Randomized phase 2 neoadjuvant trial evaluating anastrozole and fulvestrant efficacy for postmenopausal, estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer patients: Results of the UNICANCER CARMINA 02 French trial (UCBG 0609).

BACKGROUND: Treatment strategies for locally advanced breast cancer in elderly patients too frail to receive neoadjuvant chemotherapy and the introduction of new classes of drugs in the early 2000s have led to the consideration of endocrine therapy as a neoadjuvant treatment for younger hormone receptor (HR)-positive, postmenopausal patients not eligible for primary breast-conserving surgery (BCS). METHODS: This was a multicenter, phase 2, randomized trial designed to evaluate as its primary objective the clinical response rate after up to 6 months of neoadjuvant endocrine therapy (NET) alone in HR-positive/human epidermal growth factor receptor 2 (HER2)-negative patients with 1 mg of anastrozole (arm A) or 500 mg of fulvestrant (arm B). Secondary objectives included the BCS rate, tumor response assessment (breast ultrasound and magnetic resonance imaging), pathological response (Sataloff classification), safety profile, relapse-free survival (RFS), and predictive markers of responses and outcomes. RESULTS: From October 2007 to April 2011, 116 women (mean age, 71.6 years) with operable infiltrating breast adenocarcinoma (T2-T4, N0-N3, M0) were randomized to receive anastrozole or fulvestrant. The clinical response rates at 6 months were 52.6% (95% confidence interval [CI], 41%-64%) in arm A and 36.8% (95% CI, 25%-49%) in arm B. BCS was performed for 57.6% of arm A patients and 50% of arm B patients. The RFS rates at 3 years were 94.9% in arm A and 91.2% in arm B. The Preoperative Endocrine Prognostic Index status was significantly predictive of RFS. Both treatments were well tolerated. CONCLUSIONS: Both drugs are effective and well tolerated as NET in postmenopausal women with HR-positive/HER2-negative breast cancer. NET could be considered a treatment option in this subpopulation. Cancer 2016;122:3032-3040. © 2016 American Cancer Society.

Underestimation Rate at MR Imaging-guided Vacuum-assisted Breast Biopsy: A Multi-Institutional Retrospective Study of 1509 Breast Biopsies.

Purpose To assess the rate of underestimation of atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) at magnetic resonance (MR) imaging-guided vacuum-assisted breast biopsy and to explore the imaging, demographic, and histologic characteristics associated with lesion upgrade after surgery. Materials and Methods This retrospective study had institutional review board approval, and the need to obtain informed patient consent was waived. A total of 1509 MR imaging-guided vacuum-assisted biopsy procedures were performed in nine centers. A diagnosis of ADH was obtained after biopsy in 72 cases, and a diagnosis of DCIS was obtained in 118 cases. Pearson χ2 and Fisher tests were used to assess the association between demographic, MR imaging, and biopsy features and lesion upgrade. Univariate statistical analyses were performed, and each significant parameter was entered into a multivariate logistic regression analysis. Results Surgical excision was performed in 66 of the 72 ADH cases and in 117 of 118 DCIS cases. The ADH and DCIS underestimation rates were 25.8% (17 of 66) and 23.1% (27 of 117), respectively. Underestimation was 5.6-fold (odds ratio [OR] = 5.6; 95% confidence interval [CI]: 1.7, 18.3) and 3.6-fold (OR = 3.6; 95% CI: 1.2, 10) more likely in mass (n = 20 for ADH and n = 20 for DCIS) than in non-mass (n = 46 for ADH and n = 97 for DCIS), compared with nonunderestimation, in ADH and DCIS respectively. At multivariate analysis, the use of a 9- or 10-gauge needle versus a 7- or 8-gauge needle was also an independently associated with underestimation when a diagnosis of ADH was made at MR imaging-guided biopsy. No other parameters were associated with of ADH or DCIS upgrade at surgery. Conclusion The rates of underestimation in ADH and DCIS diagnosed at MR imaging-guided vacuum-assisted biopsy were high, at around 25%, and were significantly associated with the presence of a mass at MR imaging. © RSNA, 2016.

