Impact of ERAS in breast reconstruction with a latissimus dorsi flap, compared to conventional management.

BACKGROUND: Enhanced recovery after surgery (ERAS) programs are associated with improved management, reduced hospital stays, and lower complication rates. OBJECTIVE: To evaluate the impact of ERAS on mean length of stay (LOS) and postoperative morbidity in breast reconstruction with latissimus dorsi flap (LDF) compared with conventional recovery program. PATIENTS AND METHOD: All patients operated by LDF between December 2014 and October 2020: those managed before April 2018, when the ERAS protocol was introduced, were included in the "no ERAS" group, and beyond in the "ERAS" group. RESULTS: Out of 193 patients, 129 were included in the "ERAS" group and 64 in the "no ERAS" group. There was a significant difference between the two groups in LOS (4.2 ± 1.5 days in the "ERAS" group vs. 5.4 ± 1.9 days in the "no ERAS" group; p < 0.001), high-grade complications at 30 days (9.3% in the "ERAS" group vs. 25% in the "no ERAS" group; p = 0.01), reintervention rate (13.9% vs. 26.6%, respectively; p = 0.02), and 30-day rehospitalization rate (6.2% in the "ERAS" group vs. 15.6% in the "no ERAS" group; p = 0.03). CONCLUSION: The ERAS protocol has a positive impact on breast reconstruction with LDF without generating additional adverse effects. These results support the democratization of these programs for breast reconstruction surgery.

Cytochrome P-450-mediated herb and food-drug interactions can be identified in cancer patients through patient self-reporting with a tablet application: results of a prospective observational study.

BACKGROUND: Consumption of herbs, food used as medicine and dietary supplements (HFDSs) is common in cancer patients. Herbs and food-drug interactions (HFDIs) can lead to serious adverse effects and can be prevented. We previously reviewed cytochrome P-450 (CYP)-mediated HFDI for 261 HFDSs and we classified the risk of CYP inhibition and induction on a level of evidence scale from 1 (high evidence, supported by several clinical studies) to 5 (low evidence, only limited preclinical data). PATIENTS AND METHODS: We conducted a prospective, non-interventional study (NCT04128865) to assess whether self-assessment of patients could detect HFDI classified as 'probable' (i.e. level 1, 2 or 3 of the scale) in a population of cancer patients. Patients were invited through a tablet application to report their consumption of herbs, regular CYP-interacting food consumption and dietary supplements, as well as some clinical data and cancer treatments. The patient's completion of the survey could be supervised by a health care professional or not. A prespecified threshold of 5% of HFDIs classified as 'probable' detected with the application was deemed relevant. RESULTS: Between 29 March 2018 and 22 June 2018, 143 patients completed the survey. Ninety-five patients (66%) reported at least one current systemic cancer treatment and were included in the analyses. Seventy-four patients reported an intake of at least one HFDS (77.9%), while 21 patients reported no HFDS (22.1%). Twenty-two HFDIs classified as 'probable' were found in 16 patients (16.8%) with the application, which was significantly superior to the prespecified threshold (P = 0.02). The interactions were reported with food (n = 19, 86%) more frequently than with herbs (n = 3, 14%) or with dietary supplements (no interaction reported). CONCLUSIONS: Self-assessment of HFDS interaction with cancer treatment with an application is feasible and should be considered in daily routine. Prospective interventional studies should be conducted to better assess the clinical benefits of this approach.

Lymphovascular invasion has a significant prognostic impact in patients with early breast cancer, results from a large, national, multicenter, retrospective cohort study.

