Summary This articles reviews results of relevant breastcancer trials presented at the 2019 ESMO Meeting. In triple-negative disease, addition of pem- brolizumab to standard neoadjuvant chemotherapy yielded a pathologic complete response (pCR) rate of 64.8%, the highest pCR rate reported to date in this setting; in addition, a trend towards improved event- free survival was observed in the immunotherapy group. In pretreated patients with metastatic triple- negative breastcancer, single-agent pembrolizumab was not superior to conventional chemotherapy. In metastatic hormone-receptor positive disease, an up- date of the MONARCH2 and MonaLEEsa-3 studies indicated an overall-survival benefit in favour of the respective CDK4/6 inhibitor groups emphasizing the clinical importance of this class of drugs.
About one third of patients with triple-negative breastcancer (TNBC) treated with standard NACT achieve pCR. Preclinical trials stated TNBC to be more sensi- tive to interstrand crosslinking agents such as plat- inum salts due to deficiencies in the BRCA-associ- ated DNA repair mechanism . Especially in BRCA1- mutated patients treated with carboplatin as part of NACT, pCR rates of up to 75% could be reached . So far, five randomized phase II and one phase III trial addressed the use of carboplatin as part of NACT for patients with TNBC (Table 1):
breastcancer and was suggested to predict resistance to anti-hormonal therapy. As tissue heterogeneity may affect diagnostic accuracy of predictive biomarkers, CCND1 genetic heterogeneity was assessed in this study. A novel tissue microarray (TMA) platform was manufactured for this purpose. Methods: Primary breast carcinomas from 147 patients were sampled in a “heterogeneity TMA” by taking 8 different tissue cores from 4 to 8 tumor containing blocks per case. Additional tissue samples were taken from 1 to 4 corresponding nodal metastases in 35 of these patients. CCND1 amplification was assessed by fluorescence in situ hybridization (FISH). Results: CCND1 amplification was seen in 28 of 133 (21.05%) informative patients. Amplification was significantly associated with high tumor grade (p=0.042) but unrelated to tumor type (p=0.307), stage (p=0.540) and ER (p=0.061) or PR (p=0.871) expression. A discordant Cyclin D1 amplification status was detected in 6 out of 28 (21.43%) amplified tumors by heterogeneity TMA analysis. Re- testing on large sections revealed 3 patients with true heterogeneity of high level CCND1 amplification and another 3 patients with variable interpretation of borderline FISH ratios ranging between 1.7 and 2.3. No discrepancies were detected between 22 primary tumors and their matched lymph node metastases. Conclusions: The high degree of homogeneity seen for CCND1 amplification suggests that this alteration is an early event in the development of a small subset of breast cancers.
In the present study, the immune-stimulatory effects of ionizing irradiation were examined in models of breastcancer. Comparing single low dose (2 Gy), classically fractionated (4x2 Gy), and ablative irradiation regimens (20 Gy), we analyzed the quality and the extent of cell death induction in different breastcancer cell lines, the subsequent release of DAMPs, as well as their impact on endothelial cell activation, myeloid cell recruitment in vitro and in vivo, APC differentiation and maturation. Finally, we assessed phagocytosis of irradiated breastcancer cells by dendritic cells, and measured their capacity to stimulate adaptive T cell responses. Our results show that irradiation – particularly in the ablative setting – is a potent inducer of immunogenic cell death in cancer cells and stimulates the release of different DAMPs that have strong effects on other cells in the tumor microenvironment. As such, released nucleotides from dying breastcancer cells favor increased monocyte migration and chemokinesis. Proteinaceous DAMPs, including S100A8/A9, HMGB1, HSP70, and others, mediate endothelial cell activation as characterized by upregulated expression of adhesion molecules, and increased production and secretion of cytokines and chemokines. They also stimulate differentiation and maturation of APCs. Upon phagocytosis of breastcancer cells, which is clearly improved by irradiation, these APCs can potently trigger adaptive CD8 + T cell responses.
