ABC2 Consensus; Metastatic breast cancer
The developments in gene expression analysis have made it possible to sub-classify hormone receptor-positive (luminal) breast cancer in different prognostic subgroups. This sub-classification is currently used in clinical routine as prognostic signature (e.g. 21-gene Onoctype DX®, 70-gene Mammaprint®). As yet, the optimal method for sub-classification has not been defined. Moreover, there is no evidence from prospective trials. This review explores widely used genomic signatures in luminal breast cancer, making a critical appraisal of evidence from retrospective/prospective trials. It is based on systematic literature search performed using Medline (accessed September 2013) and abstracts presented at the Annual Meeting of American Society of Clinical Oncology and San Antonio Breast Cancer Symposium.
Biomarker; Breast cancer; Gene expression; Prognostic markers; Luminal breast cancer
Following primary debulking surgery, the presence of a residual tumor mass is one of the most important prognostic factors in ovarian cancer. In a previous study, we established the OVSCORE, an algorithm to predict surgical outcome, based on the clinical factors of nuclear grading and ascitic fluid volume, plus the cancer biomarkers, kallikrein-related peptidases (KLKs), KLK6 and KLK13. In the present study, OVSCORE performance was tested in an independent ovarian cancer patient cohort consisting of 87 patients. The impact of KLKs, KLK5, 6, 7 and 13 and other clinical factors on patient prognosis and outcome was also evaluated. The OVSCORE proved to be a strong and statistically significant predictor of surgical success in terms of area under the receiver operating characteristic curve (ROC AUC, 0.777), as well as positive and negative predictive value in this independent study group. KLK6 and 13 individually did not show clinical relevance in this cohort, but two other KLKs, KLK5 and KLK7, were associated with advanced FIGO stage, higher nuclear grade and positive lymph node status. In the multivariate Cox regression analysis for overall survival (OS), KLK7 had a protective impact on OS. This study confirms the role of KLKs in ovarian cancer for surgical success and survival, and validates the novel OVSCORE algorithm in an independent collective. As a key clinical application, the OVSCORE could aid gynecological oncologists in identifying those ovarian cancer patients unlikely to benefit from radical surgery who could be candidates for alternative therapeutic approaches.
kallikrein-related peptidases; kallikrein; ovarian cancer; surgical success; residual tumor; prognosis
Biomarkers predicting resistance to particular chemotherapy regimens could play a key role in optimally individualized treatment concepts. PTK7 (protein tyrosine kinase 7) belongs to the receptor tyrosine kinase family involved in several physiological, but also malignant, cell behaviors. Recent studies in acute myeloid leukemia have associated PTK7 expression with resistance to anthracycline therapy. PTK7 mRNA expression in primary tumor tissue (PTT) and corresponding lymph node tissue (LNT) were retrospectively measured in 117 patients with early breast cancer; PTK7 expression was available in 103 PTT and 108 LNT samples. Median age was 60 years (range, 27–87 years). At a median follow-up of 28.5 months, 6 deaths and 16 recurrences had occurred. PTK7 expression correlations with clinicopathological features were computed and PTK7 expression effects on patient outcome were analyzed in three cohorts defined by adjuvant treatment: anthracycline-based treatment, other chemotherapy regimens (including taxane or other substances), or no chemotherapy. Association of PTK7 expression with clinicopathological features was seen only for age in PTT and nodal stage in LNT. High LN PTK7 was associated with poorer disease-free survival (DFS) in the total population (3-year DFS: low [81.7%] versus high [70.4%]; P=0.016) and in patients without adjuvant chemotherapy (3-year DFS: low [91.7%] versus high [22.3%]; P<0.001), but not in patients receiving adjuvant chemotherapy (P=0.552). DFS stratified by PTK7 expression was compared in treatment cohorts: In patients with low LN PTK7 expression, neither chemotherapy cohort showed significantly better survival than the no-chemotherapy cohort. In patients with high LN PTK7 expression, those receiving chemotherapy, including substances other than anthracyclines, but not those receiving only anthracycline-based chemotherapy, showed significantly better DFS than those receiving no chemotherapy (P=0.001). Our results support earlier findings that PTK7 may be a prognostic and predictive marker associated with resistance to anthracycline-based chemotherapy. Further investigations are needed to validate these findings in breast cancer.
breast cancer; PTK7; protein tyrosine kinase 7; chemoresistance; prognostic factors; predictive factors
Paraneoplastic hypoglycemia is a rare syndrome amoung tumorous diseases. It is often associated with a paraneoplastic secretion of ‘big’ insulin-like growth factor-II.