BACKGROUND: We determined the prognostic impact of lymphovascular invasion (LVI) in a large, national, multicenter, retrospective cohort of patients with early breast cancer (BC) according to numerous factors. PATIENTS AND METHODS: We collected data on 17 322 early BC patients treated in 13 French cancer centers from 1991 to 2013. Survival functions were calculated using the Kaplan-Meier method and multivariate survival analyses were carried out using the Cox proportional hazards regression model adjusted for significant variables associated with LVI or not. Two propensity score-based matching approaches were used to balance differences in known prognostic variables associated with LVI status and to assess the impact of adjuvant chemotherapy (AC) in LVI-positive luminal A-like patients. RESULTS: LVI was present in 24.3% (4205) of patients. LVI was significantly and independently associated with all clinical and pathological characteristics analyzed in the entire population and according to endocrine receptor (ER) status except for the time period in binary logistic regression. According to multivariate analyses including ER status, AC, grade, and tumor subtypes, the presence of LVI was significantly associated with a negative prognostic impact on overall (OS), disease-free (DFS), and metastasis-free survival (MFS) in all patients [hazard ratio (HR) = 1.345, HR = 1.312, and HR = 1.415, respectively; P < 0.0001], which was also observed in the propensity score-based analysis in addition to the association of AC with a significant increase in both OS and DFS in LVI-positive luminal A-like patients. LVI did not have a significant impact in either patients with ER-positive grade 3 tumors or those with AC-treated luminal A-like tumors. CONCLUSION: The presence of LVI has an independent negative prognostic impact on OS, DFS, and MFS in early BC patients, except in ER-positive grade 3 tumors and in those with luminal A-like tumors treated with AC. Therefore, LVI may indicate the existence of a subset of luminal A-like patients who may still benefit from adjuvant therapy.

Lack of prognostic impact of sentinel node micro-metastases in endocrine receptor-positive early breast cancer: results from a large multicenter cohort☆.

BACKGROUND: Prognostic impact of lymph node micro-metastases (pN1mi) has been discordantly reported in the literature. The need to clarify this point for decision-making regarding adjuvant therapy, particularly for patients with endocrine receptor (ER)-positive status and HER2-negative tumors, is further reinforced by the generalization of gene expression signatures using pN status in their recommendation algorithm. PATIENTS AND METHODS: We retrospectively analyzed 13 773 patients treated for ER-positive breast cancer in 13 French cancer centers from 1999 to 2014. Five categories of axillary lymph node (LN) status were defined: negative LN (pN0i-), isolated tumor cells [pN0(i+)], pN1mi, and pN1 divided into single (pN1 = 1) and multiple (pN1 > 1) macro-metastases (>2 mm). The effect of LN micro-metastases on outcomes was investigated both in the entire cohort of patients and in clinically relevant subgroups according to tumor subtypes. Propensity-score-based matching was used to balance differences in known prognostic variables associated with pN status. RESULTS: As determined by sentinel LN biopsy, 9427 patients were pN0 (68.4%), 546 pN0(i+) (4.0%), 1446 pN1mi (10.5%) and 2354 pN1 with macro-metastases (17.1%). With a median follow-up of 61.25 months, pN1 status, but not pN1mi, significantly impacted overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS), and breast-cancer-specific survival. In the subgroup of patients with known tumor subtype, pN1 = 1, as pN1 > 1, but not pN1mi, had a significant prognostic impact on OS. DFS and MFS were only impacted by pN1 > 1. Similar results were observed in the subgroup of patients with luminal A-like tumors (n = 7101). In the matched population analysis, pN1macro, but not pN1mi, had a statistically significant negative impact on MFS and OS. CONCLUSION: LN micro-metastases have no detectable prognostic impact and should not be considered as a determining factor in indicating adjuvant chemotherapy. The evaluation of the risk of recurrence using second-generation signatures should be calculated considering micro-metastases as pN0.

[Comparing prediction performances of 18F-FDG PET and CGFL/Curie nomogram to predict pathologic complete response after neoadjuvant chemotherapy for HER2-positive breast cancers]. / Comparaison des performances prédictives du TEP-TDM et du nomogramme CGFL/Curie pour prédire la réponse histologique complète après chimiothérapie néo-adjuvante des cancers du sein HER2-positifs.

