Geyer F C, Lacroix‐Triki M, Colombo P‐E, Patani N, Gauthier A, Natrajan R, Lambros M B K, Khalifeh I, Albarracin C, Orru S, Marchiò C, Sapino A, Mackay A, Weigelt B, Schmitt F C, Wesseling J, Sneige ...N & Reis‐Filho J S
(2012) Histopathology 60, E115–E130
Molecular evidence in support of the neoplastic and precursor nature of microglandular adenosis
Aims: Microglandular adenosis (MGA) is a proliferative breast lesion, which has been proposed to be a potential precursor of triple‐negative breast cancers. The aims of this study were to determine whether MGAs harbour genetic alterations and if any such genetic aberrations found in MGAs are similar to those found in matched invasive carcinomas.
Methods and results: Twelve cases of MGA and/or atypical MGA (AMGA), 10 of which were associated with invasive carcinoma, were evaluated. Immunohistochemical profiling revealed that all invasive carcinomas were of triple‐negative phenotype and expressed S100, cytokeratins 8/18 and ‘basal’ markers. The morphologically distinct components of each case (MGA, AMGA and/or invasive carcinoma) were microdissected and subjected to microarray comparative genomic hybridization. Apart from three typical MGAs, all samples harboured genetic alterations. The percentage of the genome affected by copy number aberrations in MGA/AMGA ranged from 0.5 to 61.9%, indicating varying levels of genetic instability. In three cases, MGA/AMGA displayed copy number aberrations similar to those found in matched invasive components, providing strong circumstantial evidence that MGA may constitute the substrate for the invasive carcinoma development.
Conclusions: Our results support the contention that MGA can be a clonal lesion and non‐obligate precursor of triple‐negative breast cancer.
Purpose
Intermediate-risk early breast cancer (EBC) is a heterogeneous group in which adjuvant chemotherapy decision proves to be difficult. Clinical and pathological criteria are sometimes ...insufficient to determine the best therapeutic options, and validated biomarkers such as uPA/PAI-1, are needed to contribute to the decision-making. The objective of this study was to evaluate the clinical outcome of an unselected ER+/HER2− pN0 EBC cohort of patients in whom the routine clinical decision process included a prospective uPA/PAI-1 determination.
Method
This monocentric retrospective study included 520 patients who underwent curative surgery in our institute between 2006 and 2011. Adjuvant therapeutic strategy was decided based on clinical–pathological data, altogether with a routine prospective determination of uPA/PAI-1 tumor levels using fresh, extemporaneously sampled tissue. We evaluated the correlation between uPA/PAI-1 levels, clinical-pathological variables, and the patient’s outcome (relapse-free survival, RFS, and overall survival, OS).
Result
Median follow-up was 5.4 years. The 5- and 10-year RFS rates were ,respectively, 95 and 89%, and the five-year OS rate was 96.3%. Forty percent of tumors had low uPA/PAI-1 levels. Seventy-five percent of patients with low uPA/PAI-1 levels did not receive chemotherapy, when 25% did. Sixty percent of patients with high uPA and/or PAI-1 levels received chemotherapy, while 40% did not. No statistical significant correlation was found between the uPA/PAI-1 levels and RFS or OS.
Conclusion
The personalization of the patients’ treatment using uPA/PAI-1 tumor levels allows the reversion of the well-known poor prognostic impact of high uPA/PAI-1 levels and strongly supports the use of this biomarker in clinical practice.
The objective of this review is to evaluate the optimal positioning of cytoreduction surgery and perioperative medical treatments in the initial management and relapse of advanced-stage epithelial ...ovarian carcinoma. In the initial management, primary surgery should be proposed if the absence of tumor residue is feasible with reasonable surgery (extensive surgical resections to be considered and their complications, but also the general condition of the patient). Guidelines recommend 3 to 4 cycles of neoadjuvant chemotherapy before interval surgery for patients not eligible for primary surgery. Late interval surgery (i.e. after≥5-6 cycles of chemotherapy) is not a standard of care and should only be proposed in case of poor tumor response after 3-4 cycles and when complete interval surgery seems feasible. At first tumor recurrence in platinum-sensitive patients, a primary cytoreduction surgery can be considered if complete surgery can be managed. Predictive scores (AGO score; i-model score) can be used to select eligible patients. Given the lack of strong evidence, performing cytoreduction surgery at first recurrence in platinum-resistant patients or in the event of subsequent recurrence cannot be recommended. Nevertheless, obtaining a complete surgery in these clinical situations seems to provide a benefit in terms of overall survival and its application should be based on the expertise of specialized teams.