¹8F-FDG PET/CT imaging versus dynamic contrast-enhanced CT for staging and prognosis of inflammatory breast cancer.

PURPOSE: Inflammatory breast cancer (IBC) is the most aggressive type of breast cancer with a poor prognosis. Locoregional staging is based on dynamic contrast-enhanced (DCE) CT or MRI. The aim of this study was to compare the performances of FDG PET/CT and DCE CT in locoregional staging of IBC and to assess their respective prognostic values. METHODS: The study group comprised 50 women (median age: 51 ± 11 years) followed in our institution for IBC who underwent FDG PET/CT and DCE CT scans (median interval 5 ± 9 days). CT enhancement parameters were net maximal enhancement, net early enhancement and perfusion. RESULTS: The PET/CT scans showed intense FDG uptake in all primary tumours. Concordance rate between PET/CT and DCE CT for breast tumour localization was 92%. No significant correlation was found between SUVmax and CT enhancement parameters in primary tumours (p > 0.6). PET/CT and DCE CT results were poorly correlated for skin infiltration (kappa = 0.19). Ipsilateral foci of increased axillary FDG uptake were found in 47 patients (median SUV: 7.9 ± 5.4), whereas enlarged axillary lymph nodes were observed on DCE CT in 43 patients. Results for axillary node involvement were fairly well correlated (kappa = 0.55). Nineteen patients (38%) were found to be metastatic on PET/CT scan with a significant shorter progression-free survival than patients without distant lesions (p = 0.01). In the primary tumour, no statistically significant difference was observed between high and moderate tumour FDG uptake on survival, using an SUVmax cut-off of 5 (p = 0.7 and 0.9), or between high and low tumour enhancement on DCE CT (p > 0.8). CONCLUSION: FDG PET/CT imaging provided additional information concerning locoregional involvement to that provided by DCE CT on and allowed detection of distant metastases in the same whole-body procedure. Tumour FDG uptake or CT enhancement parameters were not correlated and were not found to have any prognostic value.

Rates of upgrade to malignancy for 271 cases of flat epithelial atypia (FEA) diagnosed by breast core biopsy.

Flat epithelial atypia (FEA) is a borderline lesion that might represent an early stage in the development of certain low-grade carcinomas in situ and invasive cancers. There are no guidelines on its management. Our objectives were to determine the upgrade to malignancy rate and identify a subpopulation of patients that might undergo just mammographic surveillance. We retrospectively reviewed the data for 271 FEA cases among 5,555 breast core biopsies obtained over a 7-year period (January 2003-2010). We collated clinical data (age, history of cancer, menopausal status), radiological data (lesion type, size, Bi-Rads category), technical data (number of biopsies, needle gauge, excision quality) and histological data and sought correlations between these factors and upgrade rate. The 271 FEA comprised 128 cases of pure FEA, 135 cases of FEA + atypical ductal hyperplasia, and 8 cases of FEA + atypical lobular hyperplasia. Overall, 184 patients underwent surgery and 46 mammographic surveillance. Surgery detected 34 cases of malignancy (23 CIS, 7 invasive cancers, and 4 mixed cases) giving a 15% upgrade rate. Quality of excision was the only factor associated with under-diagnosis. The presence of FEA at biopsy warrants surgery.

Prevalent versus incident breast cancers: benefits of clinical and radiological monitoring in women with pathogenic BRCA1/2 variants.

