Gilles Berclaz

Hypoxia-inducible factor 1 alpha in high-risk breast cancer: an independent prognostic parameter?

BackgroundHypoxia-inducible factor 1 alpha (hif-1α) furnishes tumor cells with the means of adapting to stress parameters like tumor hypoxia and promotes critical steps in tumor progression and aggressiveness. We investigated the role of hif-1α expression in patients with node-positive breast cancer.MethodsTumor samples from 77 patients were available for immunohistochemistry. The impact of hif-1α immunoreactivity on survival endpoints was determined by univariate and multivariate analyses, and correlations to clinicopathological characteristics were determined by cross-tabulations.Resultshif-1α was expressed in 56% (n = 43/77) of the patients. Its expression correlated with progesterone receptor negativity (P = 0.002). The Kaplan–Meier curves revealed significantly shorter distant metastasis-free survival (DMFS) (P = 0.04, log-rank) and disease-free survival (DFS) (P = 0.04, log-rank) in patients with increased hif-1α expression. The difference in overall survival (OS) did not attain statistical significance (5-year OS, 66% without hif-1α expression and 55% with hif-1α expression; P = 0.21). The multivariate analysis failed to reveal an independent prognostic value for hif-1α expression in the whole patient group. The only significant parameter for all endpoints was the T stage (T3/T4 versus T1/T2: DMFS, relative risk = 3.16, P = 0.01; DFS, relative risk = 2.57, P = 0.03; OS, relative risk = 3.03, P = 0.03). Restricting the univariate and multivariate analyses to T1/T2 tumors, hif-1α expression was a significant parameter for DFS and DMFS.Conclusionshif-1α is expressed in the majority of patients with node-positive breast cancer. It can serve as a prognostic marker for an unfavorable outcome in those with T1/T2 tumors and positive axillary lymph nodes.

Value of One-View Breast Tomosynthesis Versus Two-View Mammography in Diagnostic Workup of Women With Clinical Signs and Symptoms and in Women Recalled From Screening

OBJECTIVE The purpose of this study is to compare the diagnostic value of one-view digital breast tomosynthesis versus two-view full-field digital mammography (FFDM) alone, and versus a combined reading of both modalities. MATERIALS AND METHODS The datasets of one-view digital breast tomosynthesis and two-view FFDM of abnormal mammograms in 144 consecutive women admitted for diagnostic workup with clinical signs and symptoms (n = 78) or recalled from screening (n = 66) were read alone and in a combined setting. The malignant or benign nature of the lesions was established by histologic analysis of biopsied lesions or by 12-16-month follow-up. RESULTS Eighty-six of the 144 patients were found to have breast cancer. The BI-RADS categories for one-view digital breast tomosynthesis were significantly better than those for two-view FFDM (p < 0.001) and were equal to those of the combined reading in both women admitted for diagnostic workup and women recalled from screening. The sensitivity and negative predictive values of digital breast tomosynthesis were superior to those of FFDM in fatty and dense breasts overall and in women admitted for diagnostic workup and in women recalled from screening. Only 11% of digital breast tomosynthesis examinations required additional imaging, compared with 23% of FFDMs. CONCLUSION In patients with abnormal mammograms, one-view digital breast tomosynthesis had better sensitivity and negative predictive value than did FFDM in patients with fatty and dense breasts. They also suggest that digital breast tomosynthesis would likely increase the predictive values if incorporated in routine screening.

