Negative Survival Impact of Occult Lymph Node Involvement in Small HER2-Positive Early Breast Cancer Treated by Up-Front Surgery.

(1) Background: The independent negative prognostic value of isolated tumor cells or micro-metastases in axillary lymph nodes has been established in triple-negative breast cancers (BC). However, the prognostic significance of pN0(i+) or pN1mi in HER2-positive BCs treated by primary surgery remains unexplored. Therefore, our objective was to investigate the impact of pN0(i+) or pN1mi in HER2-positive BC patients undergoing up-front surgery on their outcomes. (2) Methods: We retrospectively analyzed 23,650 patients treated in 13 French cancer centers from 1991 to 2013. pN status was categorized as pN0, pN0(i+), pN1mi, and pNmacro. The effect of pN0(i+) or pN1mi on outcomes was investigated both in the entire cohort of patients and in pT1a-b tumors. (3) Results: Of 1771 HER2-positive BC patients included, pN status distributed as follows: 1047 pN0 (59.1%), 60 pN0(i+) (3.4%), 118 pN1mi (6.7%), and 546 pN1 macro-metastases (30.8%). pN status was significantly associated with sentinel lymph node biopsy, axillary lymph node dissection, age, ER status, tumor grade, and size, lymphovascular invasion, adjuvant systemic therapy (ACt), and radiation therapy. With 61 months median follow-up (mean 63.2; CI 95% 61.5-64.9), only pN1 with macro-metastases was independently associated with a negative impact on overall, disease-free, recurrence-free, and metastasis-free survivals in multivariate analysis. In the pT1a-b subgroup including 474 patients, RFS was significantly decreased in multivariate analysis for pT1b BC without ACt (HR 2.365, 1.04-5.36, p = 0.039) and for pN0(i+)/pN1mi patients (HR 2.518, 1.03-6.14, p = 0.042). (4) Conclusions: Survival outcomes were not adversely affected by pN0(i+) and pN1mi in patients with HER2-positive BC. However, in the case of pT1a-b HER2-positive BC, a negative impact on RFS was observed specifically for patients with pN0(i+) and pN1mi diseases, particularly among those with pT1b tumors without ACt. Our findings highlight the importance of considering the pN0(i+) and pN1mi status in the decision-making process when discussing trastuzumab-based ACt for these patients.

Triple-negative and Her2-positive breast cancer in women aged 70 and over: prognostic impact of age according to treatment.

Background: Elderly breast cancer (BC) patients have been underrepresented in clinical trials whereas ~60% of deaths from BC occur in women aged 70 years and older. Only limited data are available on the prognostic impact of age according to treatment, especially in the triple-negative (TN) and Her2-positive because of the lower frequency of these subtypes in elderly patients. We report herein the results of a multicenter retrospective study analyzing the prognostic impact of age according to treatment delivered in TN and Her2-positive BC patients of 70 years or older, including comparison by age groups. Methods: The medical records of 31,473 patients treated from January 1991 to December 2018 were retrieved from 13 French cancer centers for retrospective analysis. Our study population included all ≥70 patients with TN or Her2-positive BC treated by upfront surgery. Three age categories were determined: 70-74, 75-80, and > 80 years. Results: Of 528 patients included, 243 patients were 70-74 years old (46%), 172 were 75-80 years (32.6%) and 113 were >80 years (21.4%). Half the population (51.9%, 274 patients) were TN, 30.1% (159) Her2-positive/hormone receptors (HR)-positive, and, 18% (95) Her2-positive/endocrine receptors (ER)-negative BC. Advanced tumor stage was associated with older age but no other prognostic factors (tumor subtype, tumor grade, LVI). Adjuvant chemotherapy delivery was inversely proportional to age. With 49 months median follow-up, all patient outcomes (overall survival (OS), disease-free survival (DFS), breast cancer-specific survival (BCSS), and recurrence-free survival (RFS)) significantly decreased as age increased. In multivariate analysis, age >80, pT2-3 sizes, axillary macrometastases, lymphovascular involvement, and HR-negativity tumor negatively affected DFS and OS. Comparison between age >80 and <=80 years old showed worse RFS in patients aged > 80 (HR=1.771, p=0.031). Conclusion: TN and Her2-positive subtypes occur at similar frequency in elderly patients. Older age is associated with more advanced tumor stage presentation. Chemotherapy use decreases with older age without worse other pejorative prognostic factors. Age >80, but not ≤80, independently affected DFS and OS.

Lymph node positivity in different early breast carcinoma phenotypes: a predictive model.