Antihormonal treatment is regarded as the prototype of targeted therapy. As early as 1896, George Thomas Beatson proposed surgical oophorectomy for the treatment of patients with locally advanced, inoper- able breastcancer. 1 While the underlying
Risk factors determine the groups of people exposed to a greater likelihood of developing breastcancer, and should be examined more carefully and frequently. The factors that are proven by scientific research are age, family history, history of benign proliferative diseases, and prolonged exposure to endogenous estrogens, exposure to ionizing radiation, obesity and postmenopausal. Already as apparent, are considered explained by a majority of studies: nulliparity, hormone replacement therapy and use of hormonal contraceptives.³
In summary, to our best knowledge, this is the first analysis of breastcancer subtypes and their prognostic impact on clinical course and BM incidence specifically in elderly breastcancer patients. Despite the weaknesses of a monocentric retrospective design, we were able to establish a clear correlation of HER2-status, recurrence rate, and BM incidence in a large population of 571 elderly breastcancer patients. This suggests that similar to younger patients, elderly HER2-positive patients should be considered at high risk for developing cerebral as well as non-cerebral metastases, while the risk may be lower in TNBC. Further research should therefore focus on a hypothetically distinct biology of TNBC in an elderly BC population as well as on the improvement of treatment strategies in HER2-positive disease in elderly. Whether the adverse prognosis of HER2-positive disease in elderly patients can be overcome by novel (and potentially less toxic) treatment approaches such as T-DM1 awaits further clarification.
Immunohistochemically defined prognostic and pre- dictive markers, such as estrogen- (ER) and proges- terone receptor (PR), human epidermal growth factor receptor 2 (HER2) and the proliferation marker Ki67 still govern the therapy recommendation in early breastcancer in many cases [ 3 ]. However, the dis- covery that these characteristics are mirrored by well- defined patterns in gene expression allowed a fur- ther precision of prognostication and facilitated the development of transcriptome-based multigenomic assays that correlate well with pathological markers but still provide independent prognostic and in some instances, predictive information [ 4 , 5 ]. Especially in ER-positive luminal-type early breastcancer, ad- ditional prognostic information is often required to provide patients with a valid and effective therapy recommendation. Whereas endocrine therapy is of- fered for most patients with luminal breastcancer, only a subset of patients derives clinical benefit from adjuvant chemotherapy. Whereas patients with low- proliferative luminal A disease do not benefit from the addition of adjuvant chemotherapy to endocrine therapy, adjuvant chemotherapy should be offered to patients with more aggressive and highly proliferative luminal B disease [ 6 ]. Although luminal A and B dis- ease might be identified by immunohistochemical markers, especially by the proliferation marker Ki67, determination is subjected to significant inter- and intraobserver variability that impair objective and reproducible measurements [ 7 ]. Quantitative analy- sis of the RNA expression of several relevant genes of luminal tumors might capture tumor biology in a more accurate and reproducible way. Commercially available multigenomic assays are able to discrimi- nate luminal A from luminal B biology and provide patients with a clinically valid therapy recommenda- tion.
Because of the small number of patients investigated, our follow up analysis is only of exploratory nature. Nevertheless, we were able to demonstrate that the detection of ≥1 CTCs in blood of metastatic breastcancer patients was significantly associated with clinical progression of the disease (p<0.001). Although the cut-off of at least 5 CTCs per 7.5 ml of blood is considered to be the threshold of high risk for early progression in metastatic breastcancer patients using the CellSearch system , meta-analysis of Zhang et al., demonstrates prognostic value of the presence of single CTCs. Moreover, the authors demonstrated that the prognostic significance of CTCs in blood does not depend on the time point of blood collection , which is consistent with our results where blood samples were taken during therapy. However, a larger cohort with uniform treatment and longer follow-up will be required to prove the significance and clinical relevance of our findings. Moreover, the presence of CTCs in blood does not necessarily reflect the ability of the CTCs to survive in the blood stream and to spread to distant organs. The survival and metastatic potential of CTCs need to be investigated, eventually also by identification of genetic signatures associated with the spread of CTCs and their development into metastasis.
