R. Schulz-Wendtland

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

BackgroundThe 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.MethodsKi67 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.ResultsUsing 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.ConclusionsKi67 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.

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 < .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.

Fat Necrosis after Conserving Surgery and Interstitial Brachytherapy and/or External-Beam Irradiation in Women with Breast Cancer

Purpose:To investigate the incidence of fat necrosis, breast tissue fibrosis and breast pain after conserving surgery and accelerated partial-breast irradiation (APBI, group A), whole-breast external-beam irradiation (EBRT, group B), or EBRT combined with an interstitial boost (EBIB, group C) in women with breast cancer.Patients and Methods:85 patients who received breast-conserving therapy from 02/2000 to 03/2002 were analyzed. 30 patients received EBRT, 33 patients APBI, and 22 patients EBIB. Median follow-up was 35.5, 35.0, and 37.5 months, respectively. Fat necrosis was detected and rated by mammograms, fibrosis and pain were clinically rated with the LENT-SOMA scores.Results:The incidence of fat necrosis was 15.3% for all patients; and 15.2%, 20.0%, and 9.0% for groups A, B, and C, respectively. The 3-year fat necrosis-free survival probability was 83%, 76%, and 95% (difference not significant). The mean time to first diagnosis of fat necrosis was 25.6, 26.2, and 26.0 months. No patient needed surgical intervention because of fat necrosis-related pain. Fibrosis was present in 27.3%, 63.3%, and 77.3% (p < 0.001), breast pain in 9.0%, 33.4%, and 18.1% (p < 0.05).Conclusion:Asymptomatic fat necrosis is a common finding after both percutaneous and interstitial irradiation after breast-conserving surgery. This analysis did not support the hypothesis that APBI with multicatheter implants leads to higher rates of fat necrosis, fibrosis, or pain.Ziel:Untersuchung und Vergleich der Inzidenz und des Schweregrades des Auftretens von Fettnekrosen, Fibrosierung und Brustschmerz nach brusterhaltender Operation und akzelerierter Teilbrustbestrahlung (Gruppe A), externer Ganzbrustbestrahlung (Gruppe B) sowie externer Ganzbrustbestrahlung mit interstitiellem Brachytherapie-Boost (Gruppe C) bei Frauen mit einem Mammakarzinom.Patienten und Methodik:Die Auswertung umfasst 85 Patientinnen, die zwischen 02/2000 und 03/2002 brusterhaltend therapiert wurden. Davon erhielten 30 Patientinnen eine externe Ganzbrustbestrahlung, 33 Patientinnen eine Teilbrustbestrahlung und 22 Patientinnen eine kombinierte externe und interstitielle Bestrahlung. Die mediane Nachbeobachtungszeit betrug 35,5, 35,0 und 37,5 Monate. Der Endpunkt Fettnekrose wurde mittels Mammographien evaluiert, die Endpunkte Fibrosierung und Brustschmerz wurden klinisch mit den LENT-SOMA-Scores klassifiziert.Ergebnisse:Bei 15,3% aller Patientinnen wurden Fettnekrosen gefunden, in den Gruppen A, B und C bei 15,2%, 20,0% and 9,0% der Fälle. Das fettnekrosenfreie 3-Jahres-Überleben betrug 83%, 76% und 95% (Unterschied nicht signifikant). Die mittlere Zeit bis zum Auftreten der Fettnekrosen betrug 25,6, 26,2 und 26,0 Monate. Fibrosierung wurde bei 27,3%, 63,3% und 77,3% der Fälle (p < 0,001) getastet, Brustschmerz wurde von 9,0%, 33,4% und 18,1% (p < 0,05) der Patientinnen angegeben.Schlussfolgerung:Asymptomatische Fettnekrosen wurden nach brusterhaltender Operation nach externer sowie interstitieller adjuvanter Brustbestrahlung gefunden. Die Hypothese, dass eine Teilbrustbestrahlung mit interstitieller Brachytherapie zu höheren Raten von Fettnekrosen, Fibrosierung und Brustschmerz führt, wird durch die Ergebnisse der vorliegenden Studie nicht gestützt.

Mammographic density as a risk factor for breast cancer in a German case-control study.

Mammographic percent density (MD) is recognized as one of the strongest risk factors associated with breast cancer. This matched case–control study investigated whether MD represents an independent risk factor. Mammograms were obtained from 1025 breast cancer patients and from 520 healthy controls. MD was measured using a quantitative computer-based threshold method (0–100%). Breast cancer patients had a higher MD than healthy controls (38 vs. 32%, P<0.01). MD was significantly higher in association with factors such as age over 60 years, body mass index (BMI) of 25–30 kg/m2, nulliparity or low parity (one to two births). Average MD was inversely associated with age, BMI, parity and positively associated with age at first full-term pregnancy. MD was higher in women with at least one first-degree relative affected, but only among patients and not in the group of healthy controls (P<0.01/P=0.61). In women with an MD of 25% or more, the risk of breast cancer was doubled compared with women with an MD of less than 10% (odds ratio: 2.1; 95% confidence interval: 1.3–3.4; P<0.01); in the postmenopausal subgroup, the risk was nearly tripled (odds ratio: 2.7; 95% confidence interval: 1.6–4.7; P<0.001). This study provides further evidence that MD is an important risk factor for breast cancer. These results indicate strong associations between MD and the risk of breast cancer in a matched case–control study in Germany.

