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.

BIRC5 (survivin): a pejorative prognostic marker in stage II/III breast cancer with no response to neoadjuvant chemotherapy.

PURPOSE: Neoadjuvant systemic therapy (NAC) is currently used in the treatment of stage II/III breast cancer. Pathological complete response as a surrogate endpoint for clinical outcomes is not completely validated for all subgroups of breast cancers. Therefore, there is a need for reliable predictive tests of the most effective treatment. METHODS: We used a combination of predictive clinical, pathological, and gene expression-based markers of response to NAC in a prospective phase II multicentre randomized clinical trial in breast cancer patients, with a long follow-up (8 years). This study concerned the subpopulation of 188 patients with similar levels of pathological response rates to sequential epirubicin/cyclophosphamide and docetaxel to determine predictive marker of pCR and DFS. We used a set of 45 genes selected from high throughput analysis and a standardized RT-qPCR. We analyzed the predictive markers of pathological complete response (pCR) and DFS in the overall population and DFS the subpopulation of 159 patients with no pCR. RESULTS: In the overall population, combining both clinical and genomic variables, large tumor size, low TFF1, and MYBL2 overexpression were significantly associated with pCR. T4 Stage, lymphovascular invasion, negative PR status, histological type, and high values of CCNB1 were associated with DFS. In the no pCR population, only lymphovascular invasion and high values of BIRC5 were associated with DFS. CONCLUSIONS: We confirm the importance of ER-related and proliferation genes in the prediction of pCR in NAC-treated breast cancer patients. Furthermore, we identified BIRC5 (survivin) as a main pejorative prognostic factor in patients with breast cancers with no pCR. These results also open perspective for predictive markers of new targeted therapies.

Prognostic impact of 18F-FDG PET/CT staging and of pathological response to neoadjuvant chemotherapy in triple-negative breast cancer.

PURPOSE: Mortality is high in patients with locally advanced triple-negative breast cancer (TNBC), especially in those with residual tumour after neoadjuvant chemotherapy (NAC). The aim of this study was to determine if pretreatment (18)F-FDG PET/CT staging and pathological findings after NAC could together allow stratification of patients into prognostic groups. METHODS: Initial staging with (18)F-FDG PET/CT was performed prospectively in 85 consecutive patients with stage II/III TNBC. Correlations between PET findings and disease-specific survival (DSS) were examined. In patients without distant metastases on PET staging, the impact of pathological response to NAC on DSS was examined. Patterns of recurrence were also analysed. RESULTS: (18)F-DG PET/CT revealed distant metastases in 11 of 85 patients (12.9 %). Among 74 M0 patients, 23 (31.1 %) showed a pathological complete response (pCR) at surgery, while 51 had residual invasive disease (no pCR). DSS differed considerably among the three groups of patients (log-rank P < .001): among patients with occult metastases on baseline PET/CT, 2-year DSS was 18.2 %, and among patients without initial metastases on PET/CT, 5-year DSS was 61.3 % in patients without pCR after NAC and 95.2 % in those with pCR. Of the 51 patients who did not achieve pCR, 21 relapsed (17 developed distant metastases). The sites of distant recurrence were: lung/pleura (nine patients), brain (eight patients), liver (six patients), distant lymph nodes (six patients) and bone (five patients). CONCLUSION: In patients with clinical stage II/III TNBC, (18)F-FDG PET/CT findings at initial staging and pathological response at the end of NAC allow three groups of patients with quite different prognoses to be defined. Extraskeletal recurrences predominated. Specific follow-up strategies in patients with TNBC who do not achieve pCR deserve investigation.

Long-term survival of advanced triple-negative breast cancers with a dose-intense cyclophosphamide/anthracycline neoadjuvant regimen.

BACKGROUND: Triple-negative (TN) breast cancers exhibit major initial responses to neoadjuvant chemotherapy, but generally have a poor outcome. Because of the lack of validated drug targets, chemotherapy remains an important therapeutic tool in these cancers. METHODS: We report the survival of two consecutive series of 267 locally advanced breast cancers (LABC) treated with two different neoadjuvant regimens, either a dose-dense and dose-intense cyclophosphamide-anthracycline (AC) association (historically called SIM) or a conventional sequential association of cyclophosphamide and anthracycline, followed by taxanes (EC-T). We compared pathological responses and survival rates of these two groups and studied their association with tumours features. RESULTS: Although the two regimens showed equivalent pathological complete response (pCR) in the whole population (16 and 12%), the SIM regimen yielded a non-statistically higher pCR rate than EC-T (48% vs 24%, P=0.087) in TN tumours. In the SIM protocol, DFS was statistically higher for TN than for non-TN patients (P=0.019), although we showed that the TN status was associated with an increased initial risk of recurrence in both regimens. This effect gradually decreased and after 2 years, TN was associated with a significantly decreased likelihood of relapse in SIM-treated LABC (hazard ratio (HR)=0.25 (95% CI: 0.07-0.86), P=0.028). CONCLUSIONS: AC dose intensification treatment is associated with a very favourable long-term survival rate in TN breast cancers. These observations call for a prospective assessment of such dose-intense AC-based regimens in locally advanced TN tumours.