OBJECTIVES: The aim of this study was to compare the value of 18F-fluorodesoxyglucose positron emission tomography (18F-FDG PET/CT) with CGFL/Curie nomogram to predict a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in women with human epidermal growth factor 2 (HER2)-positive breast cancer treated by trastuzumab. METHODS: Fifty-one women with HER2-positive breast cancer treated with trastuzumab plus taxane-based NAC were retrospectively included from January 2005 to December 2015. For 18F-FDG PET/CT, the analyzed predictor was the maximum standardized uptake value of the primary tumor and axillary nodes after the first course of NAC (PET2.SUVmax). pCR was defined by no residual infiltrative tumor but in situ tumor was accepted. Accuracy of CGFL/Curie nomogram and PET2.SUVmax was evaluated measuring sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV). Combined prediction was evaluated testing predictor's associations. RESULTS: For CGFL/Curie nomogram's performances, Se, Sp, PPV and NPV were respectively: 76% (95%CI: 58-90%), 57% (95%CI: 43-66%), 55% (95%CI: 42-65), 77% (95%CI: 59-90%). For PET2.SUVmax's performances, Se, Sp, PPV and NPV were respectively: 67% (95%CI: 48-81%), 77% (95%CI: 64-97%), 67% (95%CI: 48-82%), 77% (95%CI: 64-87%). ROC curves for these predictors were similar; the areas under the curve were 0.6 (95%CI: 0.56-0.64) for PET2.SUVmax and 0.55 (95%CI: 0.50-0.59) for CGFL/Curie nomogram. Combined prediction was efficient with Se at 80%, VPN at 76%, Sp at 78% and VPP at 81%. CONCLUSIONS: CGFL/Curie nomogram and PET2.SUVmax were two efficient predictors of pCR in patients with HER2-positive breast cancer. Combined prediction has an improved accuracy.

A multivariate Th17 metagene for prognostic stratification in T cell non-inflamed triple negative breast cancer.

A diversity of T helper (Th) subsets (Th1, Th2, Th17) has been identified in the human tumor microenvironment. In breast cancer, the role of Th subsets remains controversial, and a systematic study integrating Th subset diversity, T cell inflammation, breast cancer molecular subtypes, and patient prognosis, is lacking. In primary untreated breast cancer samples, we analyzed 19 Th cytokines at the protein level. Eight were T cell-specific, and subsequently measured in 106 prospectively-collected untreated samples. The dominant Th cytokines across all breast cancer samples were IFN-γ and IL-2. Th2 cytokines (IL-4, IL-5, IL-13) were expressed at low levels and not associated with any breast cancer subtype. Th17 cytokines (IL-17A and IL-17F) were up-regulated in triple negative breast cancer (TNBC), specifically in T cell non-inflamed tumors. In order to get insight into prognosis, we exploited the METABRIC transcriptomic dataset. We derived Th1, Th2, and Th17 metagenes based on manually curated Th signatures, and found that a high Th17 metagene was of good prognosis in T cell non-inflamed TNBC. Multivariate Cox modeling selected the Nottingham Prognostic Index (NPI), Th2 and Th17 metagenes as additive predictors of breast cancer-specific survival, which defined novel and highly distinct prognostic groups within TNBC. Our results reveal that Th17 is a novel prognostic composite biomarker in T cell non-inflamed TNBC. Integrating immune cell and tumor molecular diversity is an efficient strategy for prognostic stratification of cancer patients.

Stromal lymphocyte infiltration after neoadjuvant chemotherapy is associated with aggressive residual disease and lower disease-free survival in HER2-positive breast cancer.

BACKGROUND: The role of tumor-infiltrating lymphocytes (TILs) in breast cancer has been extensively studied over the last decade. High TILs levels have been associated with pathological response rate in the neoadjuvant setting and with better outcomes in the adjuvant setting. However, little attention has been paid to changes in TILs and residual TIL levels after neoadjuvant chemotherapy (NAC). We investigated TIL levels before, after chemotherapy, and their dynamics during treatment; and we assessed the correlation of these levels with response to NAC and prognosis. MATERIALS AND METHODS: We identified 175 patients with primary HER2-positive breast cancers receiving NAC+/- trastuzumab between 2002 and 2011. Microbiopsy specimens and paired surgical samples were evaluated for stromal lymphocyte infiltration. Univariate and multivariate analyses were carried out to assess the association of clinical and pathological factors with pathological complete response (pCR) and disease-free survival. RESULTS: Baseline TIL levels were not significantly associated with pCR. TIL levels decreased during treatment in 78% of the patients. The magnitude of the decrease was strongly associated with pCR. After chemotherapy, TIL levels were high in tumors displaying aggressive patterns (high residual cancer burden score, mitotic index >22, tumor cellularity >5%). In the population with residual disease, TIL levels >25% at the end of NAC were significantly associated with an adverse outcome (TILs >25%, HR = 7.98, P = 0.009) after multivariate analyses including BMI, post-NAC mitotic index and tumor grade. CONCLUSION: A decrease in TIL levels during chemotherapy was positively associated with response to treatment. In tumor failing to achieve pCR, post-NAC lymphocytic infiltration was associated with higher residual tumor burden and adverse clinical outcome. Further studies are required to characterize immune infiltration in residual disease to identify candidates who could benefit from second-line therapy trials including immune checkpoint inhibitors.