Prognosis of dermal lymphatic invasion with or without clinical signs of inflammatory breast cancer

It is still an open debate whether tumor emboli in dermal lymphatics without inflammatory signs represent a similar bad prognosis like inflammatory breast cancer. We evaluated the prognostic role of dermal lymphatic invasion (DLI) in breast cancer with (DLI + ID) or without (DLI w/o ID) inflammatory disease (ID). From August 1988 to January 2000, 42 patients with DLI were irradiated. Twenty‐five were classified as pT4, 13 out of them as pT4d (inflammatory disease); the 17 remaining patients had 1 T1c, 12 T2 and 4 T3 cancers with DLI. Axillary dissection revealed node‐positive disease in 39/41 patients (median, 9 positive nodes). Thirty‐eight out of 42 patients received adjuvant systemic treatment(s). After a mean follow‐up of 33 months, 22/42 patients (52%) are disease‐free. The actuarial 3‐year disease‐free survival is 50% (DLI w/o ID, 61%; DLI + ID, 31%; p < 0.03); the corresponding overall survival was 69% (DLI w/o ID, 87%; DLI + ID, 37%; p = 0.005). The presence or absence of ID was the only significant parameter for all endpoints in multivariate analyses. Dissemination occurred in 19 (45%), local relapse in 7 (n = 17%) and regional failure in 4 (10%). Nine patients (21%) had contralateral breast cancer/relapse. Despite the same histopathologic presentation, DLI w/o ID offered a significantly better disease‐free survival and overall survival than ID. The finding of dermal lymphatic tumor invasion predicts a high probability for node‐positive disease.

Can the Addition of Regional Radiotherapy Counterbalance Important Risk Factors in Breast Cancer Patients with Extracapsular Invasion of Axillary Lymph- Node Metastases?

Purpose:To evaluate if locoregional radiotherapy (RT) versus local irradiation only can alter the pattern of failure in breast cancer patients with extranodal invasion.Patients and Methods:From 08/1988 to 06/1998, 81 patients with extranodal invasion were treated with adjuvant RT (median total dose: 50.4 Gy), 46/81 only locally, 35/81 locoregionally due to presumed adverse parameters. The mean number of resected (positive) lymph nodes was 17 (seven). 78 patients received adjuvant systemic treatment(s).Results:Patients treated with locoregional RT had significantly more often lymphatic vessel invasion (LVI; 63% vs. 28%; p = 0.003), T3/T4 tumors (43% vs. 17%; p = 0.014), and four or more positive lymph nodes (91% vs. 46%; p < 0.001) than patients irradiated only locally. Disease progression occurred in 24/81 patients (locoregional RT: 26% vs. local RT: 33%). The above risk factors were highly significant of worse outcome. Despite their overrepresentation in the locoregional RT group, no