Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial.

Immune checkpoint inhibitors have shown efficacy against metastatic triple-negative breast cancer (mTNBC) but only for PD-L1positive disease. The randomized, placebo-controlled ALICE trial ( NCT03164993 , 24 May 2017) evaluated the addition of atezolizumab (anti-PD-L1) to immune-stimulating chemotherapy in mTNBC. Patients received pegylated liposomal doxorubicin (PLD) and low-dose cyclophosphamide in combination with atezolizumab (atezo-chemo; n = 40) or placebo (placebo-chemo; n = 28). Primary endpoints were descriptive assessment of progression-free survival in the per-protocol population (>3 atezolizumab and >2 PLD doses; n = 59) and safety in the full analysis set (FAS; all patients starting therapy; n = 68). Adverse events leading to drug discontinuation occurred in 18% of patients in the atezo-chemo arm (7/40) and in 7% of patients in the placebo-chemo arm (2/28). Improvement in progression-free survival was indicated in the atezo-chemo arm in the per-protocol population (median 4.3 months versus 3.5 months; hazard ratio (HR) = 0.57; 95% confidence interval (CI) 0.33-0.99; log-rank P = 0.047) and in the FAS (HR = 0.56; 95% CI 0.33-0.95; P = 0.033). A numerical advantage was observed for both the PD-L1positive (n = 27; HR = 0.65; 95% CI 0.27-1.54) and PD-L1negative subgroups (n = 31; HR = 0.57, 95% CI 0.27-1.21). The progression-free proportion after 15 months was 14.7% (5/34; 95% CI 6.4-30.1%) in the atezo-chemo arm versus 0% in the placebo-chemo arm. The addition of atezolizumab to PLD/cyclophosphamide was tolerable with an indication of clinical benefit, and the findings warrant further investigation of PD1/PD-L1 blockers in combination with immunomodulatory chemotherapy.

Normal and unusual days for dietary intake during the 12 months after a breast cancer diagnosis in women.

PURPOSE: There are several reasons to report days as being unusual with regard to dietary intake, including special occasions and celebrations. For breast cancer patients during the 12 month post-surgery period, unusual days may also include days that are affected by being a cancer patient. The aim of this study was to study dietary intake on "normal" and "unusual" days, and to study what is reported in "free text fields" of a food diary. METHODS: Women (n = 456), mean age 55.5 years newly diagnosed with invasive breast cancer (stage I/II) were included in this clinical study. "Normal" and "unusual" days in general, over time and during the week and weekends were studied using repeated administration of a 7-day pre-coded food diary. RESULTS: The breast cancer patients reported 26% of all days as unusual. The intake of energy, most nutrients, especially alcohol and sugar, red and processed meat, and sweets, cakes, and snacks was 5-126% higher, whereas intake of fiber, fruit and berries, vegetables, and dairy products was 7-17% lower on unusual than on normal days (P < 0.001). The same pattern was seen for normal/unusual days during the weekdays, weekends and over time. Finally, 99% of the breast cancer patients used the free text fields to report additional intake with a mean energy of 1.1 MJ/day. CONCLUSION: For breast cancer patients during the 12-month post-surgery period, unusual days are important drivers of total intake, especially for alcohol. The free text fields in the pre-coded food diary contributed substantially to the total intake.

Functional diagnostics using fresh uncultured lung tumor cells to guide personalized treatments.

Functional profiling of a cancer patient's tumor cells holds potential to tailor personalized cancer treatment. Here, we report the utility of fresh uncultured tumor-derived EpCAM+ epithelial cells (FUTCs) for ex vivo drug-response interrogation. Analysis of murine Kras mutant FUTCs demonstrates pharmacological and adaptive signaling profiles comparable to subtype-matched cultured cells. By applying FUTC profiling on non-small-cell lung cancer patient samples, we report robust drug-response data in 19 of 20 cases, with cells exhibiting targeted drug sensitivities corresponding to their oncogenic drivers. In one of these cases, an EGFR mutant lung adenocarcinoma patient refractory to osimertinib, FUTC profiling is used to guide compassionate treatment. FUTC profiling identifies selective sensitivity to disulfiram and the combination of carboplatin plus etoposide, and the patient receives substantial clinical benefit from treatment with these agents. We conclude that FUTC profiling provides a robust, rapid, and actionable assessment of personalized cancer treatment options.

