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Hintergrund: Die mittlerweile 7. Internationale Konsensuskonferenz zum fortgeschrittenen Mammakarzinom ABC7 (International Consensus Conference for Advanced Breast Cancer [ABC]) fand vom 9. bis 12. November 2023 in Lissabon/Portugal statt. Bei dem Konsens handelt es sich um ein Meinungsbild von Expertinnen und Experten unterschiedlicher Länder und Fachdisziplinen. Rationale: Ziel der internationalen Konsensuskonferenz ist es, die Behandlung der Patientinnen mit primär inoperablem fortgeschrittenem bzw. mit metastasiertem Mammakarzinom auf evidenzbasierter Grundlage weltweit zu standardisieren und in allen Ländern eine adäquate Behandlung sicherzustellen. Im vorliegenden Manuskript werden die ABC7-Abstimmungsergebnisse vor Ort für den Klinikalltag in Deutschland diskutiert. Grundlage: Die Diskussion erfolgt vor dem Hintergrund der aktualisierten Therapieempfehlungen der Arbeitsgemeinschaft Gynäkologische Onkologie (AGO Organkommission Mamma; Version 2024.1D) vom März 2024. Ergebnis: In diesem Manuskript liegt der inhaltliche Fokus auf der Systemtherapie des metastasierten Mammakarzinoms. Spezielle Themen waren unter anderem die oligometastasierte Patientin, die leptomeningeale Erkrankung, die Behandlung von Hirnmetastasen sowie von schwangeren Patientinnen. Wie schon in den vergangenen Jahren nahmen auch Patientenvertreterinnen aus der ganzen Welt an der Konferenz teil und waren an der Konsensfindung beteiligt.

Antikörper-Wirkstoff-Konjugate (ADCs) kombinieren die Vorteile einer hochpotenten zytostatischen Therapie mit dem selektiven Einsatz einer zielgerichteten Therapie. Sie bestehen aus 3 Komponenten: einem monoklonalen Antikörper, einem Linker und einem zytotoxischen Wirkstoff (Payload). Der Antikörper erkennt spezifische Zielstrukturen auf Krebszellen, wodurch der Wirkstoff gezielt dorthin transportiert wird. Der Linker ermöglicht die gezielte Freisetzung des Wirkstoffs innerhalb der Zielzelle und darüber hinaus (Bystander-Effekt). Alle 3 Komponenten spielen eine wichtige Rolle bezüglich sowohl Wirksamkeit als auch Verträglichkeit der ADCs. Nebenwirkungen werden in On-Target- und Off-Target-Toxizitäten unterteilt, wobei dem erwünschten Bystander-Effekt eine wichtige Rolle in der Therapie heterogener Tumorbiologien zukommt. In der frühen Therapiesituation ist aktuell ausschließlich Trastuzumab Emtansin (T-DM1) zugelassen, die Wirksamkeit von Sacituzumab Govitecan (SG) und Trastuzumab Deruxtecan (TDXd) wird aktuell erforscht. In fortgeschrittenen Stadien haben alle 3 Substanzen ihre Wirksamkeit bewiesen. Für Datopotamab Deruxtecan (Dato-DXd) laufen aktuell Studien in der frühen und fortgeschrittenen Therapiesituation, erste Ergebnisse sind vielversprechend. Der Beitrag gibt einen Überblick über Wirkmechanismus, praktische Anwendungen, Herausforderungen und mögliche Entwicklungen in der Zukunft.

Die Knochengesundheit bei Tumorpatienten spielt in der onkologischen Versorgung eine elementare Rolle. Knochenmetastasen gehören zu den häufigsten Metastasen und bedingen klinische Probleme wie Schmerzen, pathologische Frakturen und tumorinduzierte Hyperkalzämie (TIH). Wichtig ist zudem die therapiebedingte Osteoporose aufgrund der mit ihr einhergehenden Morbidität und Mortalität. Medikamentös kommen Antiresorptiva in unterschiedlicher Dosierung zum Einsatz. Bei frakturgefährdeten Knochen oder bereits eingetretener Fraktur kommen Strahlentherapie und Operation zur Anwendung. Die Komplexität der Knochengesundheit bei Tumorpatienten erfordert eine enge interdisziplinäre Zusammenarbeit zwischen Onkologen, Radiologen, Strahlentherapeuten, Chirurgen, Endokrinologen, Gynäkologen und anderen Spezialisten.

Hintergrund: Seit über 30 Jahren findet regelmäßig die Internationale St.-Gallen(SG)-Konsensuskonferenz zur Behandlung des primären Mammakarzinoms (SGBCC) statt. Bei diesem Konsensus handelt es sich um ein internationales Meinungsbild von Expertinnen und Experten unterschiedlicher Länder und Fachdisziplinen. Rationale: Hier sollen die Abstimmungsergebnisse der SGBCC-Panel-Mitglieder für den Klinikalltag in Deutschland diskutiert werden. Grundlage: Basis der Diskussion sind die im März 2023 aktualisierten Therapieempfehlungen der Arbeitsgemeinschaft Gynäkologische Onkologie (AGO Organkommission Mamma; Version 2023.1D). Ergebnis: Die diesjährige 18. SGBCC fokussierte auf praxisorientierte Fragestellungen. Die individuelle Krankheitssituation und Nutzen-Risiko-Abwägung wurden bevorzugt anhand von Fallbeispielen diskutiert und mit der aktuellen Datenlage abgeglichen. Im Vordergrund der wichtigsten Abstimmungsergebnisse zur Systemtherapie standen die endokrine Therapie und CDK4/6-Inhibition, die Immuntherapie sowie die BRCA-Bestimmung und PARP-Inhibition.