New diagnostic criteria in real-time elastography for the assessment of breast lesions.

PURPOSE Elastography is a new ultrasonographic method that has been examined as a diagnostic tool for breast lesions. This study was intended to create and define new elastographic criteria allowing assessment of whether breast lesions are malignant or benign. MATERIALS AND METHODS 217 patients with a total of 245 breast lesions of unknown malignancy underwent ultrasound examination. The new eSie Touch Elasticity Imaging technology (Siemens, Erlangen, Germany) was used with a 10-MHz linear transducer (Acuson Antares). Lesions were examined using B-mode and real-time elastography (RTE). Each lesion was histologically assessed by core biopsy. Five RTE characteristics were examined: elasticity proportion (EP), different location on RTE in comparison with B-mode (MV), different contrast patterns (SOS), dorsal lesion limitation visibility and different size on RTE in comparison with B-mode. RESULTS 54 malignant lesions (54 %) appeared inelastic, in contrast to the benign control group (34.5 %; P = 0.001). A completely elastic pattern was visible in 10 malignant (10 %) and 39 benign lesions (26.9 %). MV was identified in 23 cases, with 22 of the lesions being malignant and one benign. The SOS was negative in 89 malignant lesions (89 %) and positive in 100 benign lesions. The dorsal lesion limitation was visible on RTE without B-mode in 88 malignant lesions (88 %) and 27 benign lesions (18.6 %). The size was assessed as larger in 45 malignant lesions (45 %) and seven benign lesions (4.8 %). CONCLUSION SOS and a larger tumor size on RTE are specific characteristics of malignant breast lesions. EP, MV and distal mass border are further helpful signs to assess the malignancy of tumors.

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.

Pooled analysis of the prognostic relevance of progesterone receptor status in five German cohort studies

The progesterone receptor (PR) has been increasingly well described as an important mediator of the pathogenesis and progression of breast cancer. The aim of this study was to assess the role of PR status as a prognostic factor in addition to other well-established prognostic factors. Data from five independent German breast cancer centers were pooled. A total of 7,965 breast cancer patients were included for whom information about their PR status was known, as well as other patient and tumor characteristics commonly used as prognostic factors. Cox proportional hazards models were built to compare the predictive value of PR status in addition to age at diagnosis, tumor size, nodal status, grading, and estrogen receptor (ER) status. PR status significantly increased the accuracy of prognostic predictions with regard to overall survival, distant disease-free survival, and local recurrence-free survival. There were differences with regard to its prognostic value relative to subgroups such as nodal status, ER status, and grading. The prognostic value of PR status was greatest in patients with a positive nodal status, negative ER status, and low grading. The PR-status adds prognostic value in addition to ER status and should not be omitted from clinical routine testing. The significantly greater prognostic value in node-positive and high-grade tumors suggests a greater role in the progression of advanced and aggressive tumors.

Accuracy of radiological tumour size assessment and the risk for re-excision in a cohort of primary breast cancer patients

BACKGROUND Re-operations after breast conserving surgery (BCS) are necessary, when specimen margins are not free of breast cancer cells. This study explored the accuracy of preoperative tumour size assessment and its influence on the rate of re-excisions and mastectomies. METHODS The study included 1591 patients with invasive breast cancer, who were planned for BCS. Patient, staging and tumor characteristics were evaluated concerning their influence on re-excision and mastectomy rates. Patient and tumor characteristics comprised histopathological tumour size, HER2 status, multifocality, in situ component, grading (G), nodal status and hormone receptor (HR) status. Staging characteristics included deviation from pathological tumour size as measured by clinical examination, sonography and mammography. RESULTS In 1316 patients (83%) sufficient treatment was possible with one operation. 275 patients (17%) had to undergo at least one further surgery as a result of positive specimen margins. In 138 patients (9%) mastectomy was ultimately necessary. In patients with a positive HER2 status, a larger tumour size, underestimation by ultrasound, an in situ component and multifocality, the risk for a re-operation was about doubled. Tumour size deviation in the mammogram or the clinical tumour size assessment did not have significant influence to the re-excision rates. CONCLUSION Tumour size and accurate presurgical assessment of the tumour size itself are independent predictors for the need of a second surgery or even a mastectomy in patients for whom a primary BCS was planned.

Calcifying tendonitis of the shoulder joint : predictive value of pretreatment sonography for the response to low-dose radiotherapy.