Dietary changes in early-stage breast cancer patients from pre-surgery and over the 12 months post-surgery.

The time after a breast cancer diagnosis is a potential period for making positive dietary changes, but previous results are conflicting. The main aim of the present study was to study breast cancer patients' dietary changes during the 12 months post-surgery and from 12 months pre-surgery to 12 months post-surgery with repeated administration of a 7-d pre-coded food diary and an FFQ, respectively. Women (n 506), mean age 55·3 years diagnosed with invasive breast cancer (stages I and II), were included. The dietary intake was quite stable over time, but the intake was lower for energy (0·3 and 0·4 MJ/d), alcohol (1·9 and 1·5 g/d) and vegetables (17 and 22 g/d) at 6 months than 3 weeks post-surgery (food diary) and at 12 months post-surgery than pre-surgery (FFQ), respectively. Furthermore, energy percentage (E%) from carbohydrates increased between 0·8 and 1·2 E% and E% from fat decreased between 0·6 and 0·8 E% over time, measured by both dietary assessment methods. We observed a higher intake of dairy products (11 g/d) at 6 months post-surgery (food diary), and a lower intake of dairy products (34 g/d) and red and processed meat (7·2 g/d) at 12 months post-surgery (FFQ). Moreover, 24 % of the patients claimed they made dietary changes, but mostly they did not change their diet differently compared with those patients who claimed no changes. In conclusion, breast cancer patients reported only minor dietary changes from 12 months pre-surgery and during the 12 months post-surgery.

Cosmetic breast implants and breast cancer. / Kosmetiske brystimplantater og brystkreft.

BACKGROUND: The number of women with cosmetic breast implants has increased in recent decades in Norway. We compared the risk of detecting breast cancer and histopathological characteristics of the tumours in women with and without implants. MATERIAL AND METHOD: We retrieved information from the Cancer Registry's databases on implants and breast cancer among women who had participated in BreastScreen Norway in the period 1996-2016. Use of the data is pursuant to the Cancer Registry Regulations. We identified 785 706 women, of whom 10 086 (1.3 %) reported that they had an implant. We calculated the incidence rate ratio (IRR) with a 95 % confidence interval (95 % CI) for detected breast cancer and compared histopathological tumour characteristics among women with and without implants with the aid of descriptive analyses. RESULTS: The incidence rate ratio for breast cancer was 30 % lower for women with implants than for women without (IRR 0.70 (95 % CI 0.60-0.81)). Women with implants who had cancer detected had tumours with a larger diameter than women without, and several of these women had metastasis to axillary lymph nodes. INTERPRETATION: Women with implants who participated in BreastScreen Norway had a lower risk of detection of breast cancer, but more advanced disease upon diagnosis than those without implants. This may be due to the difficulty caused by implants in performing and interpreting the mammograms. The women should be informed about this before undergoing augmentation mammoplasty.

Genetic Characterization of Myoid Hamartoma of the Breast.

BACKGROUND/AIM: Myoid hamartoma of the breast is a very rare benign lesion of which only a few cases have been reported. The pathogenesis is unknown and nothing is known about its genetic constitution. We report here the genetic characterization of a myoid hamartoma of the breast. MATERIALS AND METHODS: Cytogenetic, fluorescence in situ hybridization (FISH), RNA sequencing, reverse transcription polymerase chain reaction (RT-PCR), and Sanger sequencing analyses were performed on a myoid hamartoma of the breast. RESULTS: G-Banding analysis of short-term cultured tumor cells yielded the karyotype 46,XX,t(5;12)(p13;q14)[6]/46,XX[4]. FISH showed rearrangement of the high mobility group AT-hook 2 (HMGA2) gene. RNA sequencing detected fusion of HMGA2 (12q14) with a sequence from 5p13. RT-PCR together with Sanger sequencing verified the HMGA2-fusion transcript. CONCLUSION: Myoid hamartoma of the breast may be pathogenetically related to benign connective tissue tumors with HMGA2 rearrangements, such as pulmonary hamartomas, lipomas, myolipomas, and leiomyomas.