Adjuvant chemotherapy in pT1ab node-negative triple-negative breast carcinomas: Results of a national multi-institutional retrospective study.

BACKGROUND: Triple-negative breast cancers (TNBCs) are considered as associated with poor outcome, but prognosis of subcentimetric, node-negative disease remains controversial and evidence that adjuvant chemotherapy (CT) is effective in these small tumours remains limited. PATIENTS AND METHODS: Our objective was to investigate the impact of CT on survival in pT1abN0M0 TNBC. Patients were retrospectively identified from a cohort of 22,475 patients who underwent primary surgery in 15 French centres between 1987 and 2013. As rare pathological types may display very particular prognoses in these tumours, we retained only the invasive ductal carcinomas of no special type according to the last World Health Organisation (WHO) classification which is the most common TNBC histological type. End-points were disease-free survival (DFS) and metastasis-free survival (MFS). A propensity score for receiving CT was estimated using a logistic regression including age, tumour size, Scarff Bloom and Richardson (SBR) grade and lymphovascular invasion. RESULTS: Of a total of 284 patients with pT1abN0M0 ductal TNBC, 144 (51%) received CT and 140 (49%) did not. Patients receiving CT had more adverse prognostic features, such as tumour size, high grade, young age, and lymphovascular invasion. CT was not associated with a significant benefit for DFS (Hazard ratio, HR = 0.77 [0.40-1.46]; p = 0.419, log-rank test) or MFS (HR = 1.00 [0.46-2.19]; p = 0.997), with 5-year DFS and MFS in the group with CT versus without of 90% [81-94%] versus 84% [74-90%], and 90% [81-95%] versus 90% [83%-95%], respectively. Results were consistent in all supportive analyses including multivariate Cox model and the use of the propensity score for adjustment and as a matching factor for case-control analyses. CONCLUSIONS: This study did not identify a significant DFS or MFS advantage for CT in subcentimetric, node-negative ductal TNBC. Although current consensus guidelines recommend consideration of CT in all TNBC larger than 5 mm, clinicians should carefully discuss benefit/risk ratio with patients, given the unproven benefits.

Predictive factors of pathologic complete response of HER2-positive breast cancer after preoperative chemotherapy with trastuzumab: development of a specific predictor and study of its utilities using decision curve analysis.

PURPOSE: The aim of this study was to assess the Institut Gustave Roussy/M.D. Anderson Cancer Center (IGR/MDACC) nomogram in predicting pathologic complete response (pCR) to preoperative chemotherapy in a cohort of human epidermal growth factor receptor 2 (HER2)-positive tumors treated with preoperative chemotherapy with trastuzumab. We then combine clinical and pathological variables associated with pCR into a new nomogram specific to HER2-positive tumors treated by preoperative chemotherapy with trastuzumab. PATIENTS AND METHODS: Data from 270 patients with HER2-positive tumors treated with preoperative chemotherapy with trastuzumab at the Institut Curie and at the Georges François Leclerc Cancer Center were used to assess the IGR/MDACC nomogram and to subsequently develop a new nomogram for pCR based on multivariate logistic regression. Model performance was quantified in terms of calibration and discrimination. We studied the utility of the new nomogram using decision curve analysis. RESULTS: The IGR/MDACC nomogram was not accurate for the prediction of pCR in HER2-positive tumors treated by preoperative chemotherapy with trastuzumab, with poor discrimination (AUC = 0.54, 95% CI 0.51-0.58) and poor calibration (p = 0.01). After uni- and multivariate analysis, a new pCR nomogram was built based on T stage (TNM), hormone receptor status, and Ki67 (%). The model had good discrimination with an area under the curve (AUC) at 0.74 (95% CI 0.70-0.79) and adequate calibration (p = 0.93). By decision curve analysis, the model was shown to be relevant between thresholds of 0.3 and 0.7. CONCLUSION: To the best of our knowledge, ours is the first nomogram to predict pCR in HER2-positive tumors treated by preoperative chemotherapy with trastuzumab. To ensure generalizability, this model needs to be externally validated.