IMPORTANCE: Combination of chemotherapy with (dual) ERBB2 blockade is considered standard in hormone receptor (HR)-positive/ERBB2-positive early breast cancer (EBC). Despite some promising data on endocrine therapy (ET) combination with dual ERBB2 blockade in HR-positive/ERBB2-positive BC, to our knowledge, no prospective comparison of neoadjuvant chemotherapy vs ET plus ERBB2 blockade in particular with focus on molecular markers has yet been performed. OBJECTIVE: To determine whether neoadjuvant de-escalated chemotherapy is superior to endocrine therapy, both in combination with pertuzumab and trastuzumab, in a highly heterogeneous HR-positive/ERBB2-positive EBC. DESIGN, SETTING, AND PARTICIPANTS: This prospective, multicenter, neoadjuvant randomized clinical trial allocated 207 patients with centrally confirmed estrogen receptor–positive and/or progesterone receptor–positive (>1%) HR-positive/ERBB2-positive EBC to 12 weeks of standard ET (n = 100) vs paclitaxel (n = 107) plus trastuzumab and pertuzumab. A total of 186 patients were required to detect a statistically significant difference in pathological complete response (pCR) (assumptions: 19% absolute difference in pCR; power, ≥80%; 1-sided Fisher exact test, 2.5% significance level). INTERVENTIONS: Standard ET (aromatase inhibitor or tamoxifen) or paclitaxel, 80 mg/m2, weekly plus trastuzumab and pertuzumab every 21 days. MAIN OUTCOMES AND MEASURES: The primary end point was pCR (ypT0/is, ypN0). Secondary end points included safety, translational research, and health-related quality of life. Omission of further chemotherapy was allowed in patients with pCR. PAM50 analysis was performed on baseline tumor biopsies. RESULTS: Of the 207 patients included (median [range] age, 53 [25-83] years), 121 (58%) had cT2 to cT4 tumors, and 58 (28%) had clinically node-positive EBC. The pCR rate in the ET plus trastuzumab and pertuzumab arm was 23.7% (95% CI, 15.7%-33.4%) vs 56.4% (95% CI, 46.2%-66.3%) in the paclitaxel plus trastuzumab and pertuzumab arm (odds ratio, 0.24; 95% CI, 0.12-0.46; P < .001). Both immunohistochemical ERBB2 score of 3 or higher and ERBB2-enriched subtype were independent predictors for pCR in both arms. Paclitaxel was superior to ET only in the first through third quartiles but not in the highest ERBB2 quartile by messenger RNA. In contrast with the paclitaxel plus trastuzumab and pertuzumab arm, no decrease in health-related quality of life after 12 weeks was observed in the ET plus trastuzumab and pertuzumab arm. CONCLUSIONS AND RELEVANCE: The WSG-TP-II randomized clinical trial is, to our knowledge, the first prospective trial comparing 2 neoadjuvant de-escalation treatments in HR-positive/ERBB2-positive EBC and demonstrated an excellent pCR rate after 12 weeks of paclitaxel plus trastuzumab and pertuzumab that was clearly superior to the pCR rate after ET plus trastuzumab and pertuzumab. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03272477

Anthracycline–taxane chemotherapy for early-stage breast cancer substantially improves survival compared with no chemotherapy. However, concerns about short-term and long-term side-effects of anthracyclines have led to increased use of taxane chemotherapy without anthracycline, which could compromise efficacy. We aimed to better characterise the benefits and risks of including anthracycline, and the comparative benefits of different anthracycline–taxane regimens.

Die Therapie des frühen Mammakarzinoms erfolgt individualisiert in Abhängigkeit von Tumorbiologie, Tumorstadium und individuellen Faktoren. Die medikamentöse Therapie kann als primär systemische Therapie vor oder als adjuvante Therapie nach abgeschlossener Lokaltherapie durchgeführt werden. Bei der primär systemischen Therapie handelt es sich um ein 2‑Stufen-Konzept: Basierend auf dem Resultat der postoperativen histopathologischen Begutachtung kann die nachfolgende, postneoadjuvante Therapie angepasst und das Rezidivrisiko gesenkt werden. Die Auswahl und Kombination der Substanzen in der Postneoadjuvanz erfolgen individuell risikoadaptiert, wobei dem Erreichen einer pathologischen Komplettremission (pCR) neben Tumorbiologie, initialem Tumorstadium und genetischem Risiko eine wichtige Bedeutung zukommt. Da die Therapieoptionen komplex sind, sollten diese Entscheidungen individuell im interdisziplinären Tumorboard prä- und postoperativ auch in der Sequenz mit den lokalen Therapien getroffen werden.

Invasive lobular breast cancer (ILC) is a special breast cancer (BC) subtype and is mostly hormone receptor (HR)-positive and ERBB2non-amplified. Endocrine therapy restrains tumor proliferation and is the mainstay of lobular BC treatment. Mutation of ERBB2has been associated with recurrent ILC. However, it is unknown whether ERBB2mutation impacts on the otherwise exquisite responsiveness of early ILC to endocrine therapy. We have recently profiled n= 622 HR-positive early BCs from the ADAPT trial for mutations in candidate genes involved in endocrine resistance, including ERBB2. All patients were treated with short-term preoperative endocrine therapy (pET, tamoxifen or aromatase inhibitors) before tumor resection. Tumor proliferation after endocrine therapy (post-pET Ki67 index) was determined prospectively by standardized central pathology assessment supported by computer-assisted image analysis. Sustained or suppressed proliferation were defined as post-pET Ki67 ≥10% or <10%. Here, we report a subgroup analysis pertaining to ILCs in this cohort. ILCs accounted for 179/622 (28.8%) cases. ILCs were enriched in mutations in CDH1(124/179, 69.3%, P< 0.0001) and ERBB2(14/179, 7.8%, P< 0.0001), but showed fewer mutations in TP53(7/179, 3.9%, P= 0.0048) and GATA3(11/179, 6.1%, P< 0.0001). Considering all BCs irrespective of subtypes, ERBB2mutation was not associated with proliferation. In ILCs, however, ERBB2mutations were 3.5-fold more common in cases with sustained post-pET proliferation compared to cases with suppressed post-pET proliferation (10/75, 13.3% versus 4/104, 3.8%, P= 0.0248). Moreover, ERBB2mutation was associated with high Oncotype DX recurrence scores (P= 0.0087). In summary, our findings support that ERBB2mutation influences endocrine responsiveness in early lobular BC.