Metabolite and lipoprotein responses and prediction of weight gain during breast cancer treatment.

BACKGROUND: Breast cancer treatment has metabolic side effects, potentially affecting risk of cardiovascular disease (CVD) and recurrence. We aimed to compare alterations in serum metabolites and lipoproteins during treatment between recipients and non-recipients of chemotherapy, and describe metabolite profiles associated with treatment-related weight gain. METHODS: This pilot study includes 60 stage I/II breast cancer patients who underwent surgery and were treated according to national guidelines. Serum sampled pre-surgery and after 6 and 12 months was analysed by MR spectroscopy and mass spectrometry. In all, 170 metabolites and 105 lipoprotein subfractions were quantified. RESULTS: The metabolite and lipoprotein profiles of chemotherapy recipients and non-recipients changed significantly 6 months after surgery (p < 0.001). Kynurenine, the lipid signal at 1.55-1.60 ppm, ADMA, 2 phosphatidylcholines (PC aa C38:3, PC ae C42:1), alpha-aminoadipic acid, hexoses and sphingolipids were increased in chemotherapy recipients after 6 months. VLDL and small dense LDL increased after 6 months, while HDL decreased, with triglyceride enrichment in HDL and LDL. At baseline, weight gainers had less acylcarnitines, phosphatidylcholines, lyso-phosphatidylcholines and sphingolipids, and showed an inflammatory lipid profile. CONCLUSION: Chemotherapy recipients exhibit metabolic changes associated with inflammation, altered immune response and increased risk of CVD. Altered lipid metabolism may predispose for treatment-related weight gain.

Digital Breast Tomosynthesis and Synthetic 2D Mammography versus Digital Mammography: Evaluation in a Population-based Screening Program.

Purpose To compare the performance of digital breast tomosynthesis (DBT) and two-dimensional synthetic mammography (SM) with that of digital mammography (DM) in a population-based mammographic screening program. Materials and Methods In this prospective cohort study, data from 37 185 women screened with DBT and SM and from 61 742 women screened with DM as part of a population-based screening program in 2014 and 2015 were included. Early performance measures, including recall rate due to abnormal mammographic findings, rate of screen-detected breast cancer, positive predictive value of recall, positive predictive value of needle biopsy, histopathologic type, tumor size, tumor grade, lymph node involvement, hormonal status, Ki-67 level, and human epidermal growth factor receptor 2 status were compared in women who underwent DBT and SM screening and in those who underwent DM screening by using χ2 tests, two-sample unpaired t tests, and tests of proportions. Results Recall rates were 3.4% for DBT and SM screening and 3.3% for DM screening (P = .563). DBT and SM screening showed a significantly higher rate of screen-detected cancer compared with DM screening (9.4 vs 6.1 cancers per 1000 patients screened, respectively; P < .001). The rate of detection of tumors 10 mm or smaller was 3.2 per 1000 patients screened with DBT and SM and 1.8 per 1000 patients screened with DM (P < .001), and the rate of grade 1 tumors was 3.3 per 1000 patients screened with DBT and SM versus 1.4 per 1000 patients screened with DM (P < .001). On the basis of immunohistochemical analyses, rates of lymph node involvement and tumor subtypes did not differ between women who underwent DBT and SM screening and those who underwent DM screening. Conclusion DBT and SM screening increased the detection rate of histologically favorable tumors compared with that attained with DM screening. © RSNA, 2018 Online supplemental material is available for this article.

Screening-detected desmoid tumor of the breast: findings at conventional imaging and digital breast tomosynthesis.

Desmoid tumor of the breast is a rare benign entity that usually is mistaken for carcinoma clinically and radiologically. We report two cases of desmoid tumor of the breast detected by mammography screening using digital breast tomosynthesis (DBT). The larger tumor was detected at both full-field digital mammography (FFDM) and DBT. The smaller desmoid tumor, however, was identified only at tomosynthesis. Mammographic and ultrasonographic findings at diagnostic work-up were consistent with carcinoma of the breast. Preoperative needle biopsies could not conclusively diagnose the lesions. Both patients underwent excisional biopsy and histopathology revealed fibromatosis of the desmoid type.

