit from treatment with atezolizumab, provided that the tumor contains 651% of PD-L1/SP142-positive immune cells. Numbers of tumor-infiltrating lymphocytes (TILs) vary strongly according to the anatomic localization of TNBC metastases. We investigated inter-pathologist agreement in the assessment of PD-L1/SP142 immunohistochemistry and TILs. Ten pathologists evaluated PD-L1/SP142 expression in a proficiency test comprising 28 primary TNBCs, as well as PD-L1/SP142 expression and levels of TILs in 49 distant TNBC metastases with various localizations. Interobserver agreement for PD-L1 status (positive versus negative) was high in the proficiency test: the corresponding scores as percentages showed good agreement with the consensus diagnosis. In TNBC metastases, there was substantial variability in PD-L1 status at the individual patient level. For one in five patients, the chance of treatment was essentially random, with half of the pathologists designating them as positive and half negative. Assessment of PD-L1/SP142 and TILs as percentages in TNBC metastases showed poor and moderate agreement, respectively. Additional training for metastatic TNBC is required to enhance interobserver agreement. Such training, focusing on metastatic specimens, seems worthwhile, since the same pathologists obtained high percentages of concordance (ranging from 93% to 100%) on the PD-L1 status of primary TNBCs

Receptor conversion in distant breast cancer metastases

Introduction: When breast cancer patients develop distant metastases, the choice of systemic treatment is usually based on tissue characteristics of the primary tumor as determined by immunohistochemistry (IHC) and/or molecular analysis. Several previous studies have shown that the immunophenotype of distant breast cancer metastases may be different from that of the primary tumor (receptor conversion), leading to inappropriate choice of systemic treatment. The studies published so far are however small and/or methodologically suboptimal. Therefore, definite conclusions that may change clinical practice could not yet be drawn. We therefore aimed to study receptor conversion for estrogen receptor alpha (ER alpha), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in a large group of distant (non-bone) breast cancer metastases by re-staining all primary tumors and metastases with current optimal immunohistochemical and in situ hybridization methods on full sections. Methods: A total of 233 distant breast cancer metastases from different sites (76 skin, 63 liver, 43 lung, 44 brain and 7 gastro-intestinal) were IHC stained for ER alpha, PR and HER2, and expression was compared to that of the primary tumor. HER2 in situ hybridization (ISH) was done in cases of IHC conversion or when primary tumors or metastases showed an IHC 2+ result. Results: Using a 10% threshold, receptor conversion by IHC for ER alpha, PR occurred in 10.3%, 30.0% of patients, respectively. In 10.7% of patients, conversion from ER+ or PR+ to ER-/PR- and in 3.4% from ER-/PR- to ER+ or PR+ was found. Using a 1% threshold, ER alpha and PR conversion rates were 15.1% and 32.6%. In 12.4% of patients conversion from ER+ or PR+ to ER-/PR-, and 8.2% from ER-/PR-to ER+ or PR+ occurred. HER2 conversion occurred in 5.2%. Of the 12 cases that showed HER2 conversion by IHC, 5 showed also conversion by ISH. One further case showed conversion by ISH, but not by IHC. Conversion was mainly from positive in the primary tumor to negative in the metastases for ER alpha and PR, while HER2 conversion occurred equally both ways. PR conversion occurred significantly more often in liver, brain and gastro-intestinal metastases. Conclusions: Receptor conversion by immunohistochemistry in (non-bone) distant breast cancer metastases does occur, is relatively uncommon for ER alpha and HER2, and is more frequent for PR, especially in brain, liver and gastrointestinal metastase

A prediction model for underestimation of invasive breast cancer after a biopsy diagnosis of ductal carcinoma in situ: based on 2892 biopsies and 589 invasive cancers

Background: Patients with a biopsy diagnosis of ductal carcinoma in situ (DCIS) might be diagnosed with invasive breast cancer at excision, a phenomenon known as underestimation. Patients with DCIS are treated based on the risk of underestimation or progression to invasive cancer. The aim of our study was to expand the knowledge on underestimation and to develop a prediction model. Methods: Population-based data were retrieved from the Dutch Pathology Registry and the Netherlands Cancer Registry for DCIS between January 2011 and June 2012. Results: Of 2892 DCIS biopsies, 21% were underestimated invasive breast cancers. In multivariable analysis, risk factors were high-grade DCIS (odds ratio (OR) 1.43, 95% confidence interval (CI): 1.05–1.95), a palpable tumour (OR 2.22, 95% CI: 1.76–2.81), a BI-RADS (Breast Imaging Reporting and Data System) score 5 (OR 2.36, 95% CI: 1.80–3.09) and a suspected invasive component at biopsy (OR 3.84, 95% CI: 2.69–5.46). The predicted risk for underestimation ranged from 9.5 to 80.2%, with a median of 14.7%. Of the 596 invasive cancers, 39% had unfavourable features. Conclusions: The risk for an underestimated diagnosis of invasive breast cancer after a biopsy diagnosis of DCIS is considerable. With our prediction model, the individual risk of underestimation can be calculated based on routinely available preoperatively known risk factors (https://www.evidencio.com/models/show/1074)