difference was found between both groups in regard to disease-free survival (DFS; p = 0.83) and overall survival (OS; p = 0.56), suggesting that regional RT was able to counterbalance the increased risk. There was even a trend toward a better 3-year DFS, 61% in locoregional RT and 37% in local RT, in the subgroup of patients with four or more positive lymph nodes. In a Cox regression model, higher T-stage, four or more positive lymph nodes, and LVI remained significant. For DFS and distant metastasis-free survival (DMFS), the absence of estrogen receptors and the omission of regional RT were also significant.Conclusion:Our data suggest that the addition of regional RT might be beneficial in selected subgroups of patients with extranodal invasion and other poor prognostic factors.Ziel:Evaluation einer Änderung des Rückfallmusters durch eine lokoregionäre Bestrahlung (RT) im Vergleich zur rein lokalen RT bei Patientinnen mit extranodalem Wachstum.Patienten und Methodik:Von 08/1988 bis 06/1998 wurden 81 nodal positive Patientinnen mit extranodalem Wachstum adjuvant bestrahlt (mediane Gesamtdosis: 50,4 Gy), 46 nur lokal, 35 zusätzlich regionär aufgrund von Risikokriterien. Die mittlere Anzahl resezierter (positiver) Lymphknoten betrug 17 (sieben). 78 Patientinnen erhielten adjuvante systemische Therapie(n).Ergebnisse:Lokoregionär therapierte Patientinnen hatten signifikant häufiger Lymphgefäßeinbrüche (LVI; 63% vs. 28%; p = 0,003), T3/T4-Tumoren (43% vs. 17%; p = 0,014) und vier oder mehr positive Lymphknoten (91% vs. 46%; p < 0,001) als nur lokal Bestrahlte (Tabelle 1). Eine Krankheitsprogression trat in 24/81 Fällen auf (bei lokoregionärer RT: 26%; bei lokaler RT: 33%; Tabelle 2). Die genannten Risikofaktoren spiegelten ein hoch signifikant schlechteres Überleben wider (Tabelle 3). Trotz deren Überrepräsentation in der lokoregionären Bestrahlungsgruppe konnte kein Unterschied zu nur lokal behandelten Patientinnen gefunden werden (krankheitsfreies Überleben [DFS]: p = 0,83; Gesamtüberleben [OS]: p = 0,56; Abbildungen 1 und 2). Dies legt die Vermutung nahe, dass die zusätzliche regionäre Bestrahlung diese Risiken auszugleichen vermag. In der Untergruppe mit vier oder mehr positiven Lymphknoten betrug das 3-Jahres-DFS sogar 61% in der lokoregionären Gruppe versus 37% in der Gruppe mit lokaler RT (Abbildung 3). Multivariat blieben T3/T4-Tumoren, vier oder mehr positive Lymphknoten und LVI signifikant, für das DFS und fernmetastasenfreie Überleben (DMFS) zusätzlich fehlende Östrogenrezeptoren und die Abwesenheit der regionären Bestrahlung (Tabelle 4).Schlussfolgerung:Im Vergleich zur nur lokalen RT scheint eine zusätzliche regionäre RT bedeutende Risikofaktoren bei Patientinnen mit extranodalem Wachstum auszugleichen.