Erratum: Inflammation of mammary adipose tissue occurs in overweight and obese patients exhibiting early-stage breast cancer.

[This corrects the article DOI: 10.1038/s41523-017-0015-9.].

Inflammation of mammary adipose tissue occurs in overweight and obese patients exhibiting early-stage breast cancer.

Growing evidence indicates that adiposity is associated with breast cancer risk and negatively affects breast cancer recurrence and survival, a paracrine role of mammary adipose tissue being very likely in this process. In contrast to other adipose depots, occurrence of a sub-inflammatory state of mammary adipose tissue defined by dying adipocytes surrounded by macrophages forming crown-like structures in overweight and obese subjects, remains only partially described. In a general population of breast cancer patients (107 patients) mostly undergoing breast-conserving surgery, we found a positive association between patient's body composition, breast adipocytes size, and presence of crown-like structures in mammary adipose tissue close to the tumor. Overweight (BMI: 25.0-29.9 kg/m2) and obese (BMI ≥ 30.0 kg/m2) patients have 3.2 and 6.9 times higher odds ratio of crown-like structures respectively, compared with normal weight patients. The relatively small increase in adipocyte size in crown-like structures positive vs. negative patients suggests that mammary adipose tissue inflammation might occur early during hypertrophy. Our results further highlight that body mass index is an adequate predictor of the presence of crown-like structures in mammary adipose tissue among postmenopausal women, whereas in premenopausal women truncal fat percentage might be more predictive, suggesting that mammary adipose tissue inflammation is more likely to occur in patients exhibiting visceral obesity. Finally, the presence of crown-like structures was positively associated with systemic markers such as the Triglyceride/High-density lipoprotein-cholesterol ratio serum C-reactive protein and glucose/(HbA1c) glycated Haemoglobin. These compelling results demonstrate that excess adiposity, even in overweight patients, is associated with mammary adipose tissue inflammation, an event that could contribute to breast cancer development and progression.

Lipoprotein subfractions by nuclear magnetic resonance are associated with tumor characteristics in breast cancer.

BACKGROUND: High-Density Lipoprotein (HDL)-cholesterol, has been associated with breast cancer development, but the association is under debate, and whether lipoprotein subfractions is associated with breast tumor characteristics remains unclear. METHODS: Among 56 women with newly diagnosed invasive breast cancer stage I/II, aged 35-75 years, pre-surgery overnight fasting serum concentrations of lipids were assessed, and body mass index (BMI) was measured. All breast tumors were immunohistochemically examined in the surgical specimen. Serum metabolomics of lipoprotein subfractions and their contents of cholesterol, free cholesterol, phospholipids, apolipoprotein-A1 and apolipoprotein-A2, were assessed using nuclear magnetic resonance. Principal component analysis, partial least square analysis, and uni- and multivariable linear regression models were used to study whether lipoprotein subfractions were associated with breast cancer tumor characteristics. RESULTS: The breast cancer patients had following means: age at diagnosis: 55.1 years; BMI: 25.1 kg/m(2); total-Cholesterol: 5.74 mmol/L; HDL-Cholesterol: 1.78 mmol/L; Low-Density Lipoprotein (LDL)-Cholesterol: 3.45 mmol/L; triglycerides: 1.18 mmol/L. The mean tumor size was 16.4 mm, and the mean Ki67 hotspot index was 26.5%. Most (93%) of the patients had estrogen receptor (ER) positive tumors (≥ 1% ER+), and 82% had progesterone receptor (PgR) positive tumors (≥ 10% PgR+). Several HDL subfraction contents were strongly associated with PgR expression: Apolipoprotein-A1 (ß 0.46, CI 0.22-0.69, p < 0.001), HDL cholesterol (ß 0.95, CI 0.51-1.39, p < 0.001), HDL free cholesterol (ß 2.88, CI 1.28-4.48, p = 0.001), HDL phospholipids (ß 0.70, CI 0.36-1.04, p < 0.001). Similar results were observed for the subfractions of HDL1-3. We observed inverse associations between HDL phospholipids and Ki67 (ß -0.25, p = 0.008), and in particular between HDL1's contents of cholesterol, phospholipids, apolipoprotein-A1, apolipoprotein-A2 and Ki67. No association was observed between lipoproteins and ER expression. CONCLUSION: Our findings hypothesize associations between different lipoprotein subfractions, and PgR expression, and Ki 67 % in breast tumors. These findings may have clinical implications, but require confirmation in larger studies.

