The Cox model relies on the proportional hazards (PH) assumption, implying that the factors investigated have a constant impact on the hazard - or risk - over time. We emphasize the importance of ...this assumption and the misleading conclusions that can be inferred if it is violated; this is particularly essential in the presence of long follow-ups.
We illustrate our discussion by analyzing prognostic factors of metastases in 979 women treated for breast cancer with surgery. Age, tumour size and grade, lymph node involvement, peritumoral vascular invasion (PVI), status of hormone receptors (HRec), Her2, and Mib1 were considered.
Median follow-up was 14 years; 264 women developed metastases. The conventional Cox model suggested that all factors but HRec, Her2, and Mib1 status were strong prognostic factors of metastases. Additional tests indicated that the PH assumption was not satisfied for some variables of the model. Tumour grade had a significant time-varying effect, but although its effect diminished over time, it remained strong. Interestingly, while the conventional Cox model did not show any significant effect of the HRec status, tests provided strong evidence that this variable had a non-constant effect over time. Negative HRec status increased the risk of metastases early but became protective thereafter. This reversal of effect may explain non-significant hazard ratios provided by previous conventional Cox analyses in studies with long follow-ups.
Investigating time-varying effects should be an integral part of Cox survival analyses. Detecting and accounting for time-varying effects provide insights on some specific time patterns, and on valuable biological information that could be missed otherwise.
Purpose
Neurotensin receptor-1 (NTS
1
) is increasingly recognized as a potential target in diverse tumors including breast cancer, but factors associated with NTS
1
expression have not been fully ...clarified.
Methods
We studied NTS
1
expression using the Tissue MicroArray (TMA) of primary breast tumors from Institut Bergonié. We also studied association between NTS
1
expression and clinical, pathological, and biological parameters, as well as patient outcomes.
Results
Out of 1419 primary breast tumors, moderate to strong positivity for NTS
1
(≥ 10% of tumoral cells stained) was seen in 459 samples (32.4%). NTS
1
staining was cytoplasmic in 304 tumors and nuclear in 155 tumors, a distribution which appeared mutually exclusive. Cytoplasmic overexpression of NTS
1
was present in 21.5% of all breast tumors. In multivariate analysis, factors associated with cytoplasmic overexpression of NTS
1
in breast cancer samples were higher tumor grade, Ki67 ≥ 20%, and higher pT stage. Cytoplasmic NTS
1
was more frequent in tumors other than luminal A (30% versus 17.3%;
p
< 0.0001). Contrastingly, the main “correlates” of a nuclear location of NTS
1
were estrogen receptor (ER) positivity, low E&E (Elston and Ellis) grade, Ki67 < 20%, and lower pT stage. In NTS
1
-positive samples, cytoplasmic expression of NTS
1
was associated with shorter 10-year metastasis-free interval (
p
= 0.033) compared to NTS
1
nuclear staining. Ancillary analysis showed NTS
1
expression in 73% of invaded lymph nodes from NTS
1
-positive primaries.
Conclusion
NTS
1
overexpression was found in about one-third of breast tumors from patients undergoing primary surgery with two distinct patterns of distribution, cytoplasmic distribution being more frequent in aggressive subtypes. These findings encourage the development of NTS
1
-targeting strategy, including radiopharmaceuticals for imaging and therapy.
Objectives
To evaluate the diagnostic accuracy of breast MRI in identifying lesions requiring excision for patients with suspicious nipple discharge but normal mammograms and ultrasounds.
Methods
...Between September 2013 and May 2019, 106 female participants (mean age 57.9 years) were consecutively included in this prospective multicenter study; 102 were retained for analysis. MRI was considered negative in the absence of suspicious enhancement and positive in cases of ipsilateral abnormal enhancement (BI-RADS 3 to 5). Final diagnoses were based on histological findings of surgical or percutaneous biopsies or at 1-year follow-up. We considered all lesions requiring excision found on pathology (papilloma, atypia, nipple adenomatosis, or cancer) as positive results. We considered spontaneous resolution of the discharge at 1 year as a negative result.
Results
MRI showed ipsilateral abnormal enhancement in 54 patients (53%) revealing 46 lesions requiring excision (31 benign papillomas, 5 papillomas with atypia, 2 nipple adenomatosis, and 8 cancers) and 8 benign lesions not requiring excision. No suspicious enhancement was found in the remaining 48 participants (47%). Forty-two were followed up at 1 year with spontaneous resolution of the discharge and six underwent surgery (revealing 2 benign papillomas). MRI diagnostic accuracy for the detection of a lesion requiring excision was as follows: sensitivity 96%, specificity 85%, positive predictive value 85%, and negative predictive value 96%.
Conclusion
In patients with suspicious nipple discharge and normal mammogram and ultrasound, MRI demonstrates excellent performance to identify lesions for which excision is required. Normal MRI indicates it is safe to propose follow-up only management, thus avoiding unnecessary duct excision.
Trial registration
ClinicalTrials.gov
NCT02819362
Key Points
• Breast MRI can be useful for the management of patients with suspicious nipple discharge and negative mammogram and ultrasound.