Invasive lobular carcinoma (ILC) is the second most frequent type of breast cancer (BC) and its peculiar morphology is mainly driven by inactivation of CDH1, the gene coding for E-cadherin cell adhesion protein. ILC-specific therapeutic and disease-monitoring approaches are gaining momentum in the clinic, increasing the importance of accurate ILC diagnosis. Several essential and desirable morphologic diagnostic criteria are currently defined by the World Health Organization, the routine use of immunohistochemistry (IHC) for E-cadherin is not recommended. Disagreement in the diagnosis of ILC has been repeatedly reported, but interpathologist agreement increases with the use of E-cadherin IHC. In this study, we aimed to harmonize the pathological diagnosis of ILC by comparing 5 commonly used E-cadherin antibody clones (NCH-38, EP700Y, Clone 36, NCL-L-E-cad [Clone 36B5], and ECH-6). We determined their biochemical specificity for the E-cadherin protein and IHC staining performance according to type and location of mutation on the CDH1gene. Western blot analysis on mouse cell lines with conditional E-cadherin expression revealed a reduced specificity of EP700Y and NCL-L-E-cad for E-cadherin, with cross-reactivity of Clone 36 to P-cadherin. The use of IHC improved interpathologist agreement for ILC, lobular carcinoma in situ, and atypical lobular hyperplasia. The E-cadherin IHC staining pattern was associated with variant allele frequency and likelihood of nonsense-mediated RNA decay but not with the type or position of CDH1mutations. Based on these results, we recommend the indication for E-cadherin staining, choice of antibodies, and their interpretation to standardize ILC diagnosis in current pathology practice.

Background: Urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play essential roles in tumor invasion and metastasis. High levels of both uPA and PAI-1 are associated with poor prognosis in breast cancer patients. To confirm the prognostic value of uPA and PAI-1 in primary breast cancer, we reanalyzed individual patient data provided by members of the European Organization for Research and Treatment of Cancer-Receptor and Biomarker Group (EORTC-RBG). Methods: The study included 18 datasets involving 8377 breast cancer patients. During follow-up (median 79 months), 35% of the patients relapsed and 27% died. Levels of uPA and PAI-1 in tumor tissue extracts were determined by different immunoassays; values were ranked within each dataset and divided by the number of patients in that dataset to produce fractional ranks that could be compared directly across datasets. Associations of ranks of uPA and PAI-1 levels with relapse-free survival (RFS) and overall survival (OS) were analyzed by Cox multivariable regression analysis stratified by dataset, including the following traditional prognostic variables: age, menopausal status, lymph node status, tumor size, histologic grade, and steroid hormone-receptor status. All P values were two-sided. Results: Apart from lymph node status, high levels of uPA and PAI-1 were the strongest predictors of both poor RFS and poor OS in the analyses of all patients. Moreover, in both lymph node-positive and lymph node-negative patients, higher uPA and PAI-1 values were independently associated with poor RFS and poor OS. For (untreated) lymph node-negative patients in particular, uPA and PAI-1 included together showed strong prognostic ability (all P

IMPORTANCE: Whether the severity and mortality of COVID-19 in patients with cancer have improved in terms of disease management and capacity is yet to be defined. OBJECTIVE: To test whether severity and mortality from COVID-19 among patients with cancer have improved during the course of the pandemic. DESIGN, SETTING, AND PARTICIPANTS: OnCovid is a European registry that collects data on consecutive patients with solid or hematologic cancer and COVID-19. This multicenter case series study included real-world data from 35 institutions across 6 countries (UK, Italy, Spain, France, Belgium, and Germany). This update included patients diagnosed between February 27, 2020, and February, 14, 2021. Inclusion criteria were confirmed diagnosis of SARS-CoV-2 infection and a history of solid or hematologic cancer. EXPOSURES: SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES: Deaths were differentiated at 14 days and 3 months as the 2 landmark end points. Patient characteristics and outcomes were compared by stratifying patients across 5 phases (February to March 2020, April to June 2020, July to September 2020, October to December 2020, and January to February 2021) and across 2 major outbreaks (February to June 2020 and July 2020 to February 2021). RESULTS: At data cutoff, 2795 consecutive patients were included, with 2634 patients eligible for analysis (median [IQR] age, 68 [18-77] years ; 52.8% men). Eligible patients demonstrated significant time-dependent improvement in 14-day case-fatality rate (CFR) with estimates of 29.8% (95% CI, 0.26-0.33) for February to March 2020; 20.3% (95% CI, 0.17-0.23) for April to June 2020; 12.5% (95% CI, 0.06-22.90) for July to September 2020; 17.2% (95% CI, 0.15-0.21) for October to December 2020; and 14.5% (95% CI, 0.09-0.21) for January to February 2021 (all P &lt; .001) across the predefined phases. Compared with the second major outbreak, patients diagnosed in the first outbreak were more likely to be 65 years or older (974 of 1626 [60.3%] vs 564 of 1008 [56.1%]; P = .03), have at least 2 comorbidities (793 of 1626 [48.8%] vs 427 of 1008 [42.4%]; P = .001), and have advanced tumors (708 of 1626 [46.4%] vs 536 of 1008 [56.1%]; P &lt; .001). Complications of COVID-19 were more likely to be seen (738 of 1626 [45.4%] vs 342 of 1008 [33.9%]; P &lt; .001) and require hospitalization (969 of 1626 [59.8%] vs 418 of 1008 [42.1%]; P &lt; .001) and anti–COVID-19 therapy (1004 of 1626 [61.7%] vs 501 of 1008 [49.7%]; P &lt; .001) during the first major outbreak. The 14-day CFRs for the first and second major outbreaks were 25.6% (95% CI, 0.23-0.28) vs 16.2% (95% CI, 0.13-0.19; P &lt; .001), respectively. After adjusting for country, sex, age, comorbidities, tumor stage and status, anti–COVID-19 and anticancer therapy, and COVID-19 complications, patients diagnosed in the first outbreak had an increased risk of death at 14 days (hazard ratio [HR], 1.85; 95% CI, 1.47-2.32) and 3 months (HR, 1.28; 95% CI, 1.08-1.51) compared with those diagnosed in the second outbreak. CONCLUSIONS AND RELEVANCE: The findings of this registry-based study suggest that mortality in patients with cancer diagnosed with COVID-19 has improved in Europe; this improvement may be associated with earlier diagnosis, improved management, and dynamic changes in community transmission over time.

Preferred neoadjuvant regimens for early-stage triple-negative breast cancer (TNBC) include anthracycline-cyclophosphamide and taxane-based chemotherapy. IMpassion031 compared efficacy and safety of atezolizumab versus placebo combined with nab-paclitaxel followed by doxorubicin plus cyclophosphamide as neoadjuvant treatment for early-stage TNBC.

Zur onkoplastischen Rekonstruktion der Brust stehen verschiedene Ansätze zur Verfügung. Ziel ist ein bestmögliches kosmetisches Ergebnis, ohne die onkologische Sicherheit aufs Spiel zu setzen. Planungsrelevante Kriterien sind z. B. die Brust-Tumor-Relation sowie die Brustform.