Breast cancer stromal elastosis is associated with mammography screening detection, low Ki67 expression and favourable prognosis in a population-based study.

BACKGROUND: Mammography screen-detected breast cancers have a better prognosis than predicted from established prognostic markers. A search for additional features that are characteristic for these tumours and their prognosis is needed to reduce overtreatment, a recognized challenge in breast cancer patient management today. Here, we have investigated the occurrence and importance of tumour elastosis. METHODS: We performed a population based retrospective study of breast cancers detected in the Norwegian Breast Cancer Screening Programme in Vestfold County during 2004-2009. In total, 197 invasive screen-detected cancers and 75 interval cancers in patients aged 50-69 years were compared with regard to standard clinico-pathological parameters and tumour shape, as well as ER, PR, HER2 and Ki67 expression. In particular, the presence of elastotic material in tumours was graded on a 4-tiered scale (score 0-3). RESULTS: Screen-detected cancers had a significantly higher content of stromal elastosis than interval cancers (p < 0.001). High content of elastosis (score 3) correlated strongly with stellate tumour shape, low histological grade, and ER+/HER2- status. Further, high elastosis score was significantly associated with lower Ki67 expression. In survival analyses, cases with high elastosis demonstrated increased recurrence free (p = 0.03) and disease-specific survival (p = 0.11) compared to cases with low elastosis. CONCLUSION: There is a strong correlation between the presence of tumour elastosis, stellate tumour shape and mammography detection of breast cancers. To our knowledge, this is the first time elastosis has been studied in relation to breast cancer detection method. Presence of elastosis is associated with low tumour cell proliferation (Ki67) and a good prognosis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_230.

Low-potency glucocorticoid hydrocortisone has similar neurotoxic effects as high-potency glucocorticoid dexamethasone on neurons in the immature chicken cerebellum.

High-potency glucocorticoids (GC) are used in the prophylaxis and treatment of neonatal bronchopulmonal dysplasia, but there is concern about side effects on the developing brain. Recently, the low-potency GC hydrocortisone (HC) has been suggested as an alternative to high-potency GC. We compared the neurotoxic effects of HC with the high-potency GC dexamethasone (DEX) in chicken cerebellum. A single dose of GC was injected into the egg at embryonic day 16 and the death of granule neurons in histologic sections of the cerebellar cortex was examined 24 h later. DEX and HC showed a similar dose-dependent induction of morphological apoptosis and caspase-3 activation in the internal granular layer. A doubling of the apoptosis rate compared to the basal rate was seen for the highest dose of DEX (5 mg/kg) and medium dose of HC (1 mg/kg). In cultures of embryonic chicken cerebellar granule cells, DEX and HC increased cell death and induced rapid caspase-3 activation in a similar dose-dependent manner. Transfection of granule cells with a luciferase reporter gene revealed that the dose needed for the activation of gene transcription (classical signalling pathway) with DEX was much lower than for HC. In conclusion, HC does not present itself as a safer drug than DEX in this model. In addition, it appears that DEX and HC induce apoptosis in immature granule neurons via a non-genomic (non-classical) mechanism.

Assessing invasion criteria in fine needle aspirates from breast carcinoma diagnosed as DICS or invasive carcinoma: can we identify an invasive component in addition to DCIS?