We describe this syndrome in a 60-year-old patient with advanced breast cancer 8 years after primary diagnosis.
Results and Conclusion
This non-islet cell tumor-induced hypoglycemia may be the only evidence for an otherwise clinically occult disease progression. Fast diagnosis and appropriate acute and causal treatment concepts should be part of oncological management.
Hypoglycemia; Breast cancer; Metastases; Insulin-like growth factor; Paraneoplastic
Our objective was to assess the auditory function of gynaecological tumour patients who had received cytotoxic agents and to determine their associated risk of ototoxicity.
Patients and Methods
87 patients who had undergone chemotherapy for gynaecological malignancies were investigated. Of these patients, 79% had breast cancer, and 14% ovarian cancer. All of the patients had a subjective assessment of their hearing function on a visual analogue scale. Audiometric tests were performed before and at 9 weeks, 18 weeks and 3 months after completion of chemotherapy.
The age of the patients ranged from 32 to 71 years (mean age of 53.5 ± 10.5 years). The average subjective rating of the patients’ hearing function was 83.0 ± 17.2 before and 84.8 ± 16.9 3 months after completion of chemotherapy. No significant audiometric change at either the speech hearing frequency range (0.5–2 KHz) or high frequencies was observed in the patients after chemotherapy. There was also no significant difference in the hearing threshold of the patients who had received platinum analogue-based chemotherapy compared to non-platinum analogue-based chemotherapy.
Hearing loss is uncommon in patients treated with the typical gynaecological chemotherapy protocols. Hence, routine audiometric testing in these patients is not necessary.
Breast cancer; Ovarian cancer; Chemotherapy; Hearing function
Guidelines; Locoregional relapse; Metastatic breast cancer; Targeted therapy
The International Consensus Conference on the treatment of primary breast cancer takes place every two years in St. Gallen, Switzerland. The panel in St. Gallen is composed of international experts from different countries. From a German perspective, it seems reasonable to interpret the voting results in the light of AGO-recommendations and S3-guidelines for everyday practice in Germany. Consequently, a team of eight breast cancer experts, of whom two are members of the international St. Gallen panel, commented on the voting results of the St. Gallen Consensus Conference (2013). The main topics at this year's St. Gallen conference were surgical issues of the breast and axilla, radio-therapeutic and systemic treatment options, and the clinical relevance of tumour biology. The clinical utility of multigene assays for supporting individual treatment decisions was also intensively discussed.
St. Gallen Consensus; Early breast cancer; Adjuvant therapy; Multigene signatures; Targeted therapy
The Patient's Anastrozole Compliance to Therapy (PACT) program is a large randomized study designed to assess whether the provision of educational materials (EM) could improve compliance with aromatase inhibitor therapy in postmenopausal women with early, hormone receptor-positive breast cancer.
Patients and Methods
The PACT study presented a large, homogeneous dataset. The baseline analysis included patient demographics and initial treatments and patient perceptions about treatment and quality of life.
Overall, 4,923 patients were enrolled at 109 German breast cancer centers/clinics in cooperation with 1,361 office-based gynecologists/oncologists. 4,844 women were randomized 1:1 to standard therapy (n = 2,402) or standard therapy plus EM (n = 2,442). Prior breast-conserving surgery and mastectomy had been received by 76% and 24% of the patients, respectively. Radiotherapy was scheduled for 85% of the patients, adjuvant chemotherapy for 38%. Reflecting the postmenopausal, hormone-sensitive nature of this population, only 285 patients (7%) had received neoadjuvant chemotherapy.