• MRI detected a lesion requiring excision in 46 participants (45%) with unexplained discharge.
• If breast MRI is negative, follow-up is a safe alternative for these patients.
Desmoid tumors are mesenchymal fibroblastic/myofibroblastic proliferations with locoregional aggressiveness and high ability to recur after initial treatment. We present the results of the largest ...series of sporadic desmoid tumors ever published to determine the prognostic factors of these rare tumors.
Four hundred twenty-six patients with a desmoid tumor at diagnosis were included, and the following parameters were studied: age, sex, delay between first symptoms and diagnosis, tumor size, tumor site, previous history of surgery or trauma in the area of the primary tumor, surgical margins, and context of abdominal wall desmoids in women of child-bearing age during or shortly after pregnancy. We performed univariate and multivariate analysis for progression-free survival (PFS).
In univariate analysis, age, tumor size, tumor site, and surgical margins (R2 v R0/R1) had a significant impact on PFS. PFS curves were not significantly different for microscopic assessment of surgical resection quality (R0 v R1). In multivariate analysis, age, tumor size, and tumor site had independent values. Three prognostic groups for PFS were defined on the basis of the number of independent unfavorable prognostic factors (0 or 1, 2, and 3).
This study clearly demonstrates that there are different prognostic subgroups of desmoid tumors that could benefit from different therapeutic strategies, including a wait-and-see policy.
Objective factors for making choices about the treatment of elderly patients with cancer are lacking. This investigation aimed to help physicians select appropriate treatments through the ...identification of factors that predict early death (< 6 months) after initiation of chemotherapy treatment.
Previously untreated patients greater than 70 years of age who were scheduled for first-line chemotherapy for various types of cancer were included. Baseline abbreviated comprehensive geriatric assessment (aCGA), including the Mini-Mental State Exam, Timed Get Up and Go (GUG), Activities of Daily Living (ADL), Instrumental Activities in Daily Living (IADL), Mini Nutritional Assessment (MNA), Geriatric Depression Scale (GDS15), and comorbidities index (Cumulative Index Rating Scale-Geriatric), was carried out. Prognostic factors of early death were sought from aCGA results and traditional oncology measures.
A total of 348 patients were included across 12 centers in Southwest France (median age, 77.45 years; ratio of men to women, 1.47; advanced disease, 65%). Abnormal aCGA scores were observed for 18.1% of patients on the ADL, 73.0% of patients on the IADL, 24.1% of patients on the GUG, 19.0% of patients on the MMS, 44.0% of patients on the GDS15, and 64.9% of patients on the MNA. Advanced disease (odds ratio OR, 3.9; 95% CI, 1.58 to 9.73), a low MNA score (OR 2.77; 95% CI, 1.24 to 6.18), male sex (OR, 2.40; 95% CI, 1.2 to 4.82), and long GUG (OR, 2.55; 95% CI, 1.32 to 4.94 were associated with higher risk of early death.
In patients greater than 70 years of age with cancer, advanced disease, a low MNA score, and poor mobility predicted early death. We recommend that the MNA and GUG, performed by a trained nurse, be maintained as part of routine pretreatment workup in these patients to identify at-risk patients and to inform the decision-making process for chemotherapy.
Triple-negative breast cancer (TNBC) patients have an increased risk of developing visceral metastases and other primary nonbreast cancers, particularly lung cancer. The differential diagnosis of ...TNBC metastases and primary cancers from other organs can be difficult due to lack of a TNBC standard immunoprofile. We analyzed the diagnostic value of estrogen receptor, progesterone receptor, human epidermal growth factor receptor, thyroid transcription factor-1 (TTF1), Napsin A, mammaglobin, gross cystic disease fluid protein 15 (GCDFP15), Sry-related HMg-Box gene 10 (SOX10), GATA-binding protein 3 (GATA3), and androgen receptor in a series of 207 TNBC and 152 primary lung adenocarcinomas (LA). All tested TNBCs were TTF1 and Napsin A-negative. When comparing TNBC and TTF1-positive or negative LA, SOX10 had the best sensitivity (62.3%) and specificity (100%) as a marker in favor of TNBC compared with LA, irrespective of TTF1 status (P<0.0001). GATA3 had moderate sensitivity (30.4%) and excellent specificity (98.7%) and misclassified only 2/152 LA (1.3%). GCDFP15 had a moderate sensitivity (20.8%) and excellent specificity (98%) and misclassified only 3/152 (2%) LA. Mammaglobin and androgen receptor had moderate sensitivities (38.2% and 30%), good specificities (81.6% and 86%), and misclassified 28/152 and 21/152 LAs, respectively. In multivariate analysis, the best markers, enabling the distinction between SOX10-negative TNBC and TTF1 and Napsin A-negative LA were GATA3 (odds ratio=33.5; 95% confidence interval, 7.3-153.5; P<0.0001) and GCDFP15 (odds ratio=31.7; 95% confidence interval, 6.9-145.6; P<0.0001). Only 13/207 (6.3%) TNBC cases did not express any aforementioned marker. On the basis of our results, the best sequential immunohistochemical analysis to differentiate TNBC from TTF1-negative LA is first SOX10 followed by GATA3, and finally GCDFP15. This order is important in the diagnostic workup of small biopsies from lung nodules in women with a previous history of TNBC.