Sites of failure in breast cancer patients with extracapsular invasion of axillary lymph node metastases. No need for axillary irradiation

Background and Purpose:Extracapsular spread (ECS) is frequent, but the specific sites of relapse are seldom given in the literature. In this study it was evaluated, if ECS might be an indicator for axillary irradiation.Patients and Methods:After a retrospective review of pathology reports, the information about ECS was available in 254 lymph node-positive patients: ECS was absent in 34% (ECS-negative; n = 87) and present in 66% (ECS-positive; n = 167). All patients were irradiated locally, 78 patients got periclavicular and 74 axillary irradiation (median total dose: 50.4 Gy). 240/254 patients (94.5%) received systemic treatment/s. Mean follow-up was 46 months.Results:The regional relapse rate was 4.6% without ECS versus 9.6% with ECS. The 5-year axillary relapse-free survival was 100% in ECS-negative and 90% in ECS-positive patients (p = 0.01), whereas corresponding values for periclavicular relapse-free survival (with ECS: 91% ± 4%; without ECS: 94% ± 3%; p = 0.77) and local relapse-free survival (with ECS: 86% ± 4%; without ECS: 91% ± 3%; p = 0.69) were not significantly different. χ2-tests revealed a high correlation of ECS with T-stage, number of positive lymph nodes and progesterone receptor status, comparisons with estrogen receptor, grade, or age were not significant. In multivariate analysis number of positive lymph nodes was solely significant for regional failure. Dividing the patients into those with one to three and those with four or more positive lymph nodes, ECS lost its significance for axillary failure.Conclusion:ECS was accompanied by an enhanced axillary failure rate in univariate analysis, which was no longer true after adjusting for the number of positive lymph nodes.Hintergrund und Ziel:Extrakapsuläres Tumorwachstum (ECS) befallener axillärer Lymphknoten ist häufig und wird als Parameter einer erhöhten lokoregionären Rezidivrate angesehen. In der Literatur sind erstaunlich wenig Informationen bezüglich spezifischer Lokalisationen eventueller Rezidive erhältlich. In dieser Studie sollte das ECS als eventuelle Indikator für eine Bestrahlung der Axilla evaluiert werden.Patienten und Methodik:Es wurden nur jene 254 nodal positiven Patientinnen ausgewertet, bei denen gemäß histologischem Bericht zum Vorliegen oder Fehlen von ECS klar Stellung genommen wurde: In 66% (ECS-positiv; n = 167) wurde ECS beschrieben, und in 34% fehlte es (ECS-negativ; n = 87). Alle Patientinnen wurden lokal bestrahlt, 78 davon auch periklavikulär und 74 axillär (mediane Gesamtdosis: je 50,4 Gy). 240/254 Patientinnen (94,5%) erhielten Systemtherapie/n. Die mittlere Nachbeobachtungszeit betrug 46 Monate.Ergebnisse:Die regionäre Rezidivrate betrug 4,6% ohne ECS versus 9,6% mit ECS. Das axilläre rezidivfreie 5-Jahres-Überleben war 100% bei ECS-negativen und 90% bei ECS-positiven Patientinnen (p = 0,01). Die korrespondierenden Werte für das periklavikuläre rezidivfreie Überleben (mit ECS: 91% ± 4%; ohne ECS: 94% ± 3%; p = 0,77) und das lokalrezidivfreie Überleben (mit ECS: 86% ± 4%; ohne ECS: 91% ± 3%; p = 0,69) waren nicht signifikant unterschiedlich. ECS (ja/nein) korrelierte signifikant mit dem T-Stadium, der Anzahl positiver Lymphknoten und dem Progesteronrezeptorstatus, dagegen nicht mit dem Östrogenrezeptor, dem Tumorgrad oder dem Alter. Multivariat war die Anzahl positiver Lymphknoten der einzige signifikante Parameter für das regionale Tumorrezidiv. Nach der Stratifikation der Patientinnen in solche mit ein bis drei und solche mit vier oder mehr positiven Lymphknoten ließ sich keine Signifikanz von ECS für die axilläre Rezidivhäufigkeit mehr finden.Schlussfolgerung:In der univariaten Analyse war das Vorliegen von ECS mit einer erhöhten axillären Rezidivhäufigkeit vergesellschaftet. Dies konnte nach Aufteilung in ein bis drei und vier oder mehr positive Lymphknoten nicht mehr beobachtet werden.