Keywords: ITIH5, Breastcancer, Extracellular matrix, Epigenetic reprogramming, Cancer stem cells, DAPK1,
Turnover of the extracellular matrix (ECM) is a critical step in various aspects of tumor cell biology, e.g. in orchestrating breastcancer cell differentiation driving malignancy and metastasis [1, 2]. Inter- α-trypsin inhibi- tory (ITI) proteins comprise a family of secreted serine protease inhibitors found in both the ECM and in the blood circulation . ITIs are composed of a light chain, also called Bikunin, and different homologous heavy chains (i.e. ITIHs). ITIHs are covalently linked to Bikunin and thereby form a structural and functionally unique protein with a plasma protease inhibitory activity . Beyond this the biological function of ITI heavy chains remains largely unknown. Trimming of precursor ITIH proteins at a conserved cleavage site unmasks a C- terminal amino acid , which is involved in hyaluronic acid (HA) binding . Owing to that ITI heavy chains were originally referred to as serum-derived HA associ- ated proteins (SHAPs) , implicating a wide spectrum of biological activities. HA that is the major proteogly- can of the ECM interacts with a large number of HA- binding proteins (HABPs)  like HA-receptors CD44 and RHAMM [7, 8]. Unlike all other described HABPs, ITI heavy chains are covalently linked with HA ,
ErbB2/HER2-ErbB3/HER3 heterodimers are fundamental regulators of breastcancer cell growth. Clinical studies have shown that the overexpression of ErbB2/HER2 and ErbB3/HER3 is associated with the lack of response to hormonal therapy, high malignancy and poor prognosis. The most highly metastatic breastcancer cell lines, on the other hand, lack the estrogen receptor and express endogenously HRG, which promotes their growth through an autocrine loop. Our results indicate that an antibody directed against the extracellular domain of ErbB3/HER3 efficiently decreases the tyrosine-phosphorylation of ErbB2/HER2 after HRG stimulation in the breastcancer cell lines MCF- 7 ADR and MDA-MB-468; this inhibits the activation of downstream effectors and ultimately limits the proliferation and motility properties of the cells.
Summary At the 2019 ASCO (American Society of Clinical Oncology) Annual Meeting, several interest- ing trial results were presented in the field of HER2- positive metastatic breastcancer. The end-of-study analysis of the pivotal CLEOPATRA trial indicated an overall survival of 57.1 months in patients receiving pertuzumab in addition to trastuzumab and docetaxel in the first-line setting. SOPHIA was the first phase III trial comparing the Fc-engineered antibody marge- tuximab plus chemotherapy by physician’s choice with trastuzumab plus chemotherapy in heavily pretreated patients; the novel antibody yielded a statistically sig- nificant albeit short prolongation of progression-free survival (PFS) over standard treatment. The phase III NALA trial compared the second-generation tyrosine- kinase inhibitors neratinib with lapatinib; both drugs were combined with capecitabine. In this study a clin- ically meaningful prolongation of PFS by 2.2 months was observed. In addition, the time to intervention for brain metastases was prolonged in the neratinib group and the cumulative incidence of brain metas- tases was lower as well. On the downside a high rate of grade 2 and 3 diarrhoea was observed.
Summary Preoperative administration of chemother- apy is a widespread treatment approach in early stage breastcancer whenever chemotherapy is indicated in principle. In addition, neoadjuvant treatment is today regarded as the preferred way of delivering systemic therapy in triple-negative and HER2-positive breastcancer. While preoperative chemotherapy allows for disease downstaging and increases breast conserva- tion rates, achieving pathologic complete remission (pCR) is usually regarded as the most pertinent aim as pCR predicts for improved long-term outcome in high-risk breastcancer subtypes. A multitude of clin- ical trials therefore have focused on strategies to in- crease pCR rates. This short review summarizes out- comes of selected studies investigating the addition of further chemotherapeutic drugs or biologically tar- geted agents to standard regimens and provides an overview of novel strategies currently under clinical evaluation.
