[A misleading breast metastasis of medullary thyroid carcinoma]. / Métastase mammaire d'un carcinome médullaire thyroïdien : un challenge diagnostique.

Recognition of mammary metastases by pathologists is fundamental because their prognosis and treatment are different from those of primary mammary carcinomas. We report the case of a 54-year-old woman presenting on her mammography a left breast nodule known for 5 years, having discreetly increased in size. Breast ultrasound showed a regular 1.2cm hypoechogenic nodular formation. A microbiopsy was performed. On microscopic examination, we observed a tumor proliferation realizing nests within a small, richly vascularized stroma. The tumor cells had a moderately abundant, eosinophilic, granular cytoplasm and a rounded, slightly atypical nucleus. One mitosis was found for 10 fields at×400 magnification. Tumor cells did not express hormone receptors but chromogranin A, synaptophysin, TTF1 and thyrocalcitonin. The proliferation index established by the anti-Ki67 antibody was 5 %. The diagnosis was a secondary localization of a well-differentiated neuroendocrine tumor which immunohistochemical profile firstly suggests a thyroid origin. We later learned that the patient had a history of total thyroidectomy 13 years ago. It was a sporadic medullary carcinoma of the thyroid. Bone scintigraphy revealed a lacunar lesion of the posterior part of the right iliac wing suspicious of secondary location. This right iliac lesion was biopsied. It was also a localization of the medullary thyroid carcinoma. The final diagnosis is a metastatic medullary thyroid carcinoma, slowly progressive, the mammary metastasis having probably existed for 5 years.

Prospective Clinical Utility Study of the Use of the 21-Gene Assay in Adjuvant Clinical Decision Making in Women With Estrogen Receptor-Positive Early Invasive Breast Cancer: Results From the SWITCH Study.

BACKGROUND: The 21-gene Oncotype DX Recurrence Score assay is a validated assay to help decide the appropriate treatment for estrogen receptor-positive (ER+), early-stage breast cancer (EBC) in the adjuvant setting. The choice of adjuvant treatments might vary considerably in different countries according to various treatment guidelines. This prospective multicenter study is the first to assess the impact of the Oncotype DX assay in the French clinical setting. METHODS: A total of 100 patients with ER+, human epidermal growth factor receptor 2-negative EBC, and node-negative (pN0) disease or micrometastases in up to 3 lymph nodes (pN1mi) were enrolled. Treatment recommendations, physicians' confidence before and after knowing the Recurrence Score value, and physicians' perception of the assay were recorded. RESULTS: Of the 100 patients, 95 were evaluable (83 pN0, 12 pN1mi). Treatment recommendations changed in 37% of patients, predominantly from chemoendocrine to endocrine treatment alone. The proportion of patients recommended chemotherapy decreased from 52% pretest to 25% post-test. Of patients originally recommended chemotherapy, 61% were recommended endocrine treatment alone after receiving the Recurrence Score result. For both pN0 and pN1mi patients, post-test recommendations appeared to follow the Recurrence Score result for low and high values. Physicians' confidence improved significantly. CONCLUSION: These are the first prospective data on the impact of the Oncotype DX assay on adjuvant treatment decisions in France. Using the assay was associated with a significant change in treatment decisions and an overall reduction in chemotherapy use. These data are consistent with those presented from European and non-European studies.

Early Metabolic Response to Neoadjuvant Treatment: FDG PET/CT Criteria according to Breast Cancer Subtype.