Women with pathogenic germline BRCA1 or BRCA2 variants have a higher risk of breast cancer than in the general population. International guidelines recommend specific clinical and radiological breast follow-up. This specific breast screening program has already been shown to be of clinical benefit, but no information is available concerning the use of prognostic factors or specific survival to guide follow-up decisions. We evaluated "high-risk" screening in a retrospective single-center study of 520 women carrying pathogenic germline variants of the BRCA1 or BRCA2 gene treated for breast cancer between January 2000 and December 2016. We compared two groups of women: the incidental breast cancer group (IBCG) were followed before breast cancer diagnosis (N = 103), whereas the prevalent breast cancer group (PBCG) (N = 417) had no specific follow-up for high risk before breast cancer diagnosis. Breast cancers were diagnosed at an earlier stage in the IBCG than in the PBCG: T0 in 64% versus 19% of tumors, (p < 0.00001), and N0 in 90% vs. 75% (p < 0.00001), respectively. Treatment differed significantly between the 2 groups: less neoadjuvant chemotherapy (7.1% vs. 28.5%, p < 0.00001), adjuvant chemotherapy (47.7% vs. 61.9%, p = 0.004) and more mastectomies (60% vs. 42% p < 0.0001) in the IBCG vs PBCG groups respectively. Overall and breast cancer-specific mortality were similar between the two groups. However, the patients in the IBCG had a significantly longer metastasis-free survival than those in the PBCG, at three years (96.9% [95% CI 93.5-100] vs. 92.30% [95% CI 89.8-94.9]; p = 0.02), suggesting a possible long-term survival advantage.

Brain metastases from breast cancer: prognostic significance of HER-2 overexpression, effect of trastuzumab and cause of death.

BACKGROUND: To access the prognostic significance of HER-2 overexpression, the effect of trastuzumab and the cause of death in patients with brain metastases (BM) from breast cancer (BC). METHODS: We analyzed the outcome of 130 patients with BM from BC who received whole-brain radiotherapy (WBRT) (without surgery or radiosurgery) between January 1998 and April 2006. Demographic data, tumor characteristics, and treatments were prospectively recorded. The impact of HER-2 overexpression and trastuzumab-based therapy on overall survival (OS) and the cause of death were evaluated. RESULTS: The median follow-up for the whole population was 6.25 months (mean: 9.15; range: 0.23-53). The median survival time and 1-year survival rates after BM diagnosis were 7.43 months and 35.8% (95% CI: 28-45.7) respectively. The median survival time for HER-2 negative patients (n = 78), HER-2 positive patients not treated with trastuzumab (n = 20) and HER-2 positive patients treated with trastuzumab (n = 32) were 5.9 months, 5.6 months and 19.53 months, respectively. The 1-year survival rates were 26.1%, 29.2% and 62.6% respectively, (p < 0.004). Among the 18 HER-2 positive patients treated with trastuzumab who died, 11 (61%) apparently succumbed from CNS progression, in the face of stable or responsive non-CNS disease. Trastuzumab-based therapy was associated with a 51% reduction in the risk of death (multiadjusted hazard ratio: 0.49; 95% CI, 0.29-0.83). CONCLUSIONS: In our experience, trastuzumab-based therapy for HER-overexpressing tumors was associated with improved survival in BM BC patients. This subgroup of patients may benefit from innovative approaches, in order to obtain better intra cerebral control.

Early metabolic response of breast cancer to neoadjuvant endocrine therapy: comparison to morphological and pathological response.

BACKGROUND: Neoadjuvant endocrine therapy (NET) has shown efficacy in terms of clinical response and surgical outcome in postmenopausal patients with estrogen receptor-positive / HER2-negative breast cancer (ER+/HER2- BC) but monitoring of tumor response is challenging. The aim of the present study was to investigate the value of an early metabolic response compared to morphological and pathological responses in this population. METHODS: This was an ancillary study of CARMINA 02, a phase II clinical trial evaluating side-by-side the efficacy of 4 to 6 months of anastrozole or fulvestrant. Positron Emission Tomography/Computed Tomography using 2-deoxy-2-[18F]fluoro-D-glucose (FDG-PET/CT) scans were performed at baseline (M0), early after 1 month of treatment (M1) and pre-operatively in 11 patients (74.2 yo ± 3.6). Patients were classified as early "metabolic responders" (mR) when the decrease of SUVmax was higher than 40%, and "metabolic non-responders" (mNR) otherwise. Early metabolic response was compared to morphological response (palpation, US and MRI), variation of Ki-67 index, pathological response according to the Sataloff classification and also to Preoperative Endocrine Prognostic Index (PEPI) score. It was also correlated with overall survival (OS) and recurrence-free survival (RFS). RESULTS: Tumor size measured on US and on MRI was smaller in mR than mNR, with the highest statistically significant difference at M1 (p = 0.01 and 7.1 × 10- 5, respectively). No statistically significant difference in the variation of tumor size between M0 and M1 assessed on US or MRI was observed between mR and mNR. mR had a better clinical response: no progressive disease in mR vs 2 in mNR and 2 partial response in mR vs 1 partial response in mNR. One patient with a pre-operative complete metabolic response had the best pathological response. Pathological response did not show any statistically significant difference between mR and mNR. mR had better OS and RFS (Kaplan-Meier p = 0.08 and 0.06, respectively). All cancer-related events occurred in mNR: 3 patients died, 2 of them from progressive disease. CONCLUSIONS: FDG-PET/CT imaging could become a "surrogate marker" to monitor tumor response, especially as NET is a valuable treatment option in postmenopausal women with ER+/HER2- BC.