Immer häufiger kommt Brustkrebs auch bei jungen Frauen vor. Welche Besonderheiten sind bei diesen Patientinnen zu beachten? Wichtige „To-dos“ — vom Ansprechen der Famlienplanung bis zur Überprüfung der Adhärenz einer endokrinen Therapie — erfahren Sie hier.

Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy.

Background: Most patients with lymph node-negative breast cancer are cured by locoregional treatment; however, about 30% relapse. Because traditional histomorphologic and clinical factors fail to identify the high-risk patients who may benefit from adjuvant chemotherapy, other prognostic factors are needed. In a unicenter study, we have found that levels of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) in the primary tumor are predictive of disease recurrence. Thus, we designed the Chemo [N.sub.0] prospective randomized multicenter therapy trial to investigate further whether uPA and PAI-1 are such prognostic factors and whether high-risk patients identified by these factors benefit from adjuvant chemotherapy. After 4.5 years, we present results of the first interim analysis. Methods: We studied 556 patients with lymph node-negative breast cancer. The median follow-up was 32 months. All patients with low tumor levels of uPA ([is less than or equal to] 3 ng/mg of protein) and of PAI-1 ([is less than or equal to] 14 ng/mg of protein) were observed. Patients with high tumor levels of uPA ([is greater than] 3 ng/mg of protein) and/or of PAI-1 ([is greater than] 14 ng/mg of protein) were randomly assigned to combination chemotherapy or subjected to observation only. All statistical tests were two-sided. Results: A total of 241 patients had low levels of uPA and PAI-1, and 315 had elevated levels of uPA and/or PAI-1. The estimated 3-year recurrence rate for patients with low tumor levels of uPA and PAI-1 (low-risk group) was 6.7% (95% confidence interval [CI] = 2.5% to 10.8%). This rate for patients with high tumor levels of uPA and/or PAI-1 (high-risk group) was 14.7% (95% CI = 8.5% to 20.9%) (P = .006). First interim analysis suggests that high-risk patients in the chemotherapy group benefit, with a 43.8% lower estimated probability of disease recurrence at 3 years than high-risk patients in the observation group (intention-to-treat analysis: relative risk = 0.56; 95% CI = 0.25 to 1.28), but further follow-up is needed for confirmation. Conclusions: Using uPA and PAI-1, we have been able to classify about half of the patients with lymph node-negative breast cancer as low risk, for whom adjuvant chemotherapy may be avoided, and half as high risk, who appear to benefit from adjuvant chemotherapy. [J Natl Cancer Inst 2001;93: 913-20]

New markers are needed to improve diagnosis and to personalize treatments for patients with breast cancer (BC). Receptor-interacting protein of 140 kDa (RIP140) and ligand-dependent corepressor (LCoR), two transcriptional co-regulators of estrogen receptors, strongly interact in BC cells. Although their role in cancer progression has been outlined in the last few years, their function in BC has not been elucidated yet. In this study, we investigated RIP140 and LCoR localization (cytoplasm vsnucleus) in BC samples from a well-characterized cohort of patients (n = 320). RIP140 and LCoR were expressed in more than 80% of tumors, (predominantly in the cytoplasm), and the two markers were highly correlated. Expression of RIP140 and LCoR in the nucleus was negatively correlated with tumor size. Conversely, RIP140 and LCoR cytoplasmic expression strongly correlated with expression of two tumor aggressiveness markers: N-cadherin and CD133 (epithelial mesenchymal transition and cancer stem cell markers, respectively). Finally, high RIP140 nuclear expression was significantly correlated with longer overall survival, whereas high total or cytoplasmic expression of RIP140 was associated with shorter disease-free survival. Our study strongly suggests that the role of RIP140 and LCoR in BC progression could vary according to their prevalent sub-cellular localization, with opposite prognostic values for nuclear and cytoplasmic expression. The involvement in BC progression/invasiveness of cytoplasmic RIP140 could be balanced by the anti-tumor action of nuclear RIP140, thus explaining the previous contradictory findings about its role in BC.

Epigenetic misprogramming is an essential component of cancer development.DNA methylation-based risk-prediction models provide novel opportunities for risk-tailored screening and prevention of cancer.Multidisciplinary collaborative research is needed to overcome the scientific challenges associated with the discovery of DNA methylation markers for risk-prediction, such as identifying surrogate tissues and developing novel analytical methods.Implementation of epigenome-based risk-tailored screening and prevention programmes requires several ethical, legal, social, organizational and economic challenges to be addressed in addition to the engagement of policymakers, health-care professionals and the public.

ABSTRACTIntroduction: Despite improvements in the diagnosis and management of early stage breast cancer, about one third of the patients still progress to metastatic disease. Most of the patients with metastatic breast cancer have a hormone receptor positive and human epidermal growth factor receptor 2 negative subtype with a median survival of more than 3 years. For these patients, endocrine therapy with its favorable toxicity profile is the current standard of care. However, patients with metastatic breast cancer have an incurable disease. Therefore, not only efficacy but also quality of life are key when selecting a therapy regimen.Areas covered:This paper aims to discuss the efficacy and toxicity profile of the new endocrine-based therapy option palbociclib together with endocrine treatment.Expert opinion: The addition of targeted agents like palbociclib can overcome intrinsic or acquired resistance to endocrine therapy and substantially prolong progression free survival. The combination of palbociclib plus endocrine therapy is associated with a tolerable and well manageable toxicity profile as well as maintenance of quality of life. Thus, addition of palbociclib to endocrine therapy offers a new and important treatment option for hormone receptor positive metastatic breast cancer.

Transcription factor AP-2β (TFAP2B) regulates embryonic organ development and is overexpressed in alveolar rhabdomyosarcoma, a rare childhood malignancy. Gene expression profiling has implicated AP-2β in breast cancer (BC). This study characterizes AP-2β expression in the mammary gland and in BC. AP-2β protein expression was assessed in the normal mammary gland epithelium, in various reactive, metaplastic and pre-invasive neoplastic lesions and in two clinical BC cohorts comprising >2000 patients. BCs from various genetically engineered mouse (GEM) models were also evaluated. Human BC cell lines served as functional models to study siRNA-mediated inhibition of AP-2β. The normal mammary gland epithelium showed scattered AP-2β-positive cells in the luminal cell layer. Various reactive and pre-invasive neoplastic lesions, including apocrine metaplasia, usual ductal hyperplasia and lobular carcinoma in situ (LCIS) showed enhanced AP-2β expression. Cases of ductal carcinoma in situ (DCIS) were more often AP-2β-negative (P<0.001). In invasive BC cohorts, AP-2β-positivity was associated with the lobular BC subtype (P<0.001), loss of E-cadherin (P<0.001), a positive estrogen receptor (ER) status (P<0.001), low Ki67 (P<0.001), low/intermediate Oncotype DX recurrence scores (P<0.001), and prolonged event-free survival (P=0.003). BCs from GEM models were all AP-2β-negative. In human BC cell lines, AP-2β expression was independent from ER-signaling. SiRNA-mediated inhibition of AP-2β diminished proliferation of lobular BC cell lines in vitro. In summary, AP-2β is a new mammary epithelial differentiation marker. Its expression is preferentially retained and enhanced in LCIS and invasive lobular BC and has prognostic implications. Our findings indicate that AP-2β controls tumor cell proliferation in this slow-growing BC subtype.