OBJECTIVE: To evaluate invasion criteria in fine needle aspiration cytology (FNAC) of histologically diagnosed breast ductal carcinoma in situ (DCIS) and invasive carcinoma and to evaluate their usefulness in identifying an invasive component in addition to DCIS. STUDY DESIGN: The material consisted of 331 smears diagnosed as suspicious for or consistent with DCIS and in which histology had shown either DCIS or invasive ductal carcinoma. All smears were reevaluated for the following invasion criteria: invasion of fat or fibrous tissue fragments, fibroblast proliferation, cell-poor elastoid tissue fragments, tubular structures and intracytoplasmic vacuoles. RESULTS: All invasion criteria except cytoplasmic vacuoles correlated with invasiveness, but none of them were found exclusively in invasive lesions. Pseudoinvasion in fibrous or fatty tissue fragments were found in 8 cases of histologic pure DCIS. One DCIS (0.4%) revealed > or = 2 invasion features as well as 22 invasive carcinomas (20.7%), representing 7.4% of all cases. CONCLUSION: Using established invasion criteria, practically no pure DCIS lesion will be diagnosed as invasive on FNAC, but one will identify only a subset of cases harboring an invasive component.

Cytologic features of ductal carcinoma in situ in fine-needle aspiration of the breast mirror the histopathologic growth pattern heterogeneity and grading.

BACKGROUND: Approximately 20% of the breast carcinoma cases detected on mammography screening represent ductal carcinoma in situ (DCIS). Cytopathologists are exposed to cytologic material from DCIS when nonpalpable, mammographic lesions are aspirated during the workup of organized and opportunistic mammography screening. METHODS: The material in the current study was comprised of 225 representative fine-needle aspiration cytology (FNAC) smears from histologically confirmed DCIS of the breast that were diagnosed between 1990-2003. Smears were rescreened to search for the following features: nuclear size (grading), monolayer sheets, solid and cribriform epithelial aggregates, micropapillary and true papillary structures, comedo-type necrosis, microcalcifications, myoepithelial cells, and discohesion. RESULTS: There were 174 high-grade lesions (77% were Grade 3) and 51 nonhigh-grade lesions (Grades 1 and 2). The concordance between the cytologic and histologic grading was 97% in the Grade 3 lesions and 94% in the Grade 1/2 lesions. Smears from Grade 3 DCIS contained solid and/or cribriform epithelial aggregates in > 93%% of the cases, whereas smears from Grade 1/2 lesions were found to contain cribriform aggregates in 94% of the cases. Pure subtypes were virtually nonexistent. Monolayer sheets were found in 49% of nonhigh-grade DCIS and in 16% of high-grade DCIS. Myoepithelial cells were demonstrated in 51% of the nonhigh-grade DCIS lesions and 27% of the Grade 3 lesions. Microcalcifications were found on the smears from 96% of nonhigh-grade lesions and 84% of high-grade lesions. Approximately 47% of high-grade DCIS and 31% of nonhigh-grade DCIS were found to harbor a distinct single cell population. CONCLUSIONS: The findings on FNAC from DCIS of the breast completely mirror the histologic heterogeneity of growth pattern subtypes. Primary cytologic grading can effectively separate the high-grade lesions from the nonhigh-grade lesions.

Fine-needle aspiration cytology in nonpalpable mammographic abnormalities in breast cancer screening: results from the breast cancer screening programme in Oslo 1996-2001.

Fine-needle aspiration cytology (FNAC) of nonpalpable mammographic lesions has been under attack from two sides for some years. There has been much discussion and controversy as to the ability to differentiate between in situ and invasive carcinomas in cytological material. A further issue is that of optimal sampling to obtain adequate cell material in sufficient quantity. We present the results of FNAC from 832 nonpalpable mammographic abnormalities detected in the course of the breast cancer screening programme in Oslo during 1996-2001. In 11.6% of cases the smears were inadequate, and there were 7% false negatives (FN) and 1.3% false positives. Of the FN, 64% represented microcalcifications and 86% were due to sampling errors. Absolute sensitivity was 74%, complete sensitivity 88% and specificity 88%. In 255 carcinomas a cytological diagnosis of them as in situ or invasive was made. In 93% of the invasive cases (190/205) these had been correctly identified as invasive on FNAC. In 78% of cases proper follow-up could be resolved by cytology/radiology alone. Suboptimal sampling and localization remains the main cause of FN FNAC results. Problems in differentiating between in situ and invasive breast carcinomas can be significantly reduced by applying strict criteria for in situ lesions.