Quantitative CT Extent of Lung Damage in COVID-19 Pneumonia Is an Independent Risk Factor for Inpatient Mortality in a Population of Cancer Patients: A Prospective Study.

Background: CT lung extent has emerged as a potential risk factor of COVID-19 pneumonia severity with mainly semiquantitative assessment, and outcome was not assessed in the specific oncology setting. The main goal was to evaluate the prognostic role of quantitative assessment of the extent of lung damage for early mortality of patients with COVID-19 pneumonia in cancer patients. Methods: We prospectively included consecutive cancer patients with recent onset of COVID-19 pneumonia assessed by chest CT between March 15, 2020, and April 20, 2020, and followed until May 1, 2020. Demographic, clinical, laboratory test data and imaging findings were recorded. Quantitative chest CT assessment of COVID-19 pneumonia was based on the density distribution of lung lesions using a freely available software recently released (Myrian XP-Lung). The association between extent of lung damage and overall survival was studied by univariate and multivariate Cox analysis. The Uno C-index was used to assess the discriminatory value of the quantitative CT extent of lung damage. Results: Seventy cancer patients with chest CT evidence of COVID-19 were included. After a median follow-up of 25 days, 17 patients (24%) had died. The median quantitative chest CT extent of COVID-19 was 20% (IQR = 14-35, range = 3-59) for non-survivors vs. 10% (IQR = 6-15, range = 2-55) for survivors (p = 0.002). The extent of COVID-19 pneumonia was correlated with inpatient management (p = 0.003) and oxygen therapy requirements (p < 0.001). Independent factors associated with death were performance status (PS) ≥2 (HR = 3.9, 95% CI = [1.1-13.8] p = 0.04) and extent of COVID-19 pneumonia ≥30% (HR = 12.0, 95% CI = [2.2-64.4] p = 0.004). No differences were found regarding the histology of cancer, cancer stage, metastases sites, or type of oncologic treatment between the survivor and non-survivor groups. The cross-validated Uno C-index of the model including PS and extent of COVID-19 pneumonia was 0.83, 95% CI = [0.73-0.93]. Conclusions: The quantitative chest CT extent of COVID-19 pneumonia was a strong independent prognostic factor of early inpatient mortality in a population of cancer patients.

A Pre-operative Score to Discriminate Fibroepithelial Lesions of the Breast: Phyllode Tumor or Fibroadenoma?

BACKGROUND/AIM: Fibroepithelial lesions (FEL) of the breast include fibroadenomas and phyllodes tumors (PT). Their histologic characteristics on core needle biopsy can overlap, while their clinical management is different. The aim of this study was to develop and to validate a pre-operative score for the diagnosis of PT with surgical decision rules. PATIENTS AND METHODS: We developed a pre-operative score for the diagnosis of PT by performing logistic regression on 217 FEL of the Rene Huguenin Hospital. This score and the surgical decision rules were validated on 87 FEL of the Lariboisiere Hospital. RESULTS: Three variables were independently and significantly associated with PT: age ≥40 years, mammography's tumor size ≥3 cm and PT diagnosed by CNB. The pre-operative score was based on these three criteria with values ranging from 0 to 10. Surgical decision rules were created: the low-risk group of PT (score≤2) had a sensitivity of 92.6% and a LR- of 0.2, the high-risk group (score>7) had a specificity of 93.5% and a LR+ of 4.4. In the validation sample, surgical decision rules were applied. CONCLUSION: These surgical decision rules may prove useful in deciding which FEL needs surgical resection.