Transcription factor AP-2β(TFAP2B) regulates embryonic organ development and is overexpressed in alveolar rhabdomyosarcoma, a rare childhood malignancy. Gene expression profiling has implicated AP-2βin breast cancer (BC). This study characterizes AP-2βexpression in the mammary gland and in BC. AP-2βprotein expression was assessed in the normal mammary gland epithelium, in various reactive, metaplastic and pre-invasive neoplastic lesions and in two clinical BC cohorts comprising >2000 patients. BCs from various genetically engineered mouse (GEM) models were also evaluated. Human BC cell lines served as functional models to study siRNA-mediated inhibition of AP-2β. The normal mammary gland epithelium showed scattered AP-2β-positive cells in the luminal cell layer. Various reactive and pre-invasive neoplastic lesions, including apocrine metaplasia, usual ductal hyperplasia and lobular carcinoma in situ(LCIS) showed enhanced AP-2βexpression. Cases of ductal carcinoma in situ(DCIS) were more often AP-2β-negative (P<0.001). In invasive BC cohorts, AP-2β-positivity was associated with the lobular BC subtype (P<0.001), loss of E-cadherin (P<0.001), a positive estrogen receptor (ER) status (P<0.001), low Ki67 (P<0.001), low/intermediate Oncotype DX recurrence scores (P<0.001), and prolonged event-free survival (P=0.003). BCs from GEM models were all AP-2β-negative. In human BC cell lines, AP-2βexpression was independent from ER-signaling. SiRNA-mediated inhibition of AP-2βdiminished proliferation of lobular BC cell lines in vitro. In summary, AP-2βis a new mammary epithelial differentiation marker. Its expression is preferentially retained and enhanced in LCIS and invasive lobular BC and has prognostic implications. Our findings indicate that AP-2βcontrols tumor cell proliferation in this slow-growing BC subtype.

In Deutschland erkranken jährlich zwischen 600 und 650 Männer an Brustkrebs. Aufgrund des geringen öffentlichen Bewusstseins und fehlender Vorsorgeuntersuchungen wird die Erkrankung aber oft erst in einem fortgeschrittenen Stadium diagnostiziert.

Background: Modern oral antineoplastic and immune-modulating drugs offer an array of therapeutic advantages, and yet pose challenges in daily use for patients, physicians and pharmacists. In contrast to intravenous administration, these drugs are not subject to direct medical control. Recently, we have seen a huge rise in sales of non-prescription over-the-counter (OTC) medicines viathe internet without any advice from a healthcare professional.Objectives: The aim of this study was to investigate whether the risk of known potential drug-drug interactions between modern oral antineoplastic and immune-modulating drugs and OTC drugs differs between sales in traditional community pharmacies versusonline pharmacies.Design: Real-life sales data from community and online pharmacies were used as basis for the analysis.Methods: We determined the most frequently purchased antineoplastic and immune-modulating drug-substances in 14 local community pharmacies within the Munich area, Germany and identified the OTC substance groups that could potentially cause interactions with oncological therapies. Using sales data from 11 local community pharmacies and three online pharmacies, we investigated whether OTC purchases differed between the two sales channels.Results: We identified 10 relevant OTC substance classes and detected significant variations in patients’ preferred sales channels between the drug classes. Certain OTC drugs, which seem to be bought more often over the internet, pose risks during antineoplastic and immune-modulating therapy.Conclusion: Patients should therefore be proactively made aware of the corresponding risks in order not to jeopardize the activity of the antineoplastic and immune-modulating drugs and thus the success of their therapy.

In an outpatient setting, some challenges of cancer treatment include continuous patient–physician communication, lack of adherence, potential side effects and their impact on quality of life and other patient-reported outcomes. These challenges in the support of disease management can be overcome by the introduction of eHealth applications. Though the market of eHealth applications is fast growing, many applications lack evidence regarding their effectiveness, safety and utility. Only few prospective randomized trials have been conducted, so far. Results of these studies univocally show a gain in health-related quality of life, in the examined eHealth applications. It remains unclear if procedural and cost efficacy are affected by eHealth applications. The upcoming PreCycle study will be the largest randomized eHealth study in oncology.

In HER2-positive early breast cancer, neoadjuvant treatment with a combination of sequential chemotherapy and HER2-targeted therapy is currently the standard of care. This is followed by breast surgery, radiotherapy (if indicated), completion of 12 months of HER2-directed therapy, and - depending on the tumor biology - endocrine adjuvant therapy, and ultimately follow up. 10-year survival rates in the HER2-positive subgroup of breast cancer do reach now more than 75% with the introduction of first adjvuant and later neoadjuvant HER2-targeted therapies over the last 15 years. The neoadjvuant setting helps to downstage locally advanced tumors, to provide early information of tumor response, to assess the efficacy of new therapies in vivo, to reduce treatment duration, and to introduce new targeted therapies into the clinical routine. It also allows enrolling fewer patients into clinical trials in order to reach adequate effects in clinical outcome. The neoadjuvant approach and our interest in this setting are based on pCR (pathological complete response) and its translation into better long-term outcome. In recent trials, we have reached more than 60% pCR with a subsequent improvement of DFS and hopefully OS. Therefore, chemotherapy schedules and new HER2-targeted agents such as lapatinib, pertuzumab, and T-DM1 have been introduced into the neoadjuvant setting. To balance over- and undertreatment, current trials include personalized concepts and assess new biomarkers and tumorbiological factors. We have learned for example to differentiate between HR (hormone receptor)-positive and -negative tumors in the HER2-positive population. Depending on pCR or non-pCR after neoadjuvant treatment, the adjuvant therapy may be adjusted. This concept of post-neo-adjuvant trials is now entering the field of strategies in the neoadjuvant setting for HER2-positive non-metastatic primary breast cancer. The 2017 standard of care in the neoadjuvant setting according to national and international guidelines combines a taxane-containing chemotherapy with a dual blockade of trastuzumab and pertuzumab. This review will point out current trials and their strategies to continue improving outcome and reduce morbidity as well as mortality in HER2-positive early breast cancer.

