Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment

<p>Abstract</p> <p>Background</p> <p>The pathological complete response (pCR) after neoadjuvant chemotherapy is a surrogate marker for a favorable prognosis in breast cancer patients. Factors capable of predicting a pCR, such as the proliferation marker Ki67, may therefore help improve our understanding of the drug response and its effect on the prognosis. This study investigated the predictive and prognostic value of Ki67 in patients with invasive breast cancer receiving neoadjuvant treatment for breast cancer.</p> <p>Methods</p> <p>Ki67 was stained routinely from core biopsies in 552 patients directly after the fixation and embedding process. HER2/neu, estrogen and progesterone receptors, and grading were also assessed before treatment. These data were used to construct univariate and multivariate models for predicting pCR and prognosis. The tumors were also classified by molecular phenotype to identify subgroups in which predicting pCR and prognosis with Ki67 might be feasible.</p> <p>Results</p> <p>Using a cut-off value of > 13% positively stained cancer cells, Ki67 was found to be an independent predictor for pCR (OR 3.5; 95% CI, 1.4, 10.1) and for overall survival (HR 8.1; 95% CI, 3.3 to 20.4) and distant disease-free survival (HR 3.2; 95% CI, 1.8 to 5.9). The mean Ki67 value was 50.6 ± 23.4% in patients with pCR. Patients without a pCR had an average of 26.7 ± 22.9% positively stained cancer cells.</p> <p>Conclusions</p> <p>Ki67 has predictive and prognostic value and is a feasible marker for clinical practice. It independently improved the prediction of treatment response and prognosis in a group of breast cancer patients receiving neoadjuvant treatment. As mean Ki67 values in patients with a pCR were very high, cut-off values in a high range above which the prognosis may be better than in patients with lower Ki67 values may be hypothesized. Larger studies will be needed in order to investigate these findings further.</p

Interpretation of automated breast ultrasound (ABUS) with and without knowledge of mammography: a reader performance study

Background: Automated breast ultrasonography (ABUS) has the potential to be an important adjunct to mammography in women with dense breasts. Purpose: To compare reader performance and inter-observer variation of ABUS alone and in combination with mammography. Material and Methods: This retrospective study had ethical committee approval. All women gave written informed consent. One hundred and fourteen breasts in 90 women examined by digital mammography and ABUS were interpreted by five radiologists using BI-RADS categories. The 114 breasts included 38 cancers and 76 normal or benign findings. In the first reading session ABUS only was interpreted, and in the second ABUS plus digital mammography. Image interpretations were done without knowledge of clinical or imaging results. A consensus panel analyzed false negative and false positive interpretations. Reading time was recorded for one radiologist. AUC was used for performance measurement, and kappa statistic for inter-observer variability. Results: Mean size for cancers was 16.2 mm; area under the curve (AUC) values for ABUS alone and for combined reading were, respectively: reader A, 0.592–0.744; reader B, 0.740–0.947; reader, C 0.759–0.823; reader D, 0.670–0.688; reader E, 0.904–0.923; and all readers combined 0.730–0.823. The higher AUC for combined reading was statistically significant (P < 0.05) for reader B and for all readers. There was a considerable inter-observer variability. Observer agreement revealed following kappa values for ABUS alone and combined reading, respectively: reader A, 0.22–0.30; reader B, 0.33–0.44; reader C, 0.32–0.39; reader D, 0.07–0.14; and reader E, 0.34–0.43. Shadowing from dense parenchyma was the most common cause of false positive ABUS interpretations. Mean interpretation time for a bilateral normal ABUS examination was 9 min. Conclusion: Observer agreement was higher and all radiologists improved diagnostic performance using combined ABUS and mammography interpretation. Combined reading should be standard if ABUS is implemented in screening of women with dense breasts

X-Ray Induced Formation of γ-H2AX Foci after Full-Field Digital Mammography and Digital Breast-Tomosynthesis

Purpose: To determine in-vivo formation of x-ray induced c-H2AX foci in systemic blood lymphocytes of patients undergoing full-field digital mammography (FFDM) and to estimate foci after FFDM and digital breast-tomosynthesis (DBT) using a biological phantom model. Materials and Methods: The study complies with the Declaration of Helsinki and was performed following approval by the ethic committee of the University of Erlangen-Nuremberg. Written informed consent was obtained from every patient. For in-vivo tests, systemic blood lymphocytes were obtained from 20 patients before and after FFDM. In order to compare invivo post-exposure with pre-exposure foci levels, the Wilcoxon matched pairs test was used. For in-vitro experiments, isolated blood lymphocytes from healthy volunteers were irradiated at skin and glandular level of a porcine breast using FFDM and DBT. Cells were stained against the phosphorylated histone variant c-H2AX, and foci representing distinct DNA damages were quantified. Results: Median in-vivo foci level/cell was 0.086 (range 0.067–0.116) before and 0.094 (0.076–0.126) after FFDM (p = 0.0004). In the in-vitro model, the median x-ray induced foci level/cell after FFDM was 0.120 (range 0.086–0.140) at skin level and 0.035 (range 0.030–0.050) at glandular level. After DBT, the median x-ray induced foci level/cell was 0.061 (range 0.040– 0.081) at skin level and 0.015 (range 0.006–0.020) at glandular level. Conclusion: In patients, mammography induces a slight but significant increase of c-H2AX foci in systemic blood lymphocytes. The introduced biological phantom model is suitable for the estimation of x-ray induced DNA damages in breast tissue in different breast imaging techniques

Validation of γ-H2AX foci quantification.