Contraception after breast cancer: a retrospective review of the practice among French gynecologists in the 2000's.

PURPOSE OF INVESTIGATION: To describe the French practices regarding contraception after breast cancer in the 2000's. MATERIALS AND METHODS: A total of 2,500 forms were sent to gynecologists practicing in France. Inclusion criteria were premenopausal patients who had a history of breast cancer and who had been prescribed contraception after diagnosis. Between June 1, 2002 and January 1, 2003, 197 evaluable responses were retrieved. RESULTS: The median age of the sample was 38.5 years. The most commonly used form of contraception was an intrauterine device (n = 144, 73.1%). Hormonal contraception was prescribed for 42 patients (21.3%), and other methods were used in 29 patients (14.7%) (Condoms n = 14, tubal sterilization n = 7, and others n = 8). Recurrence occurred in 27 patients (13%); 2.9% in the progestin group, 16.3% in the IUD group, and 14.8% with the other methods). CONCLUSIONS: It is necessary to evaluate current contraception practices after breast cancer to evaluate the efficacy and safety of contraception in these patients.

Safety of solid oncology drugs in older patients: a narrative review.

The older population represents ∼50%-60% of the population of newly diagnosed patients with cancer. Due to physiological and pathological aging and the increased presence of comorbidities and frailty factors, this population is at higher risk of serious toxicity from anticancer drugs and, consequently, often under-treated. Despite the complexity of these treatments, a good knowledge of the pharmacology of anticancer drugs and potentially risky situations can limit the emergence of potentially lethal toxicities in this population. This review focuses on optimizing systemic oncology treatments for older patients, emphasizing the unique characteristics of each therapeutic class and the necessity for a precautionary approach for this vulnerable population.

Characteristics and clinical outcomes of breast cancer in young BRCA carriers according to tumor histology.

BACKGROUND: Young women with breast cancer (BC) have an increased chance of carrying germline BRCA pathogenic variants (PVs). Limited data exist on the prognostic impact of tumor histology (i.e. ductal versus lobular) in hereditary breast cancer. METHODS: This multicenter retrospective cohort study included women aged ≤40 years with early-stage breast cancer diagnosed between January 2000 and December 2020 and known to carry germline PVs in BRCA1/2. Histology was locally assessed in each center. The Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival and overall survival. RESULTS: Of 4628 patients included from 78 centers worldwide, 3969 (86%) had pure ductal, 135 (3%) pure lobular, and 524 (11%) other histologies. Compared with ductal tumors, lobular tumors were more often grade 1/2 (57.7% versus 22.1%), stage III (29.6% versus 18.5%), and luminal A-like (42.2% versus 12.2%). Lobular tumors were more often associated with BRCA2 PVs (71.1% BRCA2), while ductal tumors were more often associated with BRCA1 PVs (65.7% BRCA1). Patients with lobular tumors more often had mastectomy (68.9% versus 58.3%), and less often received chemotherapy (83.7% versus 92.9%). With a median follow-up of 7.8 years, no significant differences were observed in disease-free survival (adjusted hazard ratio 1.01, 95% confidence interval 0.74-1.37) or overall survival (hazard ratio 0.96, 95% confidence interval 0.62-1.50) between patients with ductal versus lobular tumors. No significant survival differences were observed according to specific BRCA gene, breast cancer subtype, or body mass index. CONCLUSIONS: In this large global cohort of young BRCA carriers with breast cancer, the incidence of pure lobular histology was low and associated with higher disease stage at diagnosis, luminal-like disease and BRCA2 PVs. Histology did not appear to impact prognosis.

BI-RADS categorisation of 2,708 consecutive nonpalpable breast lesions in patients referred to a dedicated breast care unit.