A comparison with epidemiological data from the West German Breast Center suggests that the patients in the PACT study are representative of a general postmenopausal early breast cancer population and that the findings may be applicable to ‘real-world’ Germany and beyond. Compliance data from PACT are eagerly anticipated.
Breast cancer; Compliance; Aromatase inhibitors; Breast-conserving surgery; Mastectomy
The humanized monoclonal antibody pertuzumab prevents the dimerization of HER2 with other HER receptors, in particular the pairing of the most potent signaling heterodimer HER2/HER3, thus providing a potent strategy for dual HER2 inhibition. It binds to the extracellular domain of HER2 at a different epitope than trastuzumab. Pertuzumab and trastuzumab act in a complementary fashion and provide a more complete blockade of HER2-mediated signal transduction than either agent alone. Phase II studies demonstrated that pertuzumab was generally well tolerated as a single agent or in combination with trastuzumab and/or cytotoxic agents, and implied an improved clinical efficacy of the combination of pertuzumab and trastuzumab in early and advanced HER2-positive breast cancer. Results of the pivotal phase III study CLEOPATRA in patients with HER2-positive metastatic breast cancer demonstrated that the addition of pertuzumab to first-line combination therapy with docetaxel and trastuzumab significantly prolonged progression-free and overall survival without increasing cardiac toxicity. Currently, the combination of both antibodies is being explored in the palliative setting as well as in the treatment of early HER2-positive breast cancer. Dual HER2 inhibition with the HER2 dimerization inhibitor pertuzumab and trastuzumab may change clinical practice in HER2-positive first-line metastatic breast cancer treatment.
HER2-positive; Dual inhibition; Breast cancer, metastatic; Pertuzumab; Trastuzumab
Elderly breast cancer patients are underrepresented in clinical trials and this leads to a lack of knowledge regarding the tolerance and side effects of modern chemotherapy regimens, especially in dose-dense (dd) or dose-intensified combination.
Patients and Methods
In this analysis, data from 4 German, randomized (neo-)adjuvant trials, including anthracycline-based chemotherapy, were evaluated for toxicity, compliance and feasibility. Patients were grouped according to age.
Of the 4,775 patients, 73.6% were < 60 years, 15.8% were 60–64 years and 10.6% were > 64 years. The patients’ compliance decreased with increasing age, the rate of therapy discontinuations was 10.3%; 16.0% were > 64 years old (p < 0.001). The rate of dose reductions also increased with increasing age in the docetaxel/doxorubicin/cyclophosphamide (TAC) (p overall = 0.02) and 5-fluorouracil/epirubicin-cyclophosphamide (FE120C) (p overall < 0.001) treatment groups. Neutropenia grade 3 + 4 in patients of > 64 years was 77% in FE120C- compared to 55% in TAC-treated patients (with primary granulocyte colony-stimulating factors (G-CSFs)). The incidence of febrile neutropenia (FN) was lowest in the regimens without additional taxanes. FN in patients aged > 64 years was lower in the FE120C- than in TAC-and dd-doxorubicin/docetaxel-treated groups.
The range and intensity of toxicity increased with age. Neutropenia did not increase significantly in the dd groups; the highest rate was seen in FE120C-treated patients. FE120C without G-CSFs is not an option in patients older than 64 years.
Elderly; Chemotherapy; Side effect; Tolerability; Breast cancer
The term filariasis comprises a group of parasitic infections caused by helminths belonging to different genera in the superfamily Filaroidea. The human parasites occur mainly in tropical and subtropical regions, but filariae are also found in temperate climates, where they can infect wild and domestic animals. Humans are rarely infected by these zoonotic parasites.
Patients and Methods
A 55-year-old patient presented with a new-onset, subcutaneous, non-tender palpable mass in the right axilla. Ultrasonography showed a 1.3-cm, solid, singular encapsulated node. Sonography of the breast on both sides, axilla and lymphatic drainage on the left side, lymphatic drainage on the right side, and mammography on both sides were without pathological findings. The node was excised under local anesthesia as the patient refused minimal invasive biopsy.