<p>(a) illustrates the dose effect curve. Samples were irradiated with doses ranging from 5 to 50 mGy and were incubated for 5 minutes (n = 3). (b) shows a time plot of foci in lymphocytes pre-treated with 1 nM Calyculin A after irradiation with 50 mGy (n = 3). Means and standard deviations are presented. P<0.05 was considered statistically significant.</p

In-vivo γ-H2AX foci/cell representing DNA damages in systemic blood lymphocytes of patients (n = 20) before (left) and after (right) two view full field digital mammography (FFDM) of both breasts.

<p>Dots show individual values of each patient, the middle horizontal line represents the median, and the error bars indicate the interquartile ranges. A p value is shown, p<0.05 was considered statistically significant.</p

In-vitro γ-H2AX excess foci per cell representing x-ray induced DNA damages in blood lymphocytes after a) full-field digital mammography (FFDM) and b) digital breast tomosynthesis (DBT) at glandular (gl) and skin level (sl), respectively.

<p>Dots show individual data of 10 independent experiments, the middle horizontal lines represent means and the error bars represent standard deviations.</p

Breast cancer risk assessment in a mammography screening program and participation in the IBIS-II chemoprevention trial

International audienceIt has been shown in several studies that antihormonal compounds can offer effective prophylactic treatment to prevent breast cancer. In view of the low participation rates in chemoprevention trials, the purpose of this study was to identify the characteristics of women taking part in a population-based mammography screening program who wished to obtain information about the risk of breast cancer and then participate in the the International Breast Cancer Intervention Study II (IBIS-II) trial, a randomized double-blind controlled chemoprevention trial comparing anastrozole with placebo. A paper-based survey was conducted in a population-based mammography screening program in Germany between 2007 and 2009. All women who met the criteria for the mammography screening program were invited to complete a questionnaire. A total of 2,524 women completed the questionnaire, and 17.7% ( = 446) met the eligibility criteria for the IBIS-II trial after risk assessment. The women who wished to receive further information about chemoprevention were significantly younger ( < 0.01) and had significantly more children ( = 0.03) and significantly more relatives with breast cancer ( < 0.001). There were no significant differences between the participants with regard to body mass index or hormone replacement therapy. Normal mammographic findings at screening were the main reason (42%) for declining to participate in the IBIS-II trial or attend risk counseling. The ultimate rate of recruitment to the IBIS-II trial was very low (three women). Offering chemoprevention to women within a mammography screening unit as part of a paper-based survey resulted in low participation rates for both, the survey and the final participation in the IBIS-II trial. More individualized approaches and communication of breast cancer risk at the time of the risk assessment might be helpful to increase the participation and the understanding of chemopreventive approaches

FemZone trial: a randomized phase II trial comparing neoadjuvant letrozole and zoledronic acid with letrozole in primary breast cancer patients

Background: The objective of this prospectively randomized phase II trial (Trial registration: EUCTR2004-004007-37-DE) was to compare the clinical response of primary breast cancer patients to neoadjuvant therapy with letrozole alone (LET) or letrozole and zoledronic acid (LET + ZOL). Methods: Patients were randomly assigned to receive either LET 2.5 mg/day (n = 79) or the combination of LET 2.5 mg/day and a total of seven infusions of ZOL 4 mg every 4 weeks (n = 89) for 6 months. Primary endpoint was clinical response rate as assessed by mammogram readings. The study was terminated prematurely due to insufficient recruitment. We report here on an exploratory analysis of this data. Results: Central assessment of tumor sizes during the treatment period was available for 131 patients (66 LET, 65 LET + ZOL). Clinical responses (complete or partial) were seen in 54.5% (95% CI: 41.8-66.9) of the patients in the LET arm and 69.2% (95% CI: 56.6-80.1) of those in the LET + ZOL arm (P = 0.106). A multivariate model showed an OR of 1.72 (95% CI: 0.83-3.59) for the experimental arm. Conclusion: No increase in the clinical response rate was observed with the addition of ZOL to a neoadjuvant treatment regimen with LET. However a trend towards a better reponse in the LET + ZOL arm could be observed. This trend is consistent with previous studies that have investigated the addition of ZOL to chemotherapy, and it may support the evidence for a direct antitumor action of zoledronic acid

The contributions of breast density and common genetic variation to breast cancer risk.

We evaluated whether a 76-locus polygenic risk score (PRS) and Breast Imaging Reporting and Data System (BI-RADS) breast density were independent risk factors within three studies (1643 case patients, 2397 control patients) using logistic regression models. We incorporated the PRS odds ratio (OR) into the Breast Cancer Surveillance Consortium (BCSC) risk-prediction model while accounting for its attributable risk and compared five-year absolute risk predictions between models using area under the curve (AUC) statistics. All statistical tests were two-sided. BI-RADS density and PRS were independent risk factors across all three studies (P interaction = .23). Relative to those with scattered fibroglandular densities and average PRS (2(nd) quartile), women with extreme density and highest quartile PRS had 2.7-fold (95% confidence interval [CI] = 1.74 to 4.12) increased risk, while those with low density and PRS had reduced risk (OR = 0.30, 95% CI = 0.18 to 0.51). PRS added independent information (P &lt; .001) to the BCSC model and improved discriminatory accuracy from AUC = 0.66 to AUC = 0.69. Although the BCSC-PRS model was well calibrated in case-control data, independent cohort data are needed to test calibration in the general population