PURPOSE: To investigate parameters based on fluorine 18 fluorodeoxyglucose (FDG) positron emission tomographic (PET) imaging that are best correlated with pathologic complete response (PCR) in human epidermal growth factor receptor type 2 (HER2)-positive cancer and triple-negative breast cancer (TNBC) and with partial or complete response in ER-positive/HER2-negative breast cancer. MATERIALS AND METHODS: This study was approved by institutional review board with waivers of informed written consent and included consecutive patients treated by neoadjuvant chemotherapy. Five PET examination-derived parameters were tested: standard uptake value (SUV) maximum (SUV(max)), peak (SUV(peak)), and mean (SUV(mean)), metabolically active tumor volume, and total lesion glycolysis (TLG). Absolute values at baseline PET, at PET imaging after two cycles of chemotherapy, and variation (ie, change) were measured. Correlations with pathologic response (Wilcoxon rank-sum test) and predictive power assessed (area under the curve [AUC] on the basis of receiver operating characteristic analysis) were examined. RESULTS: Included were 169 consecutive patients (mean age, 50 years). PCR was more frequent in HER2-positive tumors (16 of 33 patients [48.5%]) and TNBCs (20 of 54 patients [37%]) than in ER positive/HER2-negative tumors (four of 82 [4.9%]) (P < .001). Among patients with ER-positive/HER2-negative cancers, 33 patients had partial response. In TNBC, best association with PCR was obtained with change in SUV(max) (AUC, 0.86) or change in TLG (AUC, 0.88). In HER2-positive phenotype, absolute SUV(max) (or SUV(peak)) values at PET imaging after two cycles of chemotherapy (AUC for each cycle, 0.93) were better correlated with PCR than change in SUV(max) (AUC, 0.78; P = .11) or change in TLG (AUC, 0.62; P = .005). Regarding ER-positive/HER2-negative cancers, change in SUV(max) or change in TLG (AUC, 0.75) were parameters best correlated with partial or complete response. Baseline SUV(max) was higher in lymph nodes than in primary tumor in 31 patients. Findings were similar considering the site with highest FDG uptake. CONCLUSION: Quantitative indexes of tumor glucose use that are best correlated with pathologic response vary by phenotype: change in SUV(max) or TLG are most adequate for TNBCs and ER-positive/ HER2-negative cancers and absolute SUV(max) after two cycles of chemotherapy for HER2-positive breast cancers.

Do clinical, histological or immunohistochemical primary tumour characteristics translate into different (18)F-FDG PET/CT volumetric and heterogeneity features in stage II/III breast cancer?

PURPOSE: The aim of this retrospective study was to determine if some features of baseline (18)F-FDG PET images, including volume and heterogeneity, reflect clinical, histological or immunohistochemical characteristics in patients with stage II or III breast cancer (BC). METHODS: Included in the present retrospective analysis were 171 prospectively recruited patients with stage II/III BC treated consecutively at Saint-Louis hospital. Primary tumour volumes were semiautomatically delineated on pretreatment (18)F-FDG PET images. The parameters extracted included SUVmax, SUVmean, metabolically active tumour volume (MATV), total lesion glycolysis (TLG) and heterogeneity quantified using the area under the curve of the cumulative histogram and textural features. Associations between clinical/histopathological characteristics and (18)F-FDG PET features were assessed using one-way analysis of variance. Areas under the ROC curves (AUC) were used to quantify the discriminative power of the features significantly associated with clinical/histopathological characteristics. RESULTS: T3 tumours (>5 cm) exhibited higher textural heterogeneity in (18)F-FDG uptake than T2 tumours (AUC <0.75), whereas there were no significant differences in SUVmax and SUVmean. Invasive ductal carcinoma showed higher SUVmax values than invasive lobular carcinoma (p = 0.008) but MATV, TLG and textural features were not discriminative. Grade 3 tumours had higher FDG uptake (AUC 0.779 for SUVmax and 0.694 for TLG), and exhibited slightly higher regional heterogeneity (AUC 0.624). Hormone receptor-negative tumours had higher SUV values than oestrogen receptor-positive (ER-positive) and progesterone receptor-positive tumours, while heterogeneity patterns showed only low-level variation according to hormone receptor expression. HER-2 status was not associated with any of the image features. Finally, SUVmax, SUVmean and TLG significantly differed among the three phenotype subgroups (HER2-positive, triple-negative and ER-positive/HER2-negative BCs), but MATV and heterogeneity metrics were not discriminative. CONCLUSION: SUV parameters, MATV and textural features showed limited correlations with clinical and histopathological features. The three main BC subgroups differed in terms of SUVs and TLG but not in terms of MATV and heterogeneity. None of the PET-derived metrics offered high discriminative power.

Molecular apocrine breast cancers are aggressive estrogen receptor negative tumors overexpressing either HER2 or GCDFP15.