On histopathological examination, the tail of a parasite of the group of filariae was found. The patient revealed that she had stayed in Africa and Malaysia for professional reasons. 6 months before the time of diagnosis, she had also suffered from a fever and poor general condition after a trip abroad. The patient was referred for further treatment to the Institute for Tropical Medicine at the University of Dusseldorf, where a treatment with ivermectin was conducted on the basis of positive staining with antibodies against filariae.
Our case demonstrates the importance of interdisciplinary collaboration between breast center, pathology, and other specialties such as microbiology and tropical medicine.
Filariasis; Breast; Axilla
Adjuvant treatment decision-making based on conventional clinical/pathological and prognostic single molecular markers or genomic signatures is a therapeutic area in which over-/under-treatment are still key clinical problems even though substantial and continuous improvement of outcome has been achieved over the past decades. Response to therapy is currently not considered in the decision-making procedure.
ADAPT is one of the first new generation (neo)adjuvant trials dealing with individualization of (neo)adjuvant decision-making in early breast cancer and aims to establish early predictive surrogate markers, e.g., Ki-67, for therapy response under a short induction treatment in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment.
The prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III ADAPT trial has an innovative “umbrella” protocol design. The “umbrella” is common for all patients, consisting of dynamic testing of early therapy response. ADAPT will recruit 4,936 patients according to their respective breast cancer subtype in four distinct sub-trials at 80 trial sites in Germany; 4,000 patients with hormone receptor positive (HR+) and HER2 negative disease will be included in the ADAPT HR+/HER2- sub-trial, where treatment decision is based on risk assessment and therapy response to induction therapy, and 380 patients will be included in ADAPT HER2+/HR+. A further 220 patients will be included in ADAPT HER2+/HR- and 336 patients will be recruited for ADAPT Triple Negative. These three sub-trials focus on identification of early surrogate markers for therapy success in the neoadjuvant setting. Patients will be allocated to the respective sub-trial according to the result of their diagnostic core biopsy, as reported by local/central pathology for HR and HER2 status.
Recent trials, such as the GeparTrio, have shown that response-guided therapy using clinical response may improve outcome. For chemotherapy or HER2-targeted treatment, pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome. For endocrine therapy, response to short induction treatment – as defined by decrease in tumor cell proliferation – strongly correlates with outcome. ADAPT now aims to combine static prognostic and dynamic predictive markers, focusing not just on single therapeutic targets, but also on general markers of proliferation and cell death. Biomarker analysis will help to optimize selection of subtype-specific treatment.
ClinicalTrials.gov: ADAPT Umbrella: NCT01781338; ADAPT HR+/HER2-: NCT01779206; ADAPT HER2+/HR+: NCT01745965; ADAPT HER2+/HR-: NCT01817452; ADAPT TN:NCT01815242.
ADAPT; Biomarker; Early breast cancer; Investigator initiated trial
The 2013 St. Gallen Consensus Conference on early breast cancer provided mostly evidence-based, globally valid treatment recommendations for breast cancer care, with a broad spectrum of acceptable clinical practice. This report summarizes the results of the 2013 international panel voting procedures with regard to loco-regional and endocrine treatment, chemotherapy, targeted therapy as well as adjuvant bisphosphonate use. This report is not aimed to replace the official St. Gallen Consensus publication, some recommendations may even be altered in the final paper, but should serve a preliminary rapid report of this important meeting.
Early breast cancer; Bisphosphonates; Endocrine therapy; Chemotherapy; Surgery; Axillary dissection; Targeted therapy; Neoadjuvant therapy
The available evidence for the use of capecitabine as a single agent in the first-line treatment of patients with human epidermal growth factor receptor 2–negative metastatic breast cancer is reviewed.