The influence of CYP2D6 genotype on efficacy of tamoxifen (Tam) has been extensively analyzed in early breastcancer with conflicting results and large differences concerning study design, allelic determination and co-medication. However, there is only scarce data regarding this potential influence in advanced breastcancer (ABC). We hypothesize that Tam is more effective in patients with a functional CYP2D6 allele than without any fully functional allele.
Morgan et al. designed a coculture model where different breastcancer cell lines including the MDA-MB-231 cells were co-cultured with spleen cells and osteoblasts, which led to osteoclast formation. The production of IL-6, IL-11, TNFα and PTHrP in the tumour cells was stimulated through the addition of TGF-β which is the growth factor released from bone after osteoclast induced bone resorption. Then antibodies to the cytokines produced by the tumour cells were added but the only antibody that inhibited osteoclast formation was that to PTHrP. An antibody to IL-6 failed to inhibit osteoclast formation (69) which contradicts the result obtained by Kudo et al. A limitation to the study by Morgan et al. is that no soluble IL-6R was added to the coculture system. As osteoclasts do not express a membrane bound IL-6R (70, 71) the IL-6 produced by the breastcancer cells could not interact with the osteoclast in the first place and thus the administration of an IL-6 antibody did not reduce osteoclast formation.
50 users between the individual sub-topics. In the next section of the page, the topics of prevention and early detection are presented. Here, too, it can be clearly seen that the Patient Information page is purely an overview page, as links are provided for patients as in the previous sections. The linked topics are: Breastcancer: Early detection, and screening and mammography screening. Between these two topics there is also a sign up field for participation in a study by HAW Hamburg which is concerned with improving the information material for mammography screening. The section on prevention and early detection is followed by the section on diagnosis. This section provides an overview of further links to the main topics of breastcancer symptoms, self-examination of the breast, and diagnostic procedures for breastcancer. Following this section, the topic block on classification and the course of the disease begins. In addition to the link to information on the classification of breastcancer, there are two further links to information on the tumour biology of breastcancer and on the course of the disease. The following section contains a link to information on the treatment methods for breastcancer. The topic section about aftercare contains two links to further topic pages that deal with the question of what happens after breastcancer therapy and a further link to important information on the aftercare of a breastcancer disease. The last, and probably largest, section of the overview page for patients and relatives is the section on quality of life and self-help. In this section, patients are given the opportunity to find out more about sexuality in breastcancer, rehabilitation after breastcancer, life with the disease, the desire of younger patients to have children after breastcancer, and about various self- help groups through various links to other information pages. (cf. Deutsche Krebsgesellschaft e.V. 3 , 2018).