Axillary lymph node micrometastases decrease triple-negative early breast cancer survival.

BACKGROUND: Triple-negative breast cancers (TNBCs) are the most deadly form of breast cancer (BC) subtypes. Axillary lymph node involvement (ALNI) has been described to be prognostic in BC taken as a whole, but its prognostic value in each subtype is unclear. We explored the prognostic impact of ALNI and especially of small size axillary metastases in early TNBCs. METHODS: We analysed in this multicentre study all patients treated for early TNBC in 12 French cancer centres. We explored the correlation between clinicopathological data and ALNI, with a specific focus on the dichotomisation between macrometastases and occult metastases, which is defined as the presence of isolated tumour cells or micrometastases. The prognostic value of ALNI both in terms of disease-free survival (DFS) and overall survival (OS) was also explored. RESULTS: We included 1237 TNBC patients. Five-year DFS and OS were 83.7% and 88.5%, respectively. The identified independent prognostic features for DFS were tumour size >20 mm (hazard ratio (HR)=1.86; 95% CI: 1.11-3.10, P=0.018), lymphovascular invasion (HR=1.69; 95% CI: 1.21-2.34, P=0.002) and ALNI both in case of macrometastases (HR=1.97; 95% CI: 1.38-2.81, P<0.0001) and occult metastases (HR=1.72; 95% CI: 1.1-2.71, P=0.019). DFS and OS were similar between tumours with occult metastases and macrometastases. Tumours presenting at least two pejorative features (out of ALNI, lymphovascular invasion and large tumour size) displayed a significantly poorer DFS in both the training set and validation set, independently of chemotherapy administration. Tumours with no more than one of the above-cited pejorative features had a 5-year OS of ⩾90% vs 70% for other cases (P<0.0001). CONCLUSIONS: Axillary lymph node involvement is a key prognostic feature for early TNBC when isolated tumour cells were identified in lymph nodes. This impact is independent of chemotherapy use.

Impact of completion axillary lymph node dissection in patients with breast cancer and isolated tumour cells or micrometastases in sentinel nodes.

BACKGROUND: Omission of completion axillary lymph node dissection (ALND) is a standard practice in patients with breast cancer (BC) and negative sentinel nodes (SNs) but has shown insufficient evidence to be recommended in those with SN invasion. METHODS: A retrospective analysis of a cohort of patients with BC and micrometastases (Mic) or isolated tumour cells (ITCs) in SN. Factors associated with ALND were identified, and patients with ALND were matched to patients without ALND. Overall survival (OS) and recurrence-free survival (RFS) were estimated in the overall population, in Mic and in ITC cohorts. FINDINGS: Among 2009 patients analysed, 1390 and 619 had Mic and ITC in SN, respectively. Factors significantly associated with ALND were SN status, histological type, age, number of SN harvested and absence of adjuvant chemotherapy. After a median follow-up of 60.4 months, ALND omission was independently associated with reduced OS (hazard ratio [HR] 2.41, 90 confidence interval [CI] 1.36-4.27, p = 0.0102), but not with increased RFS (HR 1.21, 90 CI 0.74-2.0, p = 0.52) in the overall population. In matched patients, the increased risk of death in case of ALND omission was found only in the Mic cohort (HR 2.88, 90 CI 1.46-5.69), not in the ITC cohort. The risk of recurrence was also significantly increased in the subgroup of matched Mic patients (HR 1.56, 90 CI 0.90-2.73). INTERPRETATION: A separate analysis of Mic and ITC groups, matched for the determinants of ALND, suggested that patients with Mic had increased recurrence rates and shorter OS when ALND was not performed. Our results are consistent with those of previous studies for patients with ITC but not for those with Mic. Randomised controlled clinical trials are still warranted to show with a high level of evidence if ALND can be safely omitted in patients with micrometastatic disease in SN.