Hormone-dependent nuclear localization of the tyrosine kinase iyk in the normal human breast epithelium and loss of expression during carcinogenesis

iyk, a member of the frk family of non‐receptor tyrosine kinases, was originally isolated from normal mouse mammary glands and is characterized by a nuclear localizing signal within the SH2 domain. We have investigated the expression and subcellular localization of iyk in the normal human breast and in malignant breast diseases. Immuno‐histochemical analyses revealed that in normal tissue iyk localizes to both cytoplasmic and nuclear compartments of breast epithelial cells. The subcellular distribution was dependent on the hormonal state, being mostly cytoplasmic during the follicular, proliferative phase of the menstrual cycle, whereas frequent nuclear staining was observed in the resting stages during the luteal phase and, most prominently, after menopause. Strikingly, invasive carcinomas, irrespective of tumor type or hormonal status of the patient, exhibited almost complete loss of iyk expression in both the cytoplasm and the nucleus. In contrast, in situ breast carcinomas from post‐menopausal patients showed a clear reduction of the nuclear iyk localization while retaining cytoplasmic staining. Our results indicate that iyk expression is gradually lost during carcinogenesis; thus, iyk may be classified as a tumor‐suppressor gene. Int. J. Cancer 85:889–894, 2000.

Sites of Failure in Breast Cancer Patients with Extracapsular Invasion of Axillary Lymph Node Metastases

Background and Purpose:Extracapsular spread (ECS) is frequent, but the specific sites of relapse are seldom given in the literature. In this study it was evaluated, if ECS might be an indicator for axillary irradiation.Patients and Methods:After a retrospective review of pathology reports, the information about ECS was available in 254 lymph node-positive patients: ECS was absent in 34% (ECS-negative; n = 87) and present in 66% (ECS-positive; n = 167). All patients were irradiated locally, 78 patients got periclavicular and 74 axillary irradiation (median total dose: 50.4 Gy). 240/254 patients (94.5%) received systemic treatment/s. Mean follow-up was 46 months.Results:The regional relapse rate was 4.6% without ECS versus 9.6% with ECS. The 5-year axillary relapse-free survival was 100% in ECS-negative and 90% in ECS-positive patients (p = 0.01), whereas corresponding values for periclavicular relapse-free survival (with ECS: 91% ± 4%; without ECS: 94% ± 3%; p = 0.77) and local relapse-free survival (with ECS: 86% ± 4%; without ECS: 91% ± 3%; p = 0.69) were not significantly different. χ2-tests revealed a high correlation of ECS with T-stage, number of positive lymph nodes and progesterone receptor status, comparisons with estrogen receptor, grade, or age were not significant. In multivariate analysis number of positive lymph nodes was solely significant for regional failure. Dividing the patients into those with one to three and those with four or more positive lymph nodes, ECS lost its significance for axillary failure.Conclusion:ECS was accompanied by an enhanced axillary failure rate in univariate analysis, which was no longer true after adjusting for the number of positive lymph nodes.Hintergrund und Ziel:Extrakapsuläres Tumorwachstum (ECS) befallener axillärer Lymphknoten ist häufig und wird als Parameter einer erhöhten lokoregionären Rezidivrate angesehen. In der Literatur sind erstaunlich wenig Informationen bezüglich spezifischer Lokalisationen eventueller Rezidive erhältlich. In dieser Studie sollte das ECS als eventuelle Indikator für eine Bestrahlung der Axilla evaluiert werden.Patienten und Methodik:Es wurden nur jene 254 nodal positiven Patientinnen ausgewertet, bei denen gemäß histologischem Bericht zum Vorliegen oder Fehlen von ECS klar Stellung genommen wurde: In 66% (ECS-positiv; n = 167) wurde ECS beschrieben, und in 34% fehlte es (ECS-negativ; n = 87). Alle Patientinnen wurden lokal bestrahlt, 78 davon auch periklavikulär und 74 axillär (mediane Gesamtdosis: je 50,4 Gy). 240/254 Patientinnen (94,5%) erhielten Systemtherapie/n. Die mittlere Nachbeobachtungszeit betrug 46 Monate.Ergebnisse:Die regionäre Rezidivrate betrug 4,6% ohne ECS versus 9,6% mit ECS. Das axilläre rezidivfreie 5-Jahres-Überleben war 100% bei ECS-negativen und 90% bei ECS-positiven Patientinnen (p = 0,01). Die korrespondierenden Werte für das periklavikuläre rezidivfreie Überleben (mit ECS: 91% ± 4%; ohne ECS: 94% ± 3%; p = 0,77) und das lokalrezidivfreie Überleben (mit ECS: 86% ± 4%; ohne ECS: 91% ± 3%; p = 0,69) waren nicht signifikant unterschiedlich. ECS (ja/nein) korrelierte signifikant mit dem T-Stadium, der Anzahl positiver Lymphknoten und dem Progesteronrezeptorstatus, dagegen nicht mit dem Östrogenrezeptor, dem Tumorgrad oder dem Alter. Multivariat war die Anzahl positiver Lymphknoten der einzige signifikante Parameter für das regionale Tumorrezidiv. Nach der Stratifikation der Patientinnen in solche mit ein bis drei und solche mit vier oder mehr positiven Lymphknoten ließ sich keine Signifikanz von ECS für die axilläre Rezidivhäufigkeit mehr finden.Schlussfolgerung:In der univariaten Analyse war das Vorliegen von ECS mit einer erhöhten axillären Rezidivhäufigkeit vergesellschaftet. Dies konnte nach Aufteilung in ein bis drei und vier oder mehr positive Lymphknoten nicht mehr beobachtet werden.