Preoperative Breast Magnetic Resonance Imaging in Women With Local Ductal Carcinoma in Situ to Optimize Surgical Outcomes: Results From the Randomized Phase III Trial IRCIS.

PURPOSE: We evaluated the addition of breast magnetic resonance imaging (MRI) to standard radiologic evaluation on the re-intervention rate in women with ductal carcinoma in situ (DCIS) undergoing breast-conserving surgery. PATIENTS AND METHODS: Women with biopsy-proven DCIS corresponding to a unifocal microcalcification cluster or a mass less than 30 mm were randomly assigned to undergo MRI or standard evaluation. The primary end point was the re-intervention rate for positive or close margins (< 2 mm) in the 6 months after randomization ( ClinicalTrials.gov identifier: NCT01112254). RESULTS: A total of 360 patients from 10 hospitals in France were included in the study. Of the 352 analyzable patients, 178 were randomly assigned to the MRI arm, and 174 were assigned to the control arm. In the intent-to-treat analysis, 82 of 345 patients with the assessable end point were reoperated for positive or close margins within 6 months, resulting in a re-intervention rate of 20% (35 of 173) in the MRI arm and 27% (47 of 172) in the control arm. The absolute difference of 7% (95% CI, -2% to 16%) corresponded to a relative reduction of 26% (stratified odds ratio, 0.68; 95% CI, 0.41 to 1.1; P = .13). When considering only the per-protocol population with an assessable end point, the difference was 9% (stratified odds ratio, 0.59; 95% CI, 0.35 to 1.0; P = .05). Total mastectomy rates were 18% (31 of 176) in the MRI arm and 17% (30 of 173) in the control arm (stratified P = .93). For 100 lesions seen on MRI, nonmass-like enhancement was more predominant (82%) than mass enhancement (20%). Nevertheless, no specific morphologic and kinetic parameters for DCIS were identified. CONCLUSION: The study did not show sufficient surgical improvement with the use of preoperative MRI to be clinically relevant in DCIS staging. However, this could be reconsidered with the improvement of new MRI sequences and new modalities in magnetic resonance techniques.

Impact of FDG PET-CT imaging on the decision making in the biologic suspicion of ovarian carcinoma recurrence.

OBJECTIVES: The aim of this prospective study was to evaluate the impact of integrated PET-CT on treatment management in ovarian carcinoma recurrence suspicion because of increased CA-125. METHODS: Twenty-nine patients (mean age=61 years), initially treated for ovarian carcinoma (FIGO stage I n=2, stage II n=3, stage III n=21 and stage IV n=3), presenting with increased CA-125 (mean=160 IU/ml, range 33-1930), underwent subsequently a CT and a PET-CT scans. The recurrence was acknowledged by the referring physicians for all patients. The impact of PET-CT on patient's management was evaluated by comparing the therapeutic decision mentioned respectively on the pre and post PET-CT questionnaires filled in by the oncologists. RESULTS: The CT scan was positive in 22/29 patients (76%) and negative in 7/29 patients (24%). The PET-CT scan was positive in 27/29 patients (93%) and negative in 2/29 (7%) patients. Five out of the seven patients with a negative CT scan had a positive PET-CT scan. In comparison to CT scan alone, the PET-CT scan modified the disease distribution for 16 patients (55%; p<0.001) in the following ways: more advanced disease (n=11), more limited disease (n=4), and different localizations (n=1). The assessment of pre and post PET-CT questionnaires showed a statistically significant change in the decision making for 10 patients (34%, p<0.0001). CONCLUSION: This questionnaire-based study showed that PET-CT imaging allows a better restaging than CT and induces a change in clinical management in over one third of patients with suspected ovarian carcinoma recurrence on increased CA-125.