Biological network-driven gene selection identifies a stromal immune module as a key determinant of triple-negative breast carcinoma prognosis.

Triple-negative breast cancer (TNBC) is a heterogeneous group of aggressive breast cancers for which no targeted treatment is available. Robust tools for TNBC classification are required, to improve the prediction of prognosis and to develop novel therapeutic interventions. We analyzed 3,247 primary human breast cancer samples from 21 publicly available datasets, using a five-step method: (1) selection of TNBC samples by bimodal filtering on ER-HER2 and PR, (2) normalization of the selected TNBC samples, (3) selection of the most variant genes, (4) identification of gene clusters and biological gene selection within gene clusters on the basis of String© database connections and gene-expression correlations, (5) summarization of each gene cluster in a metagene. We then assessed the ability of these metagenes to predict prognosis, on an external public dataset (METABRIC). Our analysis of gene expression (GE) in 557 TNBCs from 21 public datasets identified a six-metagene signature (167 genes) in which the metagenes were enriched in different gene ontologies. The gene clusters were named as follows: Immunity1, Immunity2, Proliferation/DNA damage, AR-like, Matrix/Invasion1 and Matrix2 clusters respectively. This signature was particularly robust for the identification of TNBC subtypes across many datasets (n = 1,125 samples), despite technology differences (Affymetrix© A, Plus2 and Illumina©). Weak Immunity two metagene expression was associated with a poor prognosis (disease-specific survival; HR = 2.68 [1.59-4.52], p = 0.0002). The six-metagene signature (167 genes) was validated over 1,125 TNBC samples. The Immunity two metagene had strong prognostic value. These findings open up interesting possibilities for the development of new therapeutic interventions.

Estrogen-Receptor, Progesterone-Receptor and HER2 Status Determination in Invasive Breast Cancer. Concordance between Immuno-Histochemistry and MapQuant™ Microarray Based Assay.

BACKGROUND: Hormone receptor status and HER2 status are of critical interest in determining the prognosis of breast cancer patients. Their status is routinely assessed by immunohistochemistry (IHC). However, it is subject to intra-laboratory and inter-laboratory variability. The aim of our study was to compare the estrogen receptor, progesterone receptor and HER2 status as determined by the MapQuant™ test to the routine immuno-histochemical tests in early stage invasive breast cancer in a large comprehensive cancer center. PATIENTS AND METHODS: We retrospectively studied 163 invasive early-stage breast carcinoma with standard IHC status. The genomic status was determined using the MapQuant™ test providing the genomic grade index. RESULTS: We found only 4 tumours out of 161 (2.5%) with discrepant IHC and genomic results concerning ER status. The concordance rate between the two methods was 97.5% and the Cohen's Kappa coefficient was 0.89. Comparison between the MapQuant™ PR status and the PR IHC status gave more discrepancies. The concordance rate between the two methods was 91.4% and the Cohen's Kappa coefficient was 0.74. The HER2 MapQuant™ test was classified as « undetermined ¼ in 2 out of 163 cases (1.2%). One HER2 IHC-negative tumour was found positive with a high HER2 MapQuant™ genomic score. The concordance rate between the two methods was 99.3% and the Cohen's Kappa coefficient was 0.86. CONCLUSION: Our results show that the MapQuant™ assay, based on mRNA expression assay, provides an objective and quantitative assessment of Estrogen receptor, Progesterone receptor and HER2 status in invasive breast cancer.

p63/MT1-MMP axis is required for in situ to invasive transition in basal-like breast cancer.