Background and Purpose:Calcifying tendonitis is a degenerative inflammatory joint disorder. Pain relief can be successfully achieved with low-dose radiotherapy. It is actually unknown which types of calcifying tendonitis respond to radiotherapy and which do not. The authors tried to get predictive objectives for the response to radiotherapy on the basis of different morphological patterns of calcifications evaluated by X-ray and ultrasound.Patients and Methods:Between August 1999 and September 2002, a total of 102 patients with 115 painful shoulder joints underwent low-dose radiotherapy. At the beginning of radiotherapy, every shoulder joint was examined with a radiograph in two planes. In addition, sonography was performed before and during therapy. This examination was repeated 6 and 18 months after irradiation. Radiotherapy consisted of two series with a total dose of 6.0 Gy. 29 joints with calcifying tendonitis could be further divided using the sonographic and radiographic classification according to Farin and Gärtner, respectively.Results:Pain relief was achieved in 94/115 joints (82%) at a follow-up of 18 months (median). A different response to radiotherapy was found using the sonographic classification of Farin: calcifying tendonitis type III (n = 18) responded well in contrast to a significantly worse result in type I (n = 11). The radiologic classification did not provide a predictive value.Conclusion:Sonographic classification of calcifying tendonitis is predictive for the outcome after radiotherapy. Especially patients with Farin type III calcification will benefit from low-dose radiotherapy.Hintergrund und Ziel:Die Tendinosis calcarea ist eine degenerativ-entzündliche Gelenkerkrankung, bei der zur Schmerzlinderung auch die niedrigdosierte Strahlentherapie erfolgreich eingesetzt wird. Bisher ist nicht bekannt, welche Formen der Tendinosis calcarea auf die Radiotherapie ansprechen. Deshalb versuchten die Autoren, aufgrund der unterschiedlichen morphologischen Verkalkungsmuster im Ultraschall und Röntgenbild eine prädiktive Aussage zum Therapieansprechen zu treffen.Patienten und Methodik:Von August 1999 bis September 2002 wurden insgesamt 102 Patienten mit 115 symptomatischen Schultergelenken behandelt (Tabelle 1). Neben einer konventionellen Röntgenaufnahme des Schultergelenks in zwei Ebenen wurden alle Schultergelenke vor und unter Radiotherapie sowie 6 und 18 Monate nach Therapieende sonographisch untersucht. Die Strahlentherapie umfasste zwei Behandlungsserien bis zu einer Gesamtdosis von 6,0 Gy. Bei 29 Schultergelenken mit Tendinosis calcarea erfolgte die Subtypisierung hinsichtlich des Verkalkungstyps sonographisch nach Farin sowie röntgenologisch nach Gärtner (Tabelle 4).Ergebnisse:Insgesamt trat bei 94/115 Schultergelenken (82%) nach 18-monatiger Verlaufskontrolle eine Beschwerdebesserung ein. Bei der sonographischen Klassifizierung fand sich ein unterschiedliches Therapieansprechen: Die Tendinosis calcarea Typ Farin III (n = 18) sprach sehr gut auf die Therapie an (Abbildung 1), Typ Farin I (n = 11) zeigte ein signifikant schlechteres Therapieansprechen (Abbildung 2). Mit der röntgenologischen Subklassifizierung konnte keine prädiktive Aussage getroffen werden (Tabelle 3).Schlussfolgerung:Die Subtypisierung der Tendinosis calcarea im Ultraschall nach Farin ermöglicht eine genauere prädiktive Aussage bezüglich des Ansprechens auf eine niedrigdosierte Strahlentherapie. Zukünftig sollten inbesondere Patienten mit einem Verkalkungstyp III einer Strahlentherapie zugeführt werden.

Prognostic molecular markers and neoadjuvant therapy response in anthracycline-treated breast cancer patients

BackgroundIdentifying biomarkers that can predict the prognosis and treatment response is helpful for individualizing breast cancer (BC) therapy. A neoadjuvant treatment setting is ideal for testing biomarkers capable of predicting the treatment response. This study analyzed the value of immunohistochemical biomarkers for predicting pathological complete response (pCR) and prognosis in a group of BC patients receiving standardized treatment.Patients and methodsA total of 100 BC patients were treated with neoadjuvant chemotherapy (four cycles of epirubicin and cyclophosphamide) between 2000 and 2005. Formalin-fixed and paraffin-embedded core biopsies were taken before chemotherapy for immunohistochemical staining of ER, PgR, HER2, Bcl-2, p53, cyclin D1, CK5/6, CK8, CK18, and TOP2A. Patient and tumor characteristics and biomarker scores were used to predict pCR and prognosis, using logistic regression and Cox proportional hazard models.ResultspCR was achieved in 11 patients and was predicted by the established marker Ki-67. In addition, CK5/6 and CK18 improved the prediction model and were associated with lower pCR rates. For the prognosis, only the established markers nodal status, Ki-67, and PgR predicted overall survival and nodal status; Ki-67 and PgR predicted distant disease-free survival.ConclusionsIn this small retrospective study, CK5/6 and CK18 appeared to improve prediction of pCR in addition to the established markers. CK5/6 may indicate a tumor type resembling a basal phenotype that is more resistant to anthracycline-based therapy, and CK18 may indicate a luminal subtype that is more resistant to chemotherapy. However, these results need to be replicated in larger studies.