The goals of treatment for metastatic breast cancer (MBC) are to prolong overall survival (OS) while maximizing quality of life, palliating symptoms, and delaying tumor progression. For many years, anthracyclines and taxanes have been the mainstay of treatment for MBC, but these agents are now commonly administered earlier in the course of the disease. A recent meta-analysis revealed adverse effects on OS and overall response rates in patients with MBC receiving first-line anthracycline-based chemotherapy following relapse on adjuvant chemotherapy. Noncrossresistant cytotoxic agents and combinations that combine high clinical activity and acceptable tolerability while being convenient for patients are therefore needed for the first-line treatment of MBC patients. Capecitabine has substantial antitumor activity in the first-line treatment of patients with MBC in prospective, randomized, phase II/III clinical trials as monotherapy and in combination with biologic and novel agents. First-line capecitabine monotherapy has a favorable safety profile, lacking myelosuppression and alopecia, and does not compromise the administration of further lines of chemotherapy. Capecitabine is suitable for long-term administration without the cumulative toxicity that can limit the prolonged use of other chemotherapy agents. Here, we review the available data on capecitabine as a single agent for first-line treatment of patients with human epidermal growth factor receptor 2–negative MBC.
Metastatic breast cancer; Capecitabine; First-line therapy; Chemotherapy
A group of German breast cancer experts (medical oncologists and gynaecologists) reviewed and commented on the results of the first international ‘Advanced Breast Cancer First Consensus Conference’ (ABC1) for the diagnosis and treatment of advanced breast cancer. The ABC1 Conference is an initiative of the European School of Oncology (ESO) Metastatic Breast Cancer Task Force in cooperation with the EBCC (European Breast Cancer Conference), ESMO (European Society of Medical Oncology) and the American JNCI (Journal of the National Cancer Institute). The main focus of the ABC1 Conference was metastatic breast cancer (stage IV). The ABC1 consensus is based on the vote of 33 breast cancer experts from different countries and has been specified as a guideline for therapeutic practice by the German expert group. It is the objective of the ABC1 consensus as well as of the German comments to provide an internationally standardized and evidence-based foundation for qualified decision-making in the treatment of metastatic breast cancer.
ABC1-consensus; Metastatic breast cancer, diagnosis and staging, treatment; Tumor markers; Metastases, biopsy; Chemotherapy; Endocrine therapy; Anti-HER2-targeted therapy; Palliative care
Some drugs are known for their fetal nephrotoxicity and should be avoided during pregnancy. We report on a pregnant woman suffering from breast cancer who received a weekly neoadjuvant trastuzumab (Herceptin®) therapy from 15 weeks of gestation onward, in addition to a 3-weekly carboplatin/docetaxel chemotherapy. Fetal renal insufficiency with anhydramnios and missing visualization of the fetal bladder developed at 21 weeks. After discontinuation of trastuzumab and repeated instillation of amniotic fluid, the amount of amniotic fluid remained stable after 24 weeks of gestation. After caesarean section at 34 weeks because of fetal growth restriction, the renal function of the neonate was normal postnatally. In accordance with the current literature, our case shows a reversible adverse effect of trastuzumab on the fetal renal function and confirms the current recommendation that trastuzumab in pregnancy should be avoided. In pregnancies exposed to trastuzumab, treatment should be discontinued and the fetus should be closely monitored, with particular attention to the amniotic fluid and the fetal bladder volume, as these reflect fetal renal function.
Fetus; Renal insufficiency; Trastuzumab; Breast cancer; Pregnancy
Recently reported data from the German ZORO trial and the Italian PROMISE-GIM6 trial have come to different conclusions. The AGO Breast Commission does not recommend the general use of luteinizing hormone-releasing hormone (LHRH) analogues for the preservation of ovarian function. Instead, we distinguish between patients with hormone receptor-negative and hormone receptor-positive disease. This article reviews the AGO recommendations in light of the ZORO and PROMISE-GIM6 data. In conclusion, separate recommendations are needed for the prevention of ovarian failure and for fertility preservation because the trials did not investigate fertility rate as a primary outcome measure. The results from not yet published trials such as OPTION and POEM may shed new light on the role of LHRH analogues.