INTRODUCTION: Molecular apocrine (MA) tumors are estrogen receptor (ER) negative breast cancers characterized by androgen receptor (AR) expression. We analyzed a group of 58 transcriptionally defined MA tumors and proposed a new tool to identify these tumors. METHODS: We performed quantitative reverse transcription PCR (qRT-PCR) for ESR1, AR, FOXA1 and AR-related genes, and immunohistochemistry (IHC) for ER, PR, Human Epidermal Growth Factor Receptor 2 (HER2), CK5/6, CK17, EGFR, Ki67, AR, FOXA1 and GCDFP15 and we analyzed clinical features. RESULTS: MA tumors were all characterized by ESR1(-) AR(+) FOXA1(+) and AR-related genes positive mRNA profile. IHC staining on these tumors showed 93% ER(-), only 58% AR(+) and 90% FOXA1(+). 67% and 57% MA tumors were HER2(3+) and GCDFP15(+), respectively. Almost all MA tumors (94%) had the IHC signature HER2(3+) or GCDFP15(+) but none of the 13 control basal-like (BL) tumors did. Clinically, MA tumors were rather aggressive, with poor prognostic factors. CONCLUSION: MA tumors could be better defined by their qRT-PCR-AR profile than by AR IHC. In addition, we found that HER2 or GCDFP15 protein overexpression is a sensitive and specific tool to differentiate MA from BL in the context of ER negative tumors. A composite molecular and IHC signature could, therefore, help to identify MA tumors in daily practice.

Estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast tumors: early prediction of chemosensitivity with (18)F-fluorodeoxyglucose positron emission tomography/computed tomography during neoadjuvant chemotherapy.

BACKGROUND: The objective of this prospective study was to evaluate the ability of (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) to predict chemosensitivity in patients with estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. METHODS: Sixty-four consecutive patients underwent (18)F-FDG PET/CT scanning at baseline and after the second course of neoadjuvant chemotherapy (NAC). The evolution (Δ) between the 2 scans of image parameters (maximum standardized uptake value [SUV(max)], SUV(mean), metabolic tumor volume, and total lesion glycolysis [TLG]) was measured. Correlations between early changes in PET-derived parameters and pathologic response observed in surgical specimens after the completion of 8 courses of NAC were estimated with Mann-Whitney U tests. Response prediction on the basis of clinical data, histologic type, or molecular markers also was assessed (Fisher exact test). Receiver operating characteristic (ROC) analysis was used to compare the area under the curve (AUC) of each parameter. RESULTS: The best prediction of chemosensitivity was obtained with ΔTLG (-49% ± 31% in nonresponders vs -73% ± 25% in responders; P < .0001). Among the biologic parameters, only negative progesterone receptor status (57% responders vs 31% nonresponders; P = .04) and luminal B subtype (63% responders vs 22% nonresponders; P = .02) were predictive of a pathologic response. ROC analysis resulted in an AUC of 0.81, 0.73, 0.71, and 0.63 for ΔTLG, ΔSUV(max), luminal subtype, and progesterone receptor status, respectively. CONCLUSIONS: When patients responded to NAC, the majority of ER-positive/HER2 negative tumors exhibited partial tumor shrinkage; and the PET parameters that combined volume and activity measurements, such as TLG, offered better accuracy for early prediction than the SUV(max). Negative progesterone receptor status and luminal B subtype had weaker predictive power than PET-derived parameters.

Negative Relationship between Post-Treatment Stromal Tumor-Infiltrating Lymphocyte (TIL) and Survival in Triple-Negative Breast Cancer Patients Treated with Dose-Dense Dose-Intense NeoAdjuvant Chemotherapy.