To evaluate our long-term experience on one-day breast intraoperative radiotherapy (IORT) given as sole radiation treatment to selected patients with breast cancer.
Inclusion criteria of INTRAOBS ...study (prospective observational study) were: ER+ T1N0 unifocal ductal carcinoma; absence of lymphovascular invasion or of extensive intraductal component (Scarff-Bloom-Richardson grade III and HER2+++ excluded). Two different linacs were used (20Gy/1 fraction): one dedicated electron linac (<October 2011), and afterwards a mobile linac (50kV photons). The primary endpoint was the local recurrence rate (=ipsilateral breast cancer recurrences number). Secondary endpoints were recurrence-free survival (RFS), overall and specific survival, cosmetic results, and patient satisfaction.
Of the present pre-planned analysis for the first 200 patients (median age: 68 years; range, 59–87 years) who received IORT between January 2010 and October 2014 (median follow-up of 53.4 months). A total of 193 patients were still alive. The local recurrence rate was 2.5% (n=5). The 1- and 5-year local RFS rates were 100% and 95.2%, respectively. At 12 months post-surgery, satisfaction about IORT was excellent for 86.9% of patients. Cosmetic results were considered by patients and physicians as good or very good in 89.4% and 97.3% of cases, respectively.
IORT for selected patients with breast cancer shows low recurrence rates, good cosmetic outcomes and excellent satisfaction.
Évaluation au long terme de notre expérience de radiothérapie peropératoire comme traitement local adjuvant exclusif de cancers du sein sélectionnés.
Les critères d’inclusion d’INTRAOBS (étude prospective observationnelle) étaient: carcinome canalaire infiltrant unifocal; stafe T1N0, expression des récepturs hormonaux+; absence d’invasion lympho-vasculaire ou de composante intracanalaire extensive (grade III Scarff-Bloom-Richardson et HER2+++ exclus). Deux types d’accélérateur linéaite ont été utilisés pour délivrer 20Gy/une séance: l’un spécifique (électrons, avant octobre 2011); l’autre, mobile (photons de 50kV, après octobre 2011). Le taux de rechute locale était le critère principal (=nombre de récidives intra-mammaire homolatérales). Les critères secondaires étaient les survies sans récidive (SSR), globale et spécifique, les résultats esthétiques et la satisfaction du traitement par les patientes.
De l’analyse pré-planifiée des 200 premières patientes (âge médian: 68 ans; min-max: 59-87 ans) traitées par orrafiayion peropératoire entre janvier 2010 et octobre 2014 (suivi médian=53,4 mois). Au total, 193 patientes étaient en vie. Le taux de rechute locale était de 2,5 % (n=5), le taux de s sans récidive locale à 1 et 5 ans de respectivement 100 % et de 95,2 %. Au total, 86,9 % des patientes étaient satisfaites du traitement par irradiation peropératoire un an après la chirurgie, avec des résultats esthétiques bons ou excellents pour 89,4 % des patientes (contre 97,3 % après évaluation médicale).
Peu de récidives locales surviennent après radiothérapie peropératoire lorsqu’elle est délivrée chez des patientes atteintes d’un cancer du sein sélectionnées, avec des résultats esthétiques satisfaisant et un taux de satisfaction excellent.
Objectives:
To analyze axillary lymph node involvement (ALNI) rate and survival for mucinous (MC) and tubular (TC) breast carcinomas considered being of very good prognosis and for which an axillary ...surgical exploration could be questioned.
Methods:
Our multicentric cohort consisted of 21,135 patients with clinically node-negative invasive breast cancer, without neoadjuvant therapy, between 1999 and 2013 in 10 French centers. ALNI rate and survival were analyzed according to patient and tumor characteristics.
Results:
Our cohort consisted of 672 TC and 245 MC. Patients were older and tumor size greater for MC and pathologic factors were more pejorative. The rate of mastectomies and adjuvant chemotherapy was higher in the MC group. Axillary lymph node status was determined by SLNB alone in 71.2% of patients. ALNI rates were 17.9% and 18% for TC and MC, respectively. ALNI rate was lesser for MC (OR 0.503, p = 0.024) and greater in case of lympho-vascular invasion (OR 5.0, p < 0.0001) and for tumors >10 mm (OR 2.17, p = 0.042). Median follow-up was 58 months. The 5- and 7-year overall survival rates were 97.1% and 95% for TC, respectively; 92.3% and 91.2% for MC (p = 0.043); 5- and 7-year disease-free survival rates were 97.9% and 97.2% versus 95.2 and 93.6% (p = 0.041). Lympho-vascular invasion was the only predictive factor for overall survival (hazard ratio HR = 2.70)’ grade 2 (HR = 10) and HR-negative (HR = 4.9) were the two predictive factors for disease-free survival.