BACKGROUND: A strong correlation between breast cancer (BC) molecular subtypes and axillary status has been shown. It would be useful to predict the probability of lymph node (LN) positivity. OBJECTIVE: To develop the performance of multivariable models to predict LN metastases, including nomograms derived from logistic regression with clinical, pathologic variables provided by tumor surgical results or only by biopsy. METHODS: A retrospective cohort was randomly divided into two separate patient sets: a training set and a validation set. In the training set, we used multivariable logistic regression techniques to build different predictive nomograms for the risk of developing LN metastases. The discrimination ability and calibration accuracy of the resulting nomograms were evaluated on the training and validation set. RESULTS: Consecutive sample of 12,572 early BC patients with sentinel node biopsies and no neoadjuvant therapy. In our predictive macro metastases LN model, the areas under curve (AUC) values were 0.780 and 0.717 respectively for pathologic and pre-operative model, with a good calibration, and results with validation data set were similar: AUC respectively of 0.796 and 0.725. Among the list of candidate's regression variables, on the training set we identified age, tumor size, LVI, and molecular subtype as statistically significant factors for predicting the risk of LN metastases. CONCLUSIONS: Several nomograms were reported to predict risk of SLN involvement and NSN involvement. We propose a new calculation model to assess this risk of positive LN with similar performance which could be useful to choose management strategies, to avoid axillary LN staging or to propose ALND for patients with high level probability of major axillary LN involvement but also to propose immediate breast reconstruction when post mastectomy radiotherapy is not required for patients without LN macro metastasis.

Survival impact and predictive factors of axillary recurrence after sentinel biopsy.

BACKGROUND: The rate of axillary recurrence (AR) after sentinel lymph node biopsy is usually low but few studies investigated its impact on survival. Our aim was to determine the rate and predictive factors of AR in a large cohort of breast cancer patients and its impact on survival. PATIENTS AND METHODS: From 1999 to 2013, 14,095 patients who underwent surgery for clinically N0 previously untreated breast cancer and had sentinel lymph node biopsy were analysed. A simplified score predictive of AR was established. RESULTS: Median follow-up was 55.2 months. AR was observed in 0.51% of cases, with a median time to onset of 43.4 months. In multivariate analysis, the occurrence of AR was significantly correlated with grade 2 or 3 disease, absence of radiotherapy and tumour subtype (hormonal receptor [HR]- / human estrogen receptor [HER]+). AR rates were 1% for triple-negative tumours, 2.8% for HER2-positive tumours, 0.4% for luminal A tumours, 0.9% for HER2-negative luminal B tumours, and 0.5% for HER2-positive luminal B tumours. A simplified score predictive of the occurrence of AR was established. Patients could be divided into three different score groups (p < 0.0001). In multivariate analysis, overall survival was significantly lower in cases of AR (p < 0.0001), age >50, lymphovascular invasion, grade 3 disease, sentinel node (SN) macrometastases, tumour size >20 mm, absence of chemotherapy and triple-negative phenotype. Survival in patients with AR was significantly lower in case of early-onset (2 years) AR (p = 0.017). CONCLUSIONS: Isolated AR is more common in Her2-positive/HR-negative triple-negative tumours with a more severe prognosis in triple-negative and Her2-positive/HR-negative tumours, and represents an independent adverse factor justifying an indication for systemic treatment for AR treatment. However, the benefit of any systemic treatment remains to be proven.

Non sentinel node involvement prediction for sentinel node micrometastases in breast cancer: nomogram validation and comparison with other models.

PURPOSE: The risk of non sentinel node (NSN) involvement varies in function of the characteristics of sentinel nodes (SN) and primary tumor. Our aim was to determine and validate a statistical tool (a nomogram) able to predict the risk of NSN involvement in case of SN micro or sub-micrometastasis of breast cancer. We have compared this monogram with other models described in the literature. METHODS: We have collected data on 905 patients, then 484 other patients, to build and validate the nomogram and compare it with other published scores and nomograms. RESULTS: Multivariate analysis conducted on the data of the first cohort allowed us to define a nomogram based on 5 criteria: the method of SN detection (immunohistochemistry or by standard coloration with HES); the ratio of positive SN out of total removed SN; the pathologic size of the tumor; the histological type; and the presence (or not) of lympho-vascular invasion. The nomogram developed here is the only one dedicated to micrometastasis and developed on the basis of two large cohorts. The results of this statistical tool in the calculation of the risk of NSN involvement is similar to those of the MSKCC (the similarly more effective nomogram according to the literature), with a lower rate of false negatives. CONCLUSION: this nomogram is dedicated specifically to cases of SN involvement by metastasis lower or equal to 2 mm. It could be used in clinical practice in the way to omit ALND when the risk of NSN involvement is low.

[Sentinel lymph node negative breast cancer larger than 30 mm: is axillary lymph node dissection constantly necessary?]. / Peut-on s'abstenir d'un curage axillaire systématique pour les cancers du sein de plus de 30 millimètres sans atteinte ganglionnaire sentinelle?