Background: Patients with triple-negative breast cancers (TNBC) have a poor prognosis unless a pathological complete response (pCR) is achieved after neoadjuvant chemotherapy (NAC). Few studies have analyzed changes in TIL levels following dose-dense dose-intense (dd-di) NAC. Patients and methods: From 2009 to 2018, 117 patients with TNBC received dd-di NAC at our institution. We aimed to identify factors associated with pre- and post-NAC TIL levels, and oncological outcomes relapse-free survival (RFS), and overall survival (OS). Results: Median pre-NAC and post-NAC TIL levels were 15% and 3%, respectively. Change in TIL levels with treatment was significantly correlated with metabolic response (SUV) and pCR. High post-NAC TIL levels were associated with a weak metabolic response after two cycles of NAC, with the presence of residual disease and nodal involvement at NAC completion. In multivariate analyses, high post-NAC TIL levels independently predicted poor RFS and poor OS (HR = 1.4 per 10% increment, 95%CI (1.1; 1.9) p = 0.014 and HR = 1.8 per 10% increment 95%CI (1.3−2.3), p < 0.0001, respectively). Conclusion: Our results suggest that TNBC patients with TIL enrichment after NAC are at higher risk of relapse. These patients are potential candidates for adjuvant treatment, such as immunotherapy, in clinical trials.

Correlation of high 18F-FDG uptake to clinical, pathological and biological prognostic factors in breast cancer.

PURPOSE: The aim of this study was to determine the impact of the main clinicopathological and biological prognostic factors of breast cancer on (18)F-fluorodeoxyglucose (FDG) uptake. Only women with tumours larger than 20 mm (T2-T4) were included in order to minimize bias of partial volume effect. METHODS: In this prospective study, 132 consecutive women received FDG PET/CT imaging before starting neoadjuvant chemotherapy. Maximum standardized uptake values (SUV(max)) were compared to tumour characteristics as assessed on core biopsy. RESULTS: There was no influence of T and N stage on SUV. Invasive ductal carcinoma showed higher SUV than lobular carcinoma. However, the highest uptake was found for metaplastic tumours, representing 5% of patients in this series. Several biological features usually considered as bad prognostic factors were associated with an increase in FDG uptake: the median of SUV(max) was 9.7 for grade 3 tumours vs 4.8 for the lower grades (p < 0.0001); negativity for oestrogen receptors (ER) was associated with higher SUV (ER+ SUV = 5.5; ER- SUV = 7.6; p = 0.003); triple-negative tumours (oestrogen and progesterone receptor negative, no overexpression of c-erbB-2) had an SUV of 9.2 vs 5.8 for all others (p = 0005); p53 mutated tumours also had significantly higher SUV (7.8 vs 5.0; p < 0.0001). Overexpression of c-erbB-2 had no effect on the SUV value. CONCLUSION: Knowledge of the factors influencing uptake is important when interpreting FDG PET/CT scans. Also, findings that FDG uptake is highest in those patients with poor prognostic features (high grade, hormone receptor negativity, triple negativity, metaplastic tumours) is helpful to determine who are the best candidates for baseline staging.

Prognostic Impact of Stromal Immune Infiltration before and after Neoadjuvant Chemotherapy (NAC) in Triple Negative Inflammatory Breast Cancers (TNIBC) Treated with Dose-Dense Dose-Intense NAC.

Inflammatory breast cancers are very aggressive, and among them, triple negative breast cancer (TNBC) has the worst prognosis. While many studies have investigated the association between tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) and outcome in TNBC, the impact of post-NAC TIL and TIL variation in triple negative inflammatory breast cancer (TNIBC) outcome is unknown. Between January 2010 to December 2018, all patients with TNIBC seen at the breast disease unit (Saint-Louis Hospital) were treated with dose-dense dose-intense NAC. The main objective of the study was to determine factors associated with event-free survival (EFS), particularly pathological complete response (pCR), pre- and post-NAC TIL, delta TIL and post-NAC lymphovascular invasion (LVI). After univariate analysis, post-NAC LVI (HR 2.06; CI 1.13-3.74; p = 0.02), high post-NAC TIL (HR 1.81; CI 1.07-3.06; p = 0.03) and positive delta TIL (HR 2.20; CI 1.36-3.52; p = 0.001) were significantly associated with impaired EFS. After multivariate analysis, only a positive TIL variation remained negatively associated with EFS (HR 1.88; CI 1.05-3.35; p = 0.01). TNIBC patients treated with intensive NAC who present TIL enrichment after NAC have a high risk of relapse, which could be used as a prognostic marker in TNIBC and could help to choose adjuvant post-NAC treatment.