OBJECTIVES: To determine the malignancy rate of nonpalpable breast lesions, categorised according to the Breast Imaging Reporting and Data System (BI-RADS) classification in the setting of a Breast Care Unit. METHODS: All nonpalpable breast lesions from consecutive patients referred to a dedicated Breast Care Unit were prospectively reviewed and classified into 5 BI-RADS assessment categories (0, 2, 3, 4, and 5). RESULTS: A total of 2708 lesions were diagnosed by mammography (71.6%), ultrasound (8.7%), mammography and ultrasound (19.5%), or MRI (0.2%). The distribution of the lesions by BI-RADS category was: 152 in category 0 (5.6%), 56 in category 2 (2.1%), 742 in category 3 (27.4%), 1523 in category 4 (56.2%) and 235 in category 5 (8.7%). Histology revealed 570 malignant lesions (32.9%), 152 high-risk lesions (8.8%), and 1010 benign lesions (58.3%). Malignancy was detected in 17 (2.3%) category 3 lesions, 364 (23.9%) category 4 lesions and 185 (78.7%) category 5 lesions. Median follow-up was 36.9 months. CONCLUSION: This pragmatic study reflects the assessment and management of breast impalpable abnormalities referred for care to a specialized Breast Unit. Multidisciplinary evaluation with BI-RADS classification accurately predicts malignancy, and reflects the quality of management. This assessment should be encouraged in community practice appraisal.

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.

[Techniques and complications of non-genetic risk reducing mastectomies: Guidelines of the National College of French Gynecologists and Obstetricians (CNGOF)]. / Modalités et morbidité des mastectomies de réduction de risque en dehors du risque avéré de prédisposition héréditaire : recommandations du Collège national des gynécologues et obstétriciens français (CNGOF).

OBJECTIVE: Based on an updated review of the international literature covering the different surgical techniques and complications of risk reducing mastectomies (RRM) in non-genetic context, the Commission of Senology (CS) of the College National des Gynécologues Obstétriciens Français (CNGOF) aimed to establish recommendations on the techniques to be chosen and their implementation. DESIGN: The CNGOF CS, composed of 24 experts, developed these recommendations. A policy of declaration and monitoring of links of interest was applied throughout the process of making the recommendations. Similarly, the development of these recommendations did not benefit from any funding from a company marketing a health product. The CS adhered to and followed the AGREE II (Advancing guideline development, reporting and evaluation in healthcare) criteria and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method to assess the quality of the evidence on which the recommendations were based. The potential drawbacks of making recommendations in the presence of poor quality or insufficient evidence were highlighted. METHODS: The CS considered 6 questions in 4 thematic areas, focusing on oncologic safety, risk of complications, aesthetic satisfaction and psychological impact, and preoperative modalities. RESULTS: The application of the GRADE method resulted in 7 recommendations, 6 with a high level of evidence (GRADE 1±) and 1 with a low level of evidence (GRADE 2±). CONCLUSION: There was significant agreement among the CS members on recommendations for preferred surgical techniques and practical implementation.

Safety of assisted reproductive techniques in young women harboring germline pathogenic variants in BRCA1/2 with a pregnancy after prior history of breast cancer.

BACKGROUND: Knowledge is growing on the safety of assisted reproductive techniques (ART) in cancer survivors. No data exist, however, for the specific population of breast cancer patients harboring germline BRCA1/2 pathogenic variants. PATIENTS AND METHODS: This is a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤40 years with stage I-III breast cancer, between January 2000 and December 2012, harboring known germline BRCA1/2 pathogenic variants. Patients included in this analysis had a post-treatment pregnancy either achieved through use of ART (ART group) or naturally (non-ART group). ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection, and embryo transfer under hormonal replacement therapy. RESULTS: Among the 1424 patients registered in the study, 168 were eligible for inclusion in the present analysis, of whom 22 were in the ART group and 146 in the non-ART group. Survivors in the ART group conceived at an older age compared with those in the non-ART group (median age: 39.7 versus 35.4 years, respectively). Women in the ART group experienced more delivery complications compared with those in the non-ART group (22.1% versus 4.1%, respectively). No other apparent differences in obstetrical outcomes were observed between cohorts. The median follow-up from pregnancy was 3.4 years (range: 0.8-8.6 years) in the ART group and 5.0 years (range: 0.8-17.6 years) in the non-ART group. Two patients (9.1%) in the ART group experienced a disease-free survival event (specifically, a locoregional recurrence) compared with 40 patients (27.4%) in the non-ART group. In the ART group, no patients deceased compared with 10 patients (6.9%) in the non-ART group. CONCLUSION: This study provides encouraging safety data on the use of ART in breast cancer survivors harboring germline pathogenic variants in BRCA1/2, when natural conception fails or when they opt for ART in order to carry out preimplantation genetic testing.

[Diffusion-weighted MR imaging of the breast]. / Diffusion en IRM mammaire.