Conclusion:
This study confirms the need for an axillary exploration for these tumors even for a tumor size <10 mm and a favorable prognosis.
Abstract
Based on results of clinical trials, completion ALND (cALND) is frequently not performed for patients with breast conservation therapy and one or two involved sentinel nodes (SN) by micro- ...or macro-metastases. However, there were limitations despite a conclusion of non-inferiority for cALND omission. No trial had included patients with SN macro-metastases and total mastectomy or with >2 SN macro-metastases. The aim of the study was too analyze treatment delivered and pathologic results of patients included in SERC trial. SERC trial is a multicenter randomized non-inferiority phase-3 trial comparing no cALND with cALND in cT0-1-2, cN0 patients with SN ITC (isolated tumor cells) or micro-metastases or macro-metastases, mastectomy or breast conservative surgery. We randomized 1855 patients, 929 to receive cALND and 926 SLNB alone. No significant differences in patient’s and tumor characteristics, type of surgery, and adjuvant chemotherapy (AC) were observed between the two arms. Rates of involved SN nodes by ITC, micro-metastases, and macro-metastases were 5.91%, 28.12%, and 65.97%, respectively, without significant difference between two arms for all criteria. In multivariate analysis, two factors were associated with higher positive non-SN rate: no AC versus AC administered after ALND (OR = 3.32,
p
< 0.0001) and >2 involved SN versus ≤2 (OR = 3.45,
p
= 0.0258). Crude rates of positive NSN were 17.62% (74/420) and 26.45% (73/276) for patient’s eligible and non-eligible to ACOSOG-Z0011 trial. No significant differences in patient’s and tumor characteristics and treatment delivered were observed between the two arms. Higher positive-NSN rate was observed for patients with AC performed after ALND (17.65% for SN micro-metastases, 35.22% for SN macro-metastases) in comparison with AC administered before ALND.
Hormone therapy (HT) is an effective treatment for metastatic endometrial carcinoma (mEC), with limited toxicity and low cost. We focused on molecular analysis of mECs treated by HT and, for the ...first time to date, we compared the genomic profiles of paired metastasis and primary ECs. The main objective was to identify predictive factors of the response to HT as well as specific altered signaling pathways driving mEC biology. From 1052 patients with EC treated by HT in two French cancer centers, 32 with endometrioid EC and 6 with high grade serous EC were included. We evaluated hormone receptors (HR) and mismatch repair proteins expression by immunohistochemistry and gene alterations by targeted next-generation sequencing and array-based comparative genomic hybridization. Several variables were tested in univariate and multivariate analyses to identify potential associations with (i) the clinical benefit of HT (CBHT) and (ii) a longer response (>18 months) (LRHT) and overall survival (OS). We compared the biological and genomic profiles of 11 primary/metastatic EC pairs. Thirty tumors (78.9%) were HR-positive and 6 (15.8%) showed microsatellite instability (MSI). The genomic profiles of 34 tumors showed an average altered genome of 3.26%, DNA repair homologous recombination deficiency in five tumors (14.7%), and 17 regions significantly targeted by amplification/deletion. Thirty-three tumors had 273 variants (158 genes, median of 7 mutations/sample), including 112 driver mutations. TP53, PTEN, PPP2R1A, ARID1A, FGFR2, and PIK3CA were the most frequently mutated. Based on the genomic status, nine oncogenic pathways were altered in more than 25% of primary EC. Clinically, 22 (57.9%) and 6 (15.8%) patients presented CBHT and LRHT, respectively. Neither oncogenic pathways alterations nor the variables tested were associated with CBHT and LRHT. Only patient’s age, mitotic index and the presence of at least one HR were associated with OS. Paired analysis of the primary/metastatic samples showed that among the 22 mutations acquired in the metastatic counterparts, the most frequently targeted genes were involved in pathways that might confer a selective advantage to cancer metastasis including hormone resistance. In conclusion, only patient’s age, mitotic index and the presence of at least one HR were associated with OS. The identification of gene mutations newly acquired in metastasis might help to better understand the formation of EC metastasis and select the best actionable candidates for HT-treated patients at the metastatic stage.
•The WHO 2017 grading system is a useful tool for patient prognosis after and the tailoring of therapeutic strategy.•The WHO 2017 grading system, age and distant metastasis were independent ...predictors of worse survival.•Symptomatic panNET, lymph node metastasis were independently associated with disease recurrence.•PanNET G3 has an intermediate prognosis between panNET G2 and PNEC.•Progress in diagnosis tools to distinguish panNET G3 vs. PNEC are required.