Breast intracystic papillary carcinoma: an update.

Intracystic papillary carcinoma (IPC), a breast tumor mainly occuring in the elderly, has long been considered as a variant of ductal carcinoma in situ (DCIS). This is now debated since metastatic cases have been reported. In this study, surgical pieces of 20 IPCs were reassessed, and markers of myopepithelial layer (p63, CD10 and Smooth Muscle Actin) as well as estrogen receptors (ER) and progesterone receptors (PgR) and C-erb-B2 oncoprotein expression were systematically performed and quantified. In 10 cases, an associated unequivocal invasive component was found. In all 20 cases, no myoepithelial layer was found. Eighteen tumors were ER positive, 14 were PgR positive. Moreover, none of the tumors over-expressed C-erb-B2 oncoprotein. Therefore this study showed that in all cases of IPC there were microscopic features of invasive carcinoma despite good clinical prognostic indicators, and that precise characterization of tumors requires extensive paraffin embedding of surgical pieces.

Exquisite sensitivity of TP53 mutant and basal breast cancers to a dose-dense epirubicin-cyclophosphamide regimen.

BACKGROUND: In breast cancers, only a minority of patients fully benefit from the different chemotherapy regimens currently in use. Identification of markers that could predict the response to a particular regimen would thus be critically important for patient care. In cell lines or animal models, tumor protein p53 (TP53) plays a critical role in modulating the response to genotoxic drugs. TP53 is activated in response to DNA damage and triggers either apoptosis or cell-cycle arrest, which have opposite effects on cell fate. Yet, studies linking TP53 status and chemotherapy response have so far failed to unambiguously establish this paradigm in patients. Breast cancers with a TP53 mutation were repeatedly shown to have a poor outcome, but whether this reflects poor response to treatment or greater intrinsic aggressiveness of the tumor is unknown. METHODS AND FINDINGS: In this study we analyzed 80 noninflammatory breast cancers treated by frontline (neoadjuvant) chemotherapy. Tumor diagnoses were performed on pretreatment biopsies, and the patients then received six cycles of a dose-dense regimen of 75 mg/m(2) epirubicin and 1,200 mg/m(2) cyclophosphamide, given every 14 days. After completion of chemotherapy, all patients underwent mastectomies, thus allowing for a reliable assessment of chemotherapy response. The pretreatment biopsy samples were used to determine the TP53 status through a highly efficient yeast functional assay and to perform RNA profiling. All 15 complete responses occurred among the 28 TP53-mutant tumors. Furthermore, among the TP53-mutant tumors, nine out of ten of the highly aggressive basal subtypes (defined by basal cytokeratin [KRT] immunohistochemical staining) experienced complete pathological responses, and only TP53 status and basal subtype were independent predictors of a complete response. Expression analysis identified many mutant TP53-associated genes, including CDC20, TTK, CDKN2A, and the stem cell gene PROM1, but failed to identify a transcriptional profile associated with complete responses among TP53 mutant tumors. In patients with unresponsive tumors, mutant TP53 status predicted significantly shorter overall survival. The 15 patients with responsive TP53-mutant tumors, however, had a favorable outcome, suggesting that this chemotherapy regimen can overcome the poor prognosis generally associated with mutant TP53 status. CONCLUSIONS: This study demonstrates that, in noninflammatory breast cancers, TP53 status is a key predictive factor for response to this dose-dense epirubicin-cyclophosphamide regimen and further suggests that the basal subtype is exquisitely sensitive to this association. Given the well-established predictive value of complete responses for long-term survival and the poor prognosis of basal and TP53-mutant tumors treated with other regimens, this chemotherapy could be particularly suited for breast cancer patients with a mutant TP53, particularly those with basal features.

Targeting autophagic cancer stem-cells to reverse chemoresistance in human triple negative breast cancer.