Diffusion-weighted imaging is helpful to further characterize lesions that remain indeterminate after morphological and dynamic MR evaluation. Suspicious lesions are hyperintense on diffusion-weighted images with corresponding low ADC values, indicating restricted diffusion and hypercellularity. Benign lesions and tumors responding to treatment usually have no diffusion restriction. ADC maps are useful for T2W hyperintense lesions that could mask the presence of restricted diffusion. Image fusion is sometimes needed to accurately localize enhancing lesions on ADC maps. For indeterminate lesions, a hypocellular appearance suggests a lower ACR category whereas the presence of restricted diffusion suggests a higher category.

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.

[A study comparing previous induced abortion rates in populations of newly delivered women and infertile women]. / Etude comparative sur les antécédents d'interruption volontaire de grossesse dans une population de femmes infertiles et dans une population de femmes accouchées.

OBJECTIVE: For years, induced abortions (IA) have been deemed responsible for altered fertility. The implication of various mechanisms including tubal infertility, intra-uterine adhesions, spontaneous abortion, ectopic pregnancy, cervical incompetence, shortened gestations, and any psychological trouble leading to anovulation has been raised. Though many authors find no evidence of an increased risk on fertility for women, whose IA is not complicated by infection, it might sometimes be insinuated that infertility is the consequence of previous abortion. Thus, we compared the rate of patients with any prior IA in a population of newly delivered women and in women ongoing IVF. PATIENTS AND METHODS: A retrospective study was conducted at Sèvres hospital, comparing two populations of women, newly delivered women (n=1738) between January 1st and December 31st 2005, and women ongoing IVF at the same period (n=430). We reported the number of previous medical or surgical induced abortions and compared it in both groups. Another analysis compared these rates, among two subgroups of women with one or more prior pregnancy (secondary infertility (n=148), and secondary gestation (n=1088). RESULTS: The rate of prior IA was not different in the two populations. In the IVF group, 13% (n=56) had undergone one or more IA, versus 16.7% (n=291) in the newly delivered group (P=0.06). Among women with previous pregnancy, 37.8% (56) women of the IVF group had undergone one or more previous IA, versus 26.7% (291) of the newly delivered women (P=0.007). DISCUSSION AND CONCLUSION: As expected by literature data on IA and fertility, rates of prior induced abortions were not different in the population of fertile women versus infertile. However, women with one or more previous pregnancy are more likely to have undergone previous IA in the IVF group than in the newly delivered group, possibly due to a bias of age. More data are requested to eliminate linkage between IA and infertility.

Correlation between MRI and biopsies under second look ultrasound.

The term "second look" lesions in MRI refers to lesions detected by MRI that were not initially seen on mammography or ultrasound. The objectives of our study were to analyse the displacement of targets between MRI and ultrasound; to define discriminating BIRADS morphological criteria to predict benign or malignant character and better establish the indications of second look ultrasound and biopsy; and to analyse the agreement between ultrasound and MRI in terms of morphological criteria. A retrospective and monocentric review was performed of the records of consecutive patients with breast abnormalities (mass or non-mass) initially detected by MRI that were not initially seen on mammography or ultrasound. All patients with abnormalities found during the performance of second look ultrasound and biopsied were included in the study. All lesions were documented using the BIRADS lexicon for MRI and ultrasound. Of 100 included patients, 108 lesions were detected by MRI, found via second look ultrasound and biopsied between January 2008 and 2010. All of the included patients were followed-up for a variable period, from 2 to 5 years. Eighty-two upon 108 biopsied lesions (76%) were benign and 26/108 lesions (24%) were malignant. This study confirmed the switch from procubitus to decubitus essentially displaces the tumour in the antero-posterior direction. It showed that the risk factors were not reliable criteria for establishing an indication for second look ultrasound. This study also showed that circumscribed contours and a progressive enhancement curve (type I) for masses on MRI had the strongest negative predictive value of greater than 0.85. In ultrasound, the round or oval shape, circumscribed contours and the parallel orientation to the skin favoured benignity with a NPV of greater than 0.85. For masses, the study showed that the agreement in interpretation of the benign versus suspicious morphological criteria between the MRI and the ultrasound was very weak for the shape (Kappa=0.09) and weak for the contours (Kappa=0.23). Finally, the MRI overestimated the size of the targets compared to ultrasound (Student t-test, p=0.0001). The performance of second look ultrasound has to be performed after the detection of an abdnormality on MRI even for lesion classified BIRADS 3. The biopsy indications must be wide with insertion of a clip and a control MRI. Only this control allows to stop the investigation if the biopsied lesion is benign.