Hyperechoic breast images: all that glitters is not gold!

Hyperechogenicity is a sign classically reported to be in favour of a benign lesion and can be observed in many types of benign breast lesions such as hamartoma, lipoma, angiolipoma, haemangioma, haematoma, fat necrosis, fibrosis and galactocele, among others. However, some rare malignant breast lesions can also present a hyperechoic appearance. Most of these hyperechoic malignant lesions present other characteristics that are more typically suggestive of malignancy such as posterior shadowing, a more vertical axis or irregular margins that help to guide the diagnosis. Post magnetic resonance imaging, second-look ultrasound may visualise hyperechoic malignant lesions that would not have been identified at first sight and radiologists must know how to recognise these lesions. TEACHING POINTS: • Some rare malignant breast lesions can present a hyperechoic appearance. • Malignant lesions present other characteristics that are suggestive of malignancy. • An echogenic mass with fat density on mammography does not require biopsy.

[Shall all lobular intraepithelial neoplasia diagnosed on image-guided biopsy require a surgical management?]. / Faut-il opérer toutes les néoplasies lobulaires intraépithéliales diagnostiquées par biopsie mammaire radioguidée ?

OBJECTIVE: Lobular intraepithelial neoplasia (LIN) diagnosed on image-guided biopsy may be associated with an undiagnosed cancer. This is called under-diagnosis. The consequence is that management of these lesions is often surgical. But many surgeries finally are unnecessary. The aim of our study was to define criteria to avoid unnecessary surgery. MATERIALS AND METHODS: This is a single-center, retrospective after a database collected prospectively study. Fourteen thousand biopsies were analyzed, including 456 diagnosed NLI. Under-diagnosis rates were analyzed according to many criteria. The average duration of following was 45 months. RESULTS: For atypical lobular hyperplasia (ALH), we obtained 7.6% under-diagnosis and combining several criteria, we got a low risk of cancer (2%). For LCIS, this rate was 23% and any low-risk group could be identified. CONCLUSION: ALH with calcifications≤20 mm, without any atypical lesion associated, histologically focal and whose removal is representative may be safely observed. For other LIN, surgery remains indicated.

[Biopsy of breast microcalcifications using an 11-Gauge vacuum-assisted device: roles and challenges for the pathologist]. / Les macrobiopsies mammaires 11 G assistées par aspiration dans les foyers de microcalcifications mammaires: rôles et difficultés du pathologiste.

Stereotactic 11-Gauge vacuum-assisted biopsy provides a valuable tool in the diagnosis of mammographically detected breast microcalcifications. However, this new diagnostic technology presents some limitations and requires a close collaboration between radiologists, pathologists and physicians. The aim of this work is to propose a practical approach in the management of large core biopsies and to summarize the different difficulties faced by the pathologist in the management and histological interpretation of specimens issuing from this device.

A six-gene signature predicting breast cancer lung metastasis.

The lungs are a frequent target of metastatic breast cancer cells, but the underlying molecular mechanisms are unclear. All existing data were obtained either using statistical association between gene expression measurements found in primary tumors and clinical outcome, or using experimentally derived signatures from mouse tumor models. Here, we describe a distinct approach that consists of using tissue surgically resected from lung metastatic lesions and comparing their gene expression profiles with those from nonpulmonary sites, all coming from breast cancer patients. We show that the gene expression profiles of organ-specific metastatic lesions can be used to predict lung metastasis in breast cancer. We identified a set of 21 lung metastasis-associated genes. Using a cohort of 72 lymph node-negative breast cancer patients, we developed a 6-gene prognostic classifier that discriminated breast primary cancers with a significantly higher risk of lung metastasis. We then validated the predictive ability of the 6-gene signature in 3 independent cohorts of breast cancers consisting of a total of 721 patients. Finally, we show that the signature improves risk stratification independently of known standard clinical variables and a previously established lung metastasis signature based on an experimental breast cancer metastasis model.