There is growing evidence for the role of cancer stem-cells in drug resistance, but with few in situ studies on human tumor samples to decipher the mechanisms by which they resist anticancer agents.Triple negative breast cancer (TNBC) is the most severe sub-type of breast cancer, occurring in younger women and associated with poor prognosis even when treated at a localized stage.We investigated here the relationship between complete pathological response after chemotherapy and breast cancer stem-cell characteristics in pre-treatment biopsies of 78 women with triple negative breast carcinoma (TNBC).We found that chemoresistance was associated with large numbers of breast cancer stem-cells, and that these cancer stem-cells were neither proliferative nor apoptotic, but in an autophagic state related to hypoxia. Using relevant pharmacological models of patient-derived TNBC xenografts, we further investigated the role of autophagy in chemoresistance of breast cancer stem-cells. We demonstrated that hypoxia increased drug resistance of autophagic TNBC stem-cells, and showed that molecular or chemical inhibition of autophagic pathway was able to reverse chemoresistance.Our results support breast cancer stem-cell evaluation in pre-treatment biopsies of TNBC patients, and the need for further research on autophagy inhibition to reverse resistance to chemotherapy.

Ductal carcinoma in situ (DCIS) treated by mastectomy, or local excision with or without radiotherapy: A monocentric, retrospective study of 608 women.

OBJECTIVES: Since mammographic screening programmes, the proportion of DCIS has dramatically increased. Adjuvant radiotherapy (RT) after local excision (LE) has become a solid option for DCIS since 4 randomised trials have proven a decrease in local relapse (LR), though failing to prove a benefit on mortality rate. DCIS is a heterogeneous disease and it is unclear whether all patients uniformly benefit from radiotherapy. We report a descriptive analysis including all types of treatment. MATERIALS AND METHODS: Our retrospective cohort describes 608 women treated for DCIS in our centre between 1983 and 2013. Mastectomy was recommended before 1992, or for multifocal or >3 cm DCIS. LE alone was an option for DCIS ≤10 mm, with low or intermediate grade, and clear margins (≥2 mm). LE + RT was recommended for all other cases. RESULTS: The median follow-up time was 6.7 years. Treatment consisted in mastectomy for 252 women, LE + RT for 269 and LE for 86. The major prognosis factor for LR rate was the type of treatment: LE + RT or LE was associated with a higher LR-rate than those treated by mastectomy (HR respectively 2.06; 95%CI 1.33-3.19; p = 0.001 and 2.12; 95%CI 1.20-3.65; p = 0.007). In our selected population, women treated by LE + RT versus LE showed no significant differences in LR (HR 0.97; 95%CI 0.61-1.7; p = 0.91). The overall survival rate was 99.7% after ten years, with no differences between the treatment groups. CONCLUSION: Although retrospective, our monocentric study suggests that LE alone could be an option for DCIS with good prognosis factors. Confirmation by larger randomised studies is needed.

¹8F-FDG PET/CT for the Early Evaluation of Response to Neoadjuvant Treatment in Triple-Negative Breast Cancer: Influence of the Chemotherapy Regimen.

UNLABELLED: Patients with triple-negative breast cancer (TNBC) have poor outcome when pathologic complete response (pCR) is not reached after neoadjuvant chemotherapy. Early prediction would be helpful. We evaluated the association between metabolic response after 2 cycles of neoadjuvant chemotherapy, pCR, and outcome in patients receiving 2 different anthracycline-based regimens (conventional and intensified). METHODS: Of 77 consecutive TNBC patients, 23 received EC-D (4 cycles of epirubicin + cyclophosphamide followed by 4 cycles of docetaxel at conventional doses) and 55 received a dose-intensified, dose-dense concomitant regimen of epirubicin + cyclophosphamide (historically called SIM) for 6 cycles. PET/CT with (18)F-FDG was performed at baseline and after 2 cycles of neoadjuvant chemotherapy. The associations between clinical factors, biologic factors, early metabolic change, pCR, and event-free survival (EFS) were examined (log-rank test). RESULTS: Of the 78 patients, 29 (37%) achieved pCR. The change in SUVmax (∆SUVmax) after 2 cycles was more pronounced in patients who achieved pCR (-72% vs. -42%;P< 0.0001). ∆SUVmax was more pronounced under SIM than under EC-D (-68% vs. -35%, P= 0.009), and there was a trend for a higher pCR rate (44% vs. 22%, P= 0.078). Twenty-two patients relapsed and 10 of them died (median follow-up, 34 mo). pCR was associated with EFS (log-rank, P= 0.001). ∆SUVmax was also significantly associated with EFS both in patients receiving SIM (P= 0.028) and in those receiving EC-D (P= 0.021). The optimal ∆SUVmax for predicting pCR and EFS was, however, specific to the treatment regimen. EFS was not associated with tumor grade (P= 0.98), histologic subtype (P= 0.17), or clinical stage (P= 0.097). CONCLUSION: Early metabolic change during neoadjuvant chemotherapy can predict pathologic response and EFS in TNBC patients under different chemotherapy regimens. However, the metabolic response varies with the type of chemotherapy.