The aim of this study was to evaluate the new World Health Organization (WHO) 2017 grading system and the others clinicopathological factors in pancreatic neuroendocrine tumor (panNET) operated patients.
Histological staging was based on the WHO 2017 grading system. Outcome after surgery and predictors of overall survival (OS) and disease free survival (DFS) were evaluated.
A total of 138 patients underwent surgical resection with a severe morbidity and mortality rates of 14.5% and 0.7% respectively. Five years OS differed according to WHO 2017: 95% among 58 patients with NETG1, 82% in 68 patients with NETG2, 35% in 7 patients with NETG3 and 0% in 5 patients with NECG3 (P<0.0001). Independent predictors of worse OS were age>60 y.o (P=0.014), synchronous metastasis (P=0.005) and WHO 2017 with significant differences between NETG1 versus NETG2 (P=0.005), NETG3 (P<0.001) and NECG3 (P<0.001). Independent predictors of worse DFS were symptomatic NET (P=0.038), pN+ status (P=0.027) and WHO 2017 with significant differences between NETG1 versus NETG3 (P=0.014) and NECG3 (P=0.009).
The WHO 2017 grading system is a useful tool for patient prognosis after panNET resection and the tailoring of therapeutic strategy. Surgery could provide good results in NETG3 patients.
Background
Oncoplastic surgery for breast cancer (BC) may result in postoperative morbidity that can delay adjuvant treatment(s). The McKissock procedure is a reliable mammaplasty technique used in ...plastic surgery. The authors present their experiences in using a derived technique for the oncoplastic resection of extended malignancies located in the lower-inner (LIQ) or lower-outer (LOQ) breast quadrants.
Methods
Between 2011 and 2014, operative data of 25 patients receiving an oncoplastic resection for invasive BC or ductal carcinoma in situ (DCIS), using the modified McKissock procedure, were recorded. This technique conserved a bipedicle dermoglandular flap to improve the nipple–areola complex blood supply. Oncological and cosmetic results, as well as aesthetic outcomes and patients’ satisfaction, were analyzed.
Results
Invasive BCs (
n
= 21) and DCIS (
n
= 4) were located in the LIQ (
n
= 18) or LOQ (
n
= 7). The median age of patients was 62 years (range 34–85), the mean resection weight was 134 g (range 43–314), and the global morbidity rate was 12 %. No nipple necrosis occurred in these patients. Free margins were obtained in 22 cases (88 %) and the secondary mastectomy rate was 8 %. Contralateral symmetrization was performed, or was required, in the majority of cases (17/23). Cosmetic results were classified as excellent or good in 93 % of patients, and the median satisfaction rate on a visual analog scale was 9.6.
Conclusion
The modified McKissock procedure allows wide resection of cancers located in the LOQ or LIQ, and produced favorable postoperative outcomes and cosmetic results despite important resection weights.
The anti-HER2 antibody pertuzumab inhibits HER2 dimerization and affects HER2/HER3 dimer formation and signaling. As HER3 and its ligand neuregulin are implicated in pancreatic tumorigenesis, we ...investigated whether HER3 expression could be a predictive biomarker of pertuzumab efficacy in HER2low-expressing pancreatic cancer. We correlated in vitro and in vivo HER3 expression and neuregulin dependency with the inhibitory effect of pertuzumab on cell viability and tumor progression. HER3 knockdown in BxPC-3 cells led to resistance to pertuzumab therapy. Pertuzumab treatment of HER3-expressing pancreatic cancer cells increased HER3 at the cell membrane, whereas the anti-HER3 monoclonal antibody 9F7-F11 down-regulated it. Both antibodies blocked HER3 and AKT phosphorylation and inhibited HER2/HER3 heterodimerization but affected differently HER2 and HER3 homodimers. The pertuzumab/9F7-F11 combination enhanced tumor inhibition and the median survival time in mice xenografted with HER3-expressing pancreatic cancer cells. Finally, HER2 and HER3 were co-expressed in 11% and HER3 alone in 27% of the 45 pancreatic ductal adenocarcinomas analyzed by immunohistochemistry. HER3 is essential for pertuzumab efficacy in HER2low-expressing pancreatic cancer and HER3 expression might be a predictive biomarker of pertuzumab efficacy in such cancers. Further studies in clinical samples are required to confirm these findings and the interest of combining anti-HER2 and anti-HER3 therapeutic antibodies.
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