Breast cancer is one of the three most common cancers worldwide. Early breast cancer is considered potentially curable. Therapy has progressed substantially over the past years with a reduction in therapy intensity, both for locoregional and systemic therapy; avoiding overtreatment but also undertreatment has become a major focus. Therapy concepts follow a curative intent and need to be decided in a multidisciplinary setting, taking molecular subtype and locoregional tumour load into account. Primary conventional surgery is not the optimal choice for all patients any more. In triple-negative and HER2-positive early breast cancer, neoadjuvant therapy has become a commonly used option. Depending on clinical tumour subtype, therapeutic backbones include endocrine therapy, anti-HER2 targeting, and chemotherapy. In metastatic breast cancer, therapy goals are prolongation of survival and maintaining quality of life. Advances in endocrine therapies and combinations, as well as targeting of HER2, and the promise of newer targeted therapies make the prospect of long-term disease control in metastatic breast cancer an increasing reality.

IMPORTANCE: In neoadjuvant trials, treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancers with dual HER2 blockade resulted in increased pathologic complete response (pCR) rates compared with each targeted agent alone. Amplification and/or overexpression of HER2 currently remains the only biomarker for therapeutic decisions, but it is insufficient to explain the heterogeneous response to anti-HER2 agents. OBJECTIVE: To investigate the ability of clinically and biologically relevant genes and gene signatures (GSs) measured by RNA sequencing to predict the efficacy of anti-HER2 agents. DESIGN, SETTING, AND PARTICIPANTS: The neoadjuvant NeoALTTO trial randomized 455 women with HER2-positive early-stage breast cancer to trastuzumab, lapatinib, or the combination for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide after surgery. The present substudy, which was planned in the NeoALTTO main protocol, evaluated the association of pretreatment gene expression levels defined using RNA sequencing with pCR and event-free survival (EFS). MAIN OUTCOMES AND MEASURES: Gene expression–based biomarkers using RNA sequencing were examined for their association with response to anti-HER2 therapy and long-term outcome. RESULTS: Sequencing data were available for 254 (56%) of the NeoALTTO participants (mean [SD] age of substudy participants, 48.8 [11.2] years). The expression of ERBB2/HER2 was the most significant predictor of pCR, followed by HER2-enriched subtype, ESR1, treatment arm, ER immunohistochemical analysis scores, Genomic Grade Index, immune, proliferation, and AKT/mTOR GSs. Adjusting for clinicopathological variables and treatment arms, ERBB2/HER2, HER2-enriched subtype, ESR1, and Genomic Grade Index remained significant. Immune GSs were associated with higher pCR only in the combination arm (odds ratio, 2.1; 95% CI, 1.2-4.0; interaction test P = .01), while the stroma GSs were significantly associated with higher pCR in the single arms and with lower pCR in the combination arm (odds ratio, 0.46; 95% CI, 0.25-0.84; P = .009). None of the evaluated variables was associated with EFS after correction for multiple testing, but this analysis was underpowered. CONCLUSIONS AND RELEVANCE: High levels of ERBB2/HER2 and low levels of ESR1 were associated with pCR in all treatment arms. In the combination arm, high expression of immune and stroma GSs were significantly associated with higher and lower pCR rates, respectively, and should be further explored as candidate predictive markers. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00553358

TP53mutation is associated with primary endocrine resistance in luminal breast cancer (BC). Nuclear accumulation of p53, as determined by immunohistochemistry (IHC), is a surrogate marker for TP53mutation. The immunohistochemical p53 index that defines a p53-positive status is not well established. This study determined the optimal p53 index cutoff to identify luminal BCs harboring TP53mutations. In total, 364 luminal BCs from the West German Study Group ADAPT trial (NCT01779206) were analyzed for TP53mutations by next-generation sequencing and for p53 expression by IHC (DO-7 antibody). P53 indices were determined by automated image analysis. All tumors were from patients treated with short-term preoperative endocrine therapy (pET; tamoxifen or aromatase inhibitor) before tumor resection. IHC evaluation included needle biopsies before therapy (baseline) and resections specimens after therapy (post-pET). Optimal p53 index cutoffs were defined with Youden statistics. TP53mutations were detected in 16.3% of BC cases. The median p53 indices were significantly higher in TP53-mutated BCs compared to BCs harboring wild-type TP53(baseline: 47.0% vs 6.4%, P< .001; post-pET: 50.1% vs 1.1%, P< .001). Short-term pET decreased p53 indices in BCs harboring wild-type TP53(P< .001) but not in TP53-mutated BCs (P = .102). For baseline biopsies, the optimal p53 index cutoff was ≥34.6% (specificity 0.92, sensitivity 0.63, Youden index 0.54, accuracy: 0.87). For post-pET specimens, the optimal cutoff was ≥25.3% (specificity 0.95, sensitivity 0.65, Youden index 0.60, accuracy: 0.90). Using these cutoffs to define the p53 status, p53-positive BCs were >2-fold more common in pET nonresponders compared to pET responders (baseline: 37/162, 22.8% vs 18/162, 11.1%, P = .007; post-pET: 36/179, 20.1% vs 16/179, 8.9%, P = .004). In summary, IHC for p53 identifies TP53-mutated luminal BCs with high specificity and accuracy. Optimal cutoffs are ≥35% and ≥25% for treatment-naïve and endocrine-pretreated patients, respectively.