Sarcomas are heterogeneous and aggressive mesenchymal tumors. Histological grading has so far been the best predictor for metastasis-free survival, but it has several limitations, such as moderate ...reproducibility and poor prognostic value for some histological types. To improve patient grading, we performed genomic and expression profiling in a training set of 183 sarcomas and established a prognostic gene expression signature, complexity index in sarcomas (CINSARC), composed of 67 genes related to mitosis and chromosome management. In a multivariate analysis, CINSARC predicts metastasis outcome in the training set and in an independent 127 sarcomas validation set. It is superior to the Fédération Francaise des Centres de Lutte Contre le Cancer grading system in determining metastatic outcome for sarcoma patients. Furthermore, it also predicts outcome for gastrointestinal stromal tumors (GISTs), breast carcinomas and lymphomas. Application of the signature will permit more selective use of adjuvant therapies for people with sarcomas, leading to decreased iatrogenic morbidity and improved outcomes for such individuals.
Purpose
There is a need to refine the prognosis of triple-negative breast cancer (TNBC) patients after neoadjuvant chemotherapy (NAC) and to study the influence of the tumor microenvironment. We ...evaluated the prognostic value of pathological and immune markers in TNBC with residual disease (RD) after NAC.
Methods
In a series of 186 TNBC patients treated by NAC, we assessed the prognostic value of the Residual Cancer Burden (RCB) index. In 109 patients with RD, we studied the impact of clinicopathological features and tumor immune response in the residual tumor on overall survival (OS) and distant recurrence-free interval (DRFI).
Results
In the whole group, the OS and DRFI, at 3 years, were statistically different between the different classes of RCB (
P
= 0.0004 and
P
< 0.0001, respectively). In univariate analysis of the RD group, low RCB index and high ratios of stromal tumor-infiltrating lymphocytes (TILs), CD3 + TILs, CD4 + TILs, CD8 + TILs, and IDO1-positive cells were significant favorable prognostic factors for DRFI at 3 years. In the final multivariate model, CD4 + TILs and RCB index showed a statistically independent prognostic significance for DRFI Hazard Ratio (HR) 2.88 (95%CI 1.34–6.17),
P
= 0.007 and HR 12.04 (95%CI 2.78–52.23,
P
< 0.0001), respectively. The CD4 + TIL levels influenced survival in the different RCB classes with a significant effect observed in RCB-II and RCB-III classes (
P
= 0.05 and
P
= 0.05, respectively).
Conclusions
These results suggest that the combination of pathological (RCB index) and tumor micro-environmental features (CD4 + TILs) help refining the prognosis of TNBC patients with RD following NAC.
A recently introduced digital breast tomosynthesis (DBT) device allows acquisition of DBT spot compression views with a small paddle during DBT acquisition.
The purpose of this study was to evaluate ...the impact on diagnostic performance of obtaining a DBT spot compression view for assessment of equivocal DBT findings.
This retrospective study included 102 women (mean age, 60 years) in whom a DBT spot compression view was obtained to characterize an equivocal finding on DBT at the performing radiologist's discretion. The DBT examinations were performed from December 14, 2018, to December 18, 2019. Two fellowship-trained breast radiologists and one breast imaging fellow, who were aware of the location of the equivocal lesions, independently reviewed the examinations. Readers first assigned a BI-RADS category using standard DBT views and then immediately assigned a category using the DBT spot compression view. BI-RADS categories 2 and 3 were considered negative, and categories 4A and greater were considered positive. Histology and at least 1 year of imaging follow-up served as the reference standard. Intrareader agreement for one reader and interreader agreement among all readers were evaluated with kappa coefficients. Diagnostic performance was compared between DBT with and DBT without spot compression views by use of McNemar tests.
Intrareader agreement increased from 0.43 to 0.72, and interreader agreement increased from 0.21 to 0.45 on the basis of kappa coefficients for DBT without and with spot compression views. Eighteen cancers were present. Compared with standard DBT views, DBT spot compression views yielded significantly increased accuracy for all three readers (75% vs 90%, 74% vs 94%, 72% vs 94%); significantly increased specificity for all three readers (69% vs 90%, 75% vs 94%, 68% vs 93%); and significantly increased sensitivity for one reader (67% vs 94%) without significant change in sensitivity for the two other readers (89% vs 100%, 100% vs 89%). Radiation dose was 1.97 mGy for the DBT spot compression view versus 1.78-1.81 mGy for standard DBT craniocaudal and medio-lateral oblique views.
Use of the DBT spot compression view increased intrareader agreement, interreader agreement, and diagnostic accuracy (primarily owing to improved specificity); the supplemental dose for the spot compression view was slightly higher than that for a standard DBT view.
DBT spot compression may help characterize equivocal DBT findings, reducing further workup for benign findings.
PDF