Benefits provided by sentinel lymph node biopsy (SLNB) include improvement of pathologic examination and lower rate of sequels. The aim of this study was to assess the accuracy of this procedure in large tumors. From march 1999 and december 2003, 663 patients were operated for a breast cancer and underwent a SLNB. All patients with tumor larger than 30 mm and/or with involved SLNB underwent a complete axillary dissection (AD). One hundred and sixteen patients (17.5%) with a tumor larger than 30 mm underwent an AD. Identification rate of SLNB was 94% (109/116). Among the 43 cases with non metastatic SLNB, the AD was negative in 39 cases (90.7%). In four cases a palpable non sentinel lymph node discovered during the SLNB procedure was found to be involved. In one case the lymphoscintigraphy found only one lymph node with a very low fixation and an AD was performed because of low efficiency of the lymphoscintigraphy procedure. SLNB false negative rate was 1.4 % (1/72) among the 72 cases with lymph node involvement. AD was performed in 66 cases (60.5%) during the same operating time than the SLNB. AD showed a lymph node involvement in 30 cases (30/72, 41.7%): in 5 cases among 24 cases with microscopic disease (20.8%) and in 25 cases among 48 cases with macroscopic disease (52%). This series results suggest than AD could be avoided for negative SLNB tumors up to 50 mm at pathologic examination in patients with clinically-measured tumor smaller than 30 mm.

Nonvisualization of axillary sentinel node during lymphoscintigraphy: is there a pathologic significance in breast cancer?

UNLABELLED: The aim of this study was to define the factors associated with nonvisualization of a sentinel node (SN) in the axilla area during preoperative lymphoscintigraphy. METHODS: We retrospectively studied 332 women with T0, T1, or T2 <3-cm, N0 invasive breast cancer who underwent a sentinel lymph node biopsy procedure. All patients had intradermal and intraparenchymal injection of 37 MBq (99m)Tc-sulfur colloid in a total volume of 4 x 0.1 mL, above and around the tumor. Anterior and lateral static views were obtained a few minutes and 2-4 h after injection. Surgery was performed the next day. The SNs were localized intraoperatively with the aid of patent blue dye and using a hand-held gamma-probe. SNs were analyzed by serial sections stained with hematoxylin-eosin, with the adjacent section stained with anticytokeratin antibodies. Different parameters, such as the number of positive lymph nodes, presence of lymphovascular invasion, tumor size, tumor grade, histology (invasive vs. in situ), prior excisional biopsy, and patient age were analyzed to determine whether they had any significant correlation with nonvisualization of SNs in the axillary area. RESULTS: An axillary SN was successfully visualized on the preoperative lymphoscintigraphy in 302 of 332 patients (90.7%). No axillary drainage was found in 30 patients on the delayed images, even after a second injection of radiocolloid, and 5 of 30 patients showed uptake outside the axillary area. Positive nodes were identified in 86 of 302 patients (28.5%) with successful axillary drainage and in 19 of 30 patients (63.3%) with unsuccessful axillary drainage. More than 4 invaded axillary nodes (P < 0.0001) and the presence of lymphovascular invasion in the breast tumor (P = 0.004) were the only significant variables on univariate analysis, although multivariate analysis showed that only the increased number of invaded nodes was statistically significant. CONCLUSION: Patients with unsuccessful axillary mapping have an increased risk for axillary involvement.

[Risk of stage underestimation of breast cancer by sentinel lymph node biopsy method]. / Du risque de sous-traitement des cancers du sein en utilisant la technique du ganglion sentinelle.

Sentinel lymph node (SLN) biopsy is fast becoming the standard for testing lymph node involvement in many institutions. However questions remain as to stage underestimation. The aim of this study was to analyse this specific risk in a retrospective study. Between 1975 to 1999, 1,636 patients underwent a breast cancer excision and an axillary lymph node dissection (ALND) for 437 T0, 766 T1 or 433 T2 < or = 30 mm breast cancer without axillary lymph node involvement (NO). We analyse this population because of similar characteristics with SLN biopsy present indication. Node involvement rate was analysed regarding predictive factors of lymph node involvement (LNI): pathologic diameter, grading, peritumoral vascular embols, hormonal receptors, menopause and age. Risk of no adjuvant chemotherapy indication in case of SLN biopsy method using was analysed for pre and post menopaused women. Overall lymph node involvement was 27% (444/1,636): 17% for TO stage (74/437), 26% for T1 stage (202/766), 39% for T2 < or =30 mm stage (168/433). LNI was similar for ductai and lobular invasive breast cancer respectively 27,4% (308/1,125) and 24,3% (52/214). On the other hand LNI rate was sign lower for tubular, medullar and colloids cancers: 15% (20/155). Univariate and multivariate statistical analysis showed LNI significative predictive factors: vascular embols, grade III, age < or = 50 years, tumor diameter > 30 mm. Lymph node involvement rate was defined regarding grading, vascular embols and tumor diameter with increasing rate according to different sub-groups. Among pre-menopaused patients with a false negative rate of SLN of 5%, SLN biopsy without ALND give a specific risk of wrong non-adjuvant chemotherapy indication of 1,4 case/1,000. Among menopaused patients SLN biopsy without ALND give a specific risk of 0,93 cases/1,000. Expected LNI regarding major predictive factors (vascular embols, grading and tumor diameter) allows SLN biopsy risk/benefit evaluation in different sub-groups. SLN biopsy indication could he improved according these data which could be obtain pre-operatively by micro-biopsy.