Background: A variety of epigenetic clocks utilizing DNA methylation changes have been developed; these clocks are either tissue-independent or designed to predict chronological age based on blood or saliva samples. Whether discordant tick rates between tissue-specific and general epigenetic clocks play a role in health and disease has not yet been explored. Results: Here we analyze 1941 cervical cytology samples, which contain a mixture of hormone-sensitive cervical epithelial cells and immune cells, and develop the WID general clock (Women’s IDentification of risk), an epigenetic clock that is shared by epithelial and immune cells and optimized for cervical samples. We then develop the WID epithelial clock and WID immune clock, which define epithelial- and immune-specific clocks, respectively. We find that the WID-relative-epithelial-age (WID-REA), defined as the difference between the epithelial and general clocks, is significantly reduced in cervical samples from pre-menopausal women with breast cancer (OR 2.7, 95% CI 1.28-5.72). We find the same effect in normal breast tissue samples from pre-menopausal women at high risk of breast cancer and show that potential risk reducing anti-progesterone drugs can reverse this. In post-menopausal women, this directionality is reversed. Hormone replacement therapy consistently leads to a significantly lower WID-REA in cancer-free women, but not in post-menopausal women with breast or ovarian cancer. Conclusions: Our findings imply that there are multiple epigenetic clocks, many of which are tissue-specific, and that the differential tick rate between these clocks may be an informative surrogate measure of disease risk.

Introduction:Trastuzumab has dramatically improved outcomes for those diagnosed with human EGFR2 (HER2)-positive breast cancer. Resistance to trastuzumab, however, is an ongoing problem that has led to the development of a number of new HER2-targeted therapies. Afatinibis a novel, orally bioavailable irreversible pan-HER inhibitor that has been evaluated in multiple tumor types. It has also shown promise in NSCLC where it has earned FDA approval. Its activity in breast cancer is currently being evaluated.Areas covered:This review briefly summarizes the current therapies available for HER2-positive metastatic disease. This article also describes the data available for afatinib in breast cancer from preclinical analyses, published Phase I and II trials to ongoing and upcoming Phase II and III studies.Expert opinion:While Phase I and II studies have demonstrated promising activity in HER2-positive breast cancer, the Phase III randomized study of afatinib in trastuzumab-resistant metastatic breast cancer was halted early due to unfavorable risk–benefit analysis from the Independent Data Monitoring Committee (IDMC). The successful development of afatinib in breast cancer will thus depend on aggressively preventing and managing its associated toxicities.

Only a few studies have investigated the association between hospital characteristics and breast cancer patients’ satisfaction with nursing staff.

For over two decades, clinical researchers have been studying the invasion markers uPA and PAI‐I in women suffering from breast cancer. The long‐term studies enable them to perform more accurate risk assessment and give more individual care to the patients

An improved understanding of the important role of angiogenesis in tumor biology has led to development of different antiangiogenic therapies. This review highlights therapeutic agents from recent breast cancer trials showing the greatest potential for further clinical use in the near future.

Brustkrebs: Über zwei Jahrzehnte untersuchten klinische Forscher bei erkrankten Frauen die beiden Invasionsmarker uPA und PAI‐I. Die Langzeitstudien erlauben eine bessere Risikoabschätzung und individuellere Behandlungen der Patientinnen

Despite the fact that people older than 65 years of age have the highest incidence of developing breast cancer, these patients are excluded from clinical trials in most cases. Furthermore, most physicians tend towards therapy regimens without the use of dose-dense, highly active taxane-based treatments because of a lack of data regarding toxicities of these compounds in older patients. Pooled side-effect data were analyzed from four prospective, randomized clinical trials in which patients of different age groups (< 60 years, between 60 and 64 years, and > 64 years) with primary breast cancer received taxane-based chemotherapy. Dose delays, dose reductions, hospitalization, and therapy discontinuation increased with age. Hematologic toxicities and some nonhematologic toxicities were generally more common in older patients. Leucopenia increased from 55.3% in patients aged < 60 years to 65.5% in patients aged > 64 years (P< 0.001), and neutropenia increased from 46.9% to 57.4% (P< 0.001). There was no difference, however, in clinically more relevant febrile neutropenia between the different age groups. Thrombopenia shows a similar age-dependent increase, whereas there is no difference between the age groups concerning anemia. Hot flushes and elevated liver enzymes decreased with increasing age. The present pooled analysis of a substantial cohort of older primary breast cancer patients demonstrates that taxane-containing (neo)adjuvant chemotherapy is feasible in older patients and that toxicity can be reduced by sequential therapy regimens.

Trastuzumab—a humanised monoclonal antibody against HER2—has been shown to improve disease-free survival after chemotherapy in women with HER2-positive early breast cancer. We investigated the drug's effect on overall survival after a median follow-up of 2 years in the Herceptin Adjuvant (HERA) study.

Combined determination of urokinase-type plasminogen activator (uPA) and its inhibitor, activator inhibitor type 1 (PAI-1), supports risk-adapted individualized therapy concepts, particularly in node-negative breast cancer. The prognostic impact of both factors in primary breast cancer was substantiated by a pooled analysis of 8000 patients with breast cancer and a multicenter prospective randomized therapy trial in nodenegative breast cancer; findings achieved the highest level of evidence for tumor biomarkers. Patients with node-negative breast cancer with low antigen levels of uPA and PAI-1 in their primary tumor tissue have a very good prognosis and therefore may be spared the burden of adjuvant chemotherapy, whereas those with elevated uPA/PAI-1 antigen levels carry an increased risk of disease recurrence. Recent retrospective analysis of 3000 patients indicated that patients with breast cancer with high uPA/PAI-1 values derive a significantly greater benefit from adjuvant chemotherapy than patients with low uPA/PAI-1 levels. Similarly, in the multicenter prospective Chemo N0 trial, administration of cyclophosphamide/methotrexate/5-fluorouracil— based chemotherapy led to a substantial reduction in risk of disease recurrence in patients with high uPA/PAI-1. However, benefit from adjuvant endocrine therapy appears to be independent of a patient's uPA/PAI-1 status. In metastatic breast cancer, retrospective studies showed that elevated uPA or PAI-1 present in the primary tumor tissue are associated with a poor response to later palliative endocrine therapy. These findings suggest that high levels of uPA and/or PAI-1 do reflect an aggressive phenotype that may be overcome or suppressed by early systemic therapy in the adjuvant setting but may be too advanced for response to palliative therapy at a later stage.