The transition of ductal carcinoma in situ (DCIS) to invasive breast carcinoma requires tumor cells to cross the basement membrane (BM). However, mechanisms underlying BM transmigration are poorly understood. Here, we report that expression of membrane-type 1 (MT1)-matrix metalloproteinase (MMP), a key component of the BM invasion program, increases during breast cancer progression at the in situ to invasive breast carcinoma transition. In the intraductal xenograft model, MT1-MMP is required for BM transmigration of MCF10DCIS.com breast adenocarcinoma cells and is overexpressed in cell clusters overlying focal BM disruptions and at the invasive tumor front. Mirrored upregulation of p63 and MT1-MMP is observed at the edge of MCF10DCIS.com xenograft tumors and p63 is required for induction of MT1-MMP-dependent invasive program in response to microenvironmental signals. Immunohistochemistry and analysis of public database reveal that p63 and MT1-MMP are upregulated in human basal-like breast tumors suggesting that p63/MT1-MMP axis contributes to progression of basal-like breast cancers with elevated p63 and MT1-MMP levels.

Prognostic impact of discrepant Ki67 and mitotic index on hormone receptor-positive, HER2-negative breast carcinoma.

BACKGROUND: Inconsistencies between mitotic index (MI) and Ki67 measures have been identified in many breast tumour samples. The aim of this study was to describe the prognosis of hormone receptor-positive (HR+) HER2- tumours having discrepant MI and Ki67. METHODS: We included a cohort of breast cancer patients initially treated by surgery between 2001 and 2005 in the Institut Curie. Breast cancer-specific survival (BCSS) and disease-free survival (DFS) were analysed according to three proliferation groups: high MI/high Ki67 (MI=3, Ki67>20%), low MI/low Ki67 (MI<3, Ki67⩽20%) and discrepant (high MI/low Ki67 or low MI/high Ki67). RESULTS: Among the 1430 patients, 19.6% had discrepant Ki67 and MI, 11.6% had high markers and 68.8% had low markers. The 5-year BCSS was 95.8%, 95% CI (0.93-0.98) in the discrepant group, 99.3%, 95% CI (0.993-0.999) in the low-proliferation group and 91.8%, 95% CI (0.88-0.96) in the high-proliferation group. In multivariate analysis, the survival of the discrepant group was lower than that of the low-proliferation group: BCSS hazard ratio (HR)=3.01 (1.32-6.84; P=0.008) and DFS HR=2.07, 95% CI (1.31-3.26; P=0.002). Among grade 2 tumours in multivariate analysis, DFS of the discrepant group was lower than that of the low MI/low Ki67 group: HR=1.98, 95% CI (1.14-3.46), P=0.02. Regarding BCSS, the obtained results were similar. CONCLUSION: The prognosis of patients with discrepant MI and Ki67 appears intermediate between that of low MI/low Ki67 and high MI/high Ki67 groups. These markers should be jointly analysed to clarify prognosis.

Time-varying effect and long-term survival analysis in breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: Recent studies have indicated the prognostic value of tumour subtype and pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). However these results were reported after a short follow-up and using a standard Cox model which could be unsatisfactory for time-dependent factors. In the present study, we identified the prognostic factors for long-term outcome after NAC, considering that they could have an inconstant impact over time. METHODS: Prognostic factors from 956 consecutive breast cancer patients treated with NAC were identified and associated with long-term outcomes. We estimated survival by a time function multivariate Cox model regression and stratified by follow-up length. RESULTS: The prognostic value of tumour histological grade and hormone receptors status varied as distant recurrence-free interval (DRFI) increased. The multivariate analysis identified the following significant prognostic factors: tumour size, N stage, clinical and pathological response to NAC, hormone receptors (HR) status and histological tumour grade. The 'prognostic benefit' of low-grade and positive-HR status decreased over the years. Thus, in the early years after cancer diagnosis, the hazard ratio of distant recurrences in patients with positive-HR status increased from 0.26 (95% CI 0.1-0.4) at 6 months to 2.2 (95% CI 1.3-3.7) at 120 months. The histological tumour grade followed a similar trend. The hazard ratio of grade III patients compared with grade I was 1.83 (95% CI 1.1-2.8) at 36 months and diminished over time to 0.70 (95% CI 0.4-1.3) at 120 months. This indicates that the risk of recurrence for positive-HR patients was 74% lower at 6 months compared with the negative-hormone receptor group, but 30% higher at 5 years and more than double at 10 years. High-grade tumours presented a risk of 83% in the earlier years decreasing to 30% at 10 years versus the low-grade group. CONCLUSION: From the present study, we conclude the importance of identifying time-dependent prognostic factors. Distant recurrence-free interval within women who receive NAC are influenced by achieving pCR and breast cancer subtype. Tumours with more aggressive biology have poorer survival during the first 5 years, but if they exceed this point their prognostic impact is no longer significant. Conversely, positive-HR patients remain at risk for distant recurrence for many years.