Increased incidence of ERBB2 overexpression and TP53 mutation in inflammatory breast cancer.

Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. We studied the biological characteristics of these tumours by comparing the overexpression of oncogenes ERBB2, MYC, CCND1 and RHOC and TP53 gene mutation rates in IBC with those found in locally advanced and not otherwise specified breast cancers. The prevalence of the TP53 mutation was much higher in IBC than in the two other types of cancer (57% vs 30). Unexpectedly, however, in IBC tumours, histological grade was independent of TP53 status. In addition, ERBB2 overexpression was twice as frequent in inflammatory as in non-inflammatory tumours, whereas the frequencies of MYC, CCND1 and RHOC overexpression did not vary significantly among the three types of breast cancer. These findings suggest that IBC tumours constitute a distinct subset with a specific pathogenesis. Given the importance of TP53 and ERBB2 in the response to treatments, our observations have important therapeutic implications for the clinical management of IBC patients.

Prognostic significance of a combined clinicopathologic score for response to primary systemic therapy in locally advanced breast cancer.

The response to chemotherapy is one of the best indicators of prognosis in locally advanced breast cancer (LABC). The pathologic response (pR) of 108 LABC patients was analysed and compared with their clinical response (cR). Our aim was to define a new combined clinicopathologic response score (cpR) and to explore its correlation with survival data. The 108 stage IIB to IIIB breast carcinomas were first treated with high-dose anthracycline-based chemotherapy. Standard criteria were used to assess cR. Pathologic analysis of surgical specimens allowed the definition of 5 types of pR. Three groups of combined clinicopathologic response were defined. Twenty-two patients (20%) had complete or almost complete pR. Most patients (88, 81%) had partial cR. This large group of partial cR was very heterogeneous, ranging from pR1 to pR5 and from cpR1 to cpR3. In univariate analysis, pR and cpR both strongly correlated with EFS. cR, pR and cpR all correlated with OS. Subgroups of incomplete pathologic responses were not prognostically different. In multivariate analysis, only cpR correlated strongly with both EFS and OS (p<0.002), identifying good (20%), intermediate (61%) and poor (19%) prognosis patients. In conclusion, in 108 stage IIB to IIIB breast cancer patients initially treated by high-dose chemotherapy, combined grading of clinical and pathologic responses in a single score allowed accurate prediction of outcome.

Baseline Tumor 18F-FDG Uptake and Modifications After 2 Cycles of Neoadjuvant Chemotherapy Are Prognostic of Outcome in ER+/HER2- Breast Cancer.

UNLABELLED: This study investigated whether (18)F-FDG PET/CT performed at baseline and during neoadjuvant chemotherapy (NAC) was able to early depict estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer patients with poor clinical outcome. METHODS: The NAC regimen consisted of 4 cycles of epirubicin plus cyclophosphamide, followed by 4 courses of docetaxel. The patients underwent (18)F-FDG PET/CT at baseline and after 2 cycles of chemotherapy. After completion of NAC, all patients had breast surgery with axillary lymph node dissection. We assessed the impact of 2 PET parameters, maximum standardized uptake values (SUVmax) and total lesion glycolysis, on event-free survival (EFS). RESULTS: Ninety-eight consecutive patients with clinical stage II or III ER+/HER2- breast cancer were included. (18)F-FDG PET/CT revealed distant metastases in 14 patients (14%). Overall survival was significantly shorter in these patients than in the 84 patients classified as M0 at baseline (18)F-FDG PET/CT (P < 0.001). In M0 patients, a high SUVmax at baseline was associated with shorter EFS (P < 0.001). Twelve patients had a tumor SUVmax of 10 or greater and a 3-y EFS of 49% (vs. 92% in patients with baseline SUVmax < 10). A low change in SUVmax between (18)F-FDG PET/CT examination before starting NAC and after the second cycle of chemotherapy was also associated with recurrence (P = 0.033), as was a low change in total lesion glycolysis (P < 0.001). Contrarily to PET-based prediction, the extent of pathologic response after completion of NAC (partial/complete vs. nonresponders) was poorly correlated to the risk of relapse. CONCLUSION: Baseline tumor (18)F-FDG uptake and modifications after 2 cycles of NAC are prognostic of outcome in patients with ER+/HER2- breast cancer.