US is a ubiquitous, available, cost-eﬀective, and reliable imaging modality that does not use ionizing radiation. The reported cancer detection rate of US, in combin- ation with FFDM, yields 3–4 additional cancers per 1000 screening examinations (78–80). However, the increased cancer detection rate of supplemental US screening comes at the expense of increased false- positive recall rates, costs, and patient anxiety (81). In a multicenter RCT that investigated screening with FFDM and US, Berg et al. (78) reported an increased cancer detection rate of 11.8 cancers per 1000 women, compared to FFDM alone (7.6 detected cancers per 1000 women) at the expense of a false-positive rate of up to 8.1% with US alone, and of up to 10.4% for combined FFDM and US. Other data by Berg et al. (80), using a RCT with a triennial observation of women with higher-density breast categories, yielded a cancer detection of 32 cases by US only, nearly as much as with FFDM only (33 cancers). Supplemental US after mammography yielded an additional cancer detection of 5.3 per 1000 women in the ﬁrst year and 3.7 cancers per 1000 women in each of the next two years, with an average additional cancer detection rate of 4.3 per 1000 screened women (80). Similar results with respect to additional cancer yield—3.2 (79), 3.4 (82), and 7.1 (83)—and false-positive rates of 4.7% (79) and 3.3% (83) were reported by retro- and prospective studies. The Japan Strategic Anti-Cancer Randomized Trial (J-STAT) investigated the eﬃcacy of additional US in a large nationwide screening program for breastcancer, with a signiﬁcantly higher breastcancer detection rate, a lower number of interval cancers, and the detection of additional cancers, compared to mam- mography alone, in women aged 40–49 years (84). In addition, Austria started a nationwide biannual mam- mography screening program oﬀering additional US for those with density categories C and D. Initial results are expected to be presented soon (39). To overcome the observer-dependency of hand-held supplemental screening US, automated, 3D, whole-breast US (ABUS) has been introduced (85–87). A recently pub- lished study by Wilczek et al., where ABUS was used in addition to mammography, yielded an increased cancer detection rate of 6.6 per 1000 screening exams in con- trast to 4.2 cancers detected with mammography alone. Initial results suggest that ABUS can provide 3D volu- metric imaging (86,87), and thus, may be a valid option in this setting to enable the detection of additional breast cancers that are invisible on mammography (88). Breast magnetic resonance imaging
Conclusions and recommendations
In view of current data, it may be considered a fact that shift work represents a risk factor for the development of breastcancer. In this context, not only shift work in itself constitutes a risk but also many other factors which are related to the disruption of the sleep-wake rhythm such as a lack of melatonin, the disruption of the circadian rhythms of the body on a molecular level, disruptions of the circadian rhythm of the release of stress hormones such as cortisol and of sex hormones such as estradiol. Likewise, increased stress due to sleep deprivation, the coordination of shift work with family life, irregular meals, a lack of physical exercise and smoking contribute to a heightened risk.
Insulin-like growth factor-I receptor (IGF-IR) is integral to cancer cell proliferation, survival, migration, and invasion, and resistance to anti-cancer therapies in many human malignancies including breastcancer. Within the last few years several drugs targeting IGF-IR have entered clinical trials and are showing promising early results. One of the integral goals of my thesis is to identify patients who are most likely to benefit from therapy. The Lee Laboratory previously reported an IGF gene expression signature, based upon genes induced or repressed by IGF-I, which correlated with poor prognosis in breastcancer. Confirming that this signature can measure IGF activity, I report here that the signature is reversed in three different cancer models (cell lines or xenografts) treated with three different anti-IGF-IR therapies. The Lee laboratory originally reported that the IGF signature was present in triple- negative human breast cancers (TNBC), and I found here that the signature is similarly present in TNBC cell lines. Supporting a role for IGF-IR signaling in this subtype of breastcancer, I found that TNBC cell lines were especially sensitive to an IGF-IR tyrosine kinase inhibitor (BMS-754807), and that sensitivity was significantly correlated to expression of the IGF gene signature. Consistent with this, comparative gene expression analysis among the most resistant and sensitive cell lines identified 114 differentially expressed genes which identified TNBC as being sensitive. To examine this association further we determined levels and activity of the IGF-IR in several recently developed primary human TNBC tumorgraft models. I found high activity in many models, and chose the TNBC model MC1, which had the highest levels of both IGF signature score and IGF-IR expression and activity, for testing an anti-IGF-IR tyrosine kinase inhibitor (BMS-754807) in vivo. MC1 tumorgrafts treated with BMS-754807 as a single agent showed growth inhibition, and in combination with chemotherapy tumor regression occurred until no tumor was palpable. This regression was associated with reduced proliferation, increased apoptosis, and mitotic catastrophe. These data provide a clear biological rationale to test anti-IGF-IR therapy in combination with chemotherapy in patients with TNBC.