Response to dual HER2 blockade in a patient with HER3-mutant metastatic breast cancer.

BACKGROUND: HER3 activating mutations have been shown in preclinical models to be oncogenic and ligand-independent, but to depend on kinase-active HER2. PATIENTS AND METHODS: Whole-exome sequencing of the primary HER2-negative breast cancer and its HER2-negative synchronous liver metastasis from a 46-year-old female revealed the presence of an activating and clonal HER3 G284R mutation. RESULTS: HER2 dual blockade with trastuzumab and lapatinib as third-line therapy led to complete metabolic response in 2 weeks and confirmed radiological partial response after 8 weeks. Following the resection of the liver metastasis, the patient remains disease-free 40 weeks after initiation of the HER2 dual blockade therapy. Immunohistochemical analysis demonstrated a substantial reduction of phospho-rpS6 and phospho-AKT in the post-therapy biopsy of the liver metastasis. DISCUSSION: This is the first-in-man evidence that anti-HER2 therapies are likely effective in breast cancers harboring HER3 activating mutations.

Are we able to predict survival in ER-positive HER2-negative breast cancer? A comparison of web-based models.

BACKGROUND: Several prognostic models have been proposed and demonstrated to be predictive of survival outcomes in breast cancer. In the present article, we assessed whether three of these models are comparable at an individual level. METHODS: We used a large data set (n=965) of women with hormone receptor-positive and HER2-negative early breast cancer from the public data set of the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) study. We compared the overall performance of three validated web-based models: Adjuvant!, CancerMath.net and PREDICT, and we assessed concordance of these models in 10-year survival prediction. RESULTS: Discrimination performances of the three calculators to predict 10-year survival were similar for the Adjuvant! Model, 0.74 (95% CI 0.71-0.77) for the Cancermath.net model and 0.72 (95% CI 0.69-0.75) for the PREDICT model). Calibration performances, assessed graphically, were satisfactory. Predictions were concordant and stable in the subgroup, with a predicted survival higher than 90% with a median score dispersion at 0.08 (range 0.06-0.10). Dispersion, however, reached 30% for the subgroups with a predicted survival between 10 and 50%. CONCLUSION: This study revealed that the three web-based predictors equally perform well at the population level, but exhibit a high degree of discordance in the intermediate and poor prognosis groups.

Association of the number of sentinel lymph nodes harvested with survival in breast cancer.

AIMS: In patients with breast cancer, the association between the number of sentinel lymph node (SLN) removed and survival is poorly known. Our objective was to evaluate this association on disease-specific survival (DSS). METHODS: Data of 144 517 patients with invasive T1-3M0 breast carcinoma and initial treatment with SLN biopsy were extracted from the SEER database. Univariate and multivariate analyses were performed. RESULTS: The number of SLNs harvested and the completion of axillary lymph node dissection (ALND) were not associated with DSS improvement for patients without metastatic nodes. After adjustment, patients with three SLNs had a better DSS than did other groups (HR of 0.73 CI 95% [0.60-0.88], p = 0.001). This result was mainly driven by the group of patients with one metastatic LN. When patients had two or more metastatic LNs, there was no difference in DSS according to the number of SLNs or to completion of ALND. CONCLUSIONS: The number of SLN harvested was associated with DSS. According to DSS, the optimal number of SLNs harvested was three in this large series, thereby calling into question the understaging or undertreatment of SLN biopsy in which only one or two SLNs are harvested but also the therapeutic effect of completion ALND.