Interobserver and intraobserver reproducibility in the histopathology of follicular thyroid carcinoma.

We evaluated the interobserver and intraobserver reproducibility in the histopathology of follicular thyroid carcinoma (FTC). Forty-one anonymous FTC pathology slides were independently reviewed by 5 pathologists, and 31 of them were also evaluated twice by the same pathologist. A final consensus diagnosis (FCD) was made at the end of the study. Interobserver and intraobserver agreement was determined as the kappa statistic for qualitative data and intraclass correlation coefficient for quantitative data. The agreement between the 5 observers' initial diagnosis and the FCD was 0.69, 0.41, 0.35, 0.28 and 0.11, respectively, strongly suggesting a leadership phenomenon. The FCD classified 30 cases as malignant, including 24 cases diagnosed as FTC. There was unanimous agreement about 13 of the 24 FTCs. Diagnostic reproducibility was found to be acceptable for the nonminimally invasive FTC. Diagnostic discrepancies occurred in 57% of the seven cases classified as minimally invasive FTC by the FCD. FCD excluded malignancy in 11 cases including 6 atypical adenomas. Interobserver and intraobserver agreement for FTC diagnosis was 0.23 (standard error [SE], 0.04) and 0.68, respectively. Interobserver and intraobserver agreement for the presence of vascular invasion was 0.20 (SE, 0.04) and 0.51, respectively, contrasting with a moderate to substantial level of agreement when considering the number of vascular invasion. Interobserver and intraobserver agreement for nucleus optical clearing were slight and moderate, respectively. The importance of the study is the confirmation that diagnostic reproducibility of minimally invasive FTC is low and that this has clinical implications, and also implications for the design of studies into the treatment and outcome of FTC.

[Ductal carcinomas in situ]. / Cancers canalaires in situ.

EPIDEMIOLOGY: Presently representing 15 to 30% of new cases of breast cancer, ductal carcinomas in situ do not have specific epidemiological characteristics. The age at which they occur is between 49 and 54 years. DIAGNOSTIC METHODS: The diagnosis is evoked primarily when confronted with an area of micro-calcifications discovered on a mammography. Needle aspiration cytology, useful in cases of palpable abnormalities or infra-clinical masses, is of no interest in isolated micro-calcifications for which surgical biopsy following radiological localisation is the technique of choice. Needle micro-biopsy permits collecting analysable tissue for histological but not cytological examination. Macro-biopsies combine stereotaxic localisation of micro-calcification areas and their excision when isolated. The choice of the method varies depending on the case. FROM AN ANATOMOPATHOLOGICAL POINT OF VIEW: Ductal or intra-galactophoric carcinomas are carcinomas of the glactophores that do not infiltrate the connective tissue. They are defined histologically by architectural and cytological characteristics, which differentiate them from lobular carcinomas in situ. They constitute a group of heterogenic lesions not only morphologically but also histologically and with regard to their progression. THERAPEUTIC MODALITIES: The aim of treatment is to ensure that the patients have a maximum of chances of cure at the cost of the least possible therapeutic consequences. Mastectomy, treatment of choice for many years, is still recommended in certain situations. In other cases, conservative treatment is possible so long as excision of the micro-calcifications is complete on the post-surgical mammography and, in the case of biopsy excision, that healthy margins of at least 10 millimetres exist. Following surgery, there is no sufficient consensus to propose essential recommendations concerning the place of monitoring alone, irradiation or tamoxifen.