Human kallikrein 5 (hK5; encoded by the KLK5gene) is a secreted serine protease expressed in hormonally regulated tissues, including the breast and ovary. We have previously reported regulation of the KLK5gene by estrogens and progestins and its clinical value as a marker of poor prognosis in breast and ovarian cancers. We thus hypothesized that hK5 may represent a potential biomarker for ovarian carcinomas, at the protein level. Using a newly developed ELISA, hK5 levels were quantified (nanograms per milligram of total protein) in 22 low malignant potential (LMP) and 132 epithelial ovarian tumors and correlated with various clinicopathological variables and outcome [progression-free survival (PFS), overall survival (OS)]. hK5 concentration in LMP tumors ranged from 0 to 2.3 ng/mg (mean = 0.24) and from 0 to 220 ng/mg (mean = 3.35) in ovarian tumor cytosols (p = 0.002). Using a cutoff value of 0.15 ng/mg, 60% of ovarian tumors were categorized as hK5 positive. We found a strong correlation between patients with hK5-positive tumors and disease stages III/IV and grade 3 tumors (all p < 0.05). Univariate survival analysis revealed that hK5-positive patients had a significantly shorter PFS and OS (p < 0.05). Kaplan-Meier survival curves further confirmed an increased risk of relapse and death in women with hK5-positive tumors (p = 0.015 and p = 0.019, respectively). Multivariate analysis indicated that the prognostic value of hK5 was not independent from other parameters in the entire group of patients. When stratified by tumor grade (G1/2 vs. G3) and debulking success (optimal vs. suboptimal), univariate and multivariate analyses demonstrated that hK5 was an independent indicator of poor prognosis for patients with grade 3 tumors and with optimal debulking (p < 0.05). In patients with disease stage I/II versus III/IV, hK5 positivity was independently associated with a shorter PFS (p = 0.046) and marginally decreased OS (p = 0.08), in multivariate analysis. Lastly, we observed a fairly weak, positive, but statistically significant correlation between the expression levels of tissue hK5 and tissue CA125 (rs = 0.297; p < 0.001). Our findings provide evidence for an association between hK5 and more aggressive forms of epithelial ovarian cancer.

The gene coding for the human homologue of the Drosophila segment polarity gene patched (PTCH1) is mutated in several common human tumors. In mice, haplodeficiency at the Ptch1 locus results in severe histologic defects in mammary ductal structure. We found no mutations within the coding region of PTCH1 in 17 human primary breast carcinomas. However, the biallelic Pro1315Leu (C3944T) polymorphism of PTCH1 was significantly associated with breast cancer in 41 Bavarian patients compared to 85 healthy controls. We investigated whether this variant influences susceptibility for breast cancer in 611 breast cancer patients diagnosed by age 50 years and 1,057 controls matched by age and study region in Germany and in 1,093 breast cancer patients from the United Kingdom. Allele and genotype frequencies were not different between cases and controls. However, multivariate logistic regression analysis revealed an effect modification of oral contraceptive use (OC) on breast cancer risk by Leu-carrier status. Compared to women who have Pro/Pro and never used OC, Pro/Pro OC users had an increased odds ratio for breast cancer of 1.7. The odds ratio was also 1.7 for Leu-carriers who never used OC, but this was attenuated among Leu-carriers who ever used OC by 20%. The gene-environmental interaction was confirmed in case-only analysis of the German and British studies, yielding an interaction odds ratio of 0.7 for premenopausal women (p = 0.06). Longer duration of pill use was associated with a significantly greater risk reduction (p for trend = 0.015). Our novel observation of a differential effect of OC use on breast cancer risk by PTCH1 1315Leu-carrier status suggests the interesting possibility of the Sonic hedgehog/Patched (SHH/PTCH1) signaling pathway being involved in hormone-induced development of breast carcinoma. © 2002 Wiley-Liss, Inc.

Invasion factors urokinase-type plasminogen activator (uPA) and its plasminogen activator inhibitor (PAI-1) are the only novel tumor biological prognostic factors validated at the highest level of evidence with regard to their clinical utility in breast cancer. Antigen levels of both factors present in extracts of primary tumor tissue are determined by standardized, quality-assured enzyme-linked immunosorbent assays. Numerous studies showed that patients with low levels of uPA and PAI-1 have a significantly better survival than patients with high levels of either factor. Recently, these data have been validated by a European Organization for Research and Treatment of Cancer pooled analysis comprising more than 8000 breast cancer patients. The particular combination of both factors, uPA/PAI-1 (both low vs. either or both factors high), outperforms the single factors as well as other traditional prognostic factors with regard to risk group assessment, particularly in nodenegative breast cancer. Node-negative breast cancer patients with low levels of uPA and PAI-1 have a very good prognosis and, as such, may be candidates for being spared the burden of adjuvant chemotherapy. In contrast, node-negative patients with high uPA/PAI-1 are at a substantially increased risk of relapse, comparable to that of patients with ≥ 3 involved axillary lymph nodes. First results from a multicenter prospective randomized therapy trial in node-negative breast cancer (Chemo N0) as well as recent retrospective analyses indicate that these high-risk patients benefit from adjuvant chemotherapy. Thus, combined determination of the invasion factors uPA and PAI-1 supports risk-adapted individualized therapeutic strategies in patients with primary breast cancer, particularly in those with node-negative breast cancer.

Intrinsic or acquired resistance to chemotherapy is responsible for failure of current treatment regimens in breast cancer patients. The Y-box protein YB-1 regulates expression of the P-glycoprotein gene mdr1, which plays a major role in the development of a multidrug-resistant tumor phenotype. In human breast cancer, overexpression and nuclear localization of YB-1 is associated with upregulation of P-glycoprotein. In our pilot study, we analyzed the clinical relevance of YB-1 expression in breast cancer (n = 83) after a median follow-up of 61 months and compared it with tumor-biologic factors already used for clinical risk-group discrimination, i.e., HER2, urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1). High YB-1 expression in tumor tissue and surrounding benign breast epithelial cells was significantly associated with poor patient outcome. In patients who received postoperative chemotherapy, the 5-year relapse rate was 66% in patients with high YB-1 expression. In contrast, in patients with low YB-1 expressions, no relapse has been observed so far. YB-1 expression thus indicates clinical drug resistance in breast cancer. Moreover, YB-1 correlates with breast cancer aggressiveness: in patients not treated with postoperative chemotherapy, those with low YB-1 expression are still free of disease, whereas the 5-year relapse rate in those with high YB-1 was 30%. There was no significant correlation between YB-1 expression and either HER2 expression or uPA and PAI-1 levels. Risk-group assessment achieved by YB-1 differed significantly from that by HER2 or uPA/PAI-1. In conclusion, YB-1 demonstrated prognostic and predictive significance in breast cancer by identifying high-risk patients in both the presence and absence of postoperative chemotherapy, independent of tumor-biologic factors currently available for clinical decision making. © 2001 Wiley-Liss, Inc.