LHRH; Ovarian function preservation; Fertility preservation; Chemotherapy; Breast cancer
Afatinib (BIBW 2992) is an ErbB-family blocker that irreversibly inhibits signaling from all relevant ErbB-family dimers. Afatinib has demonstrated preclinical activity in human epidermal growth factor receptor HER2 (ErbB2)-positive and triple-negative xenograft models of breast cancer, and clinical activity in phase I studies. This was a multicenter phase II study enrolling patients with HER2-negative metastatic breast cancer progressing following no more than three lines of chemotherapy. No prior epidermal growth factor receptor-targeted therapy was allowed. Patients received 50-mg afatinib once daily until disease progression. Tumor assessment was performed at every other 28-day treatment course. The primary endpoint was clinical benefit (CB) for ≥4 treatment courses in triple-negative (Cohort A) metastatic breast cancer (TNBC) and objective responses measured by Response Evaluation Criteria in Solid Tumors in patients with HER2-negative, estrogen receptor-positive, and/or progesterone receptor-positive breast cancer (Cohort B). Fifty patients received treatment, including 29 patients in Cohort A and 21 patients in Cohort B. No objective responses were observed in either cohort. Median progression-free survival was 7.4 and 7.7 weeks in Cohorts A and B, respectively. Three patients with TNBC had stable disease for ≥4 treatment courses, one of them for 12 courses (median 26.3 weeks; range 18.9–47.9 weeks). The most frequently observed afatinib-associated adverse events (AEs) were gastrointestinal and skin-related side effects, which were manageable by symptomatic treatment and dose reductions. Afatinib pharmacokinetics were comparable to those observed in previously reported phase I trials. In conclusion, afatinib had limited activity in HER2-negative breast cancer. AEs were generally manageable and mainly affected the skin and the gastrointestinal tract.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-012-2126-1) contains supplementary material, which is available to authorized users.
Afatinib; Metastatic breast cancer; Triple-negative breast cancer; HER2-negative breast cancer; EGFR TKI
To comply with the World Health Organization (WHO) recommendations, our institution's administrative directives were adopted to advocate the provision of palliative care (PC) early in the disease trajectory of breast cancer (BC). To assess the outcome of this recommendation, this study evaluated the effects of this approach.
A retrospective systematic chart analysis of a 2-year period was performed. The first PC consultation of patients was analyzed according to (a) physical condition, (b) symptom burden of the patients, and (c) reasons for PC consultation.
Many patients were already in a reduced physical state and experienced burdening symptoms when first counselled by PC. After a 1-year experience with PC consultations, the number of burdening symptoms identified at first PC consultation decreased and senologists increasingly requested PC support also for non-somatic issues.
A development towards a better understanding of PC competencies after a 1-year initiation period could be demonstrated, but BC patients continued to be in late stages of the disease at the time of first PC contact. Disease-specific guidelines may facilitate and optimize the integration of PC into breast cancer therapy.
Comprehensive cancer care; Palliative medicine; Simultaneous care; Shared care; Quality of life; Symptom control
To comply with patients' needs as well as ASCO and WHO recommendations, our institution aims to integrate palliative care (PC) early in the course of breast cancer (BC) therapy. The evaluation of relevant pilot project data revealed that these recommendations were too vague to trigger PC integration. Therefore, a standard operating procedure (SOP) was developed by our interdisciplinary working group to provide disease-specific information to overcome the ambiguity of the WHO recommendations and guide PC integration. Literally, the SOP states that ‘Specialized PC is recommended regularly for all BC patients without curative treatment options, specifically for patients with i) metastasized and inoperable, or ii) locally advanced and inoperable, or iii) relapsing BC, who are receiving intravenous chemotherapy’. This SOP for the first time presents disease-specific guidelines for PC integration into comprehensive BC therapy by defining ‘green flags’ for early integration of PC and delineating PC from senology assignments. Although disease-specific SOPs have also been developed by this working group for other malignancies, the decision when to first integrate PC into BC therapy differs substantially because of the different clinical characteristics of the disease.
Comprehensive cancer care; Palliative medicine; Early integration; Quality of Life