Dormancy of Mammary Carcinoma After Mastectomy

Expert Opinion on Therapeutic Targets, 2012

Breast Cancer Online, 2007

This historical perspective on breast cancer tells us how and why certain therapeutic eras have reached ascendancy and then declined. Therapeutic revolutions occur after a crisis develops when there is a general recognition that clinical interventions are not producing positive results predicted by the prevailing paradigm. The attitude of pre-modern surgeons was influenced by the very real possibility of doing more harm than good by operating upon women with breast cancer. Up until Halsted, the general consensus was clearly that, unless forced by the circumstances, surgical resection should be avoided for disease much more advanced than very early stage tumours (the cacoethesis of Celsus). Twentieth century progress in antisepsis, anaesthesia, and surgery changed this point of view. The first three quarters of that century saw more and more aggressive operations performed while the last quarter century reversed this trend, with reduction of the size of breast cancer operations based largely on the teachings of Fisher. A new crisis is upon us now in that trials of early detection have resulted in unexpected disadvantages to certain subgroups and there is previously unreported structure in early hazard of relapse, clinical data that suggests the act of surgery might accelerate the appearance of distant metastases. The explanation we propose that agrees with these results, as well as physicians of antiquity, is that surgery can induce angiogenesis and proliferation of distant dormant micrometastases, especially in young patients with positive nodes.

Breast Cancer Research, 2007

Delayed recurrences, common in breast cancer, are well explained by the concept of tumour dormancy. Numerous publications describe clinical times to disease recurrence or death, using mathematical approaches to infer mechanisms responsible for delayed recurrences. However, most of the clinical literature discussing tumour dormancy uses data from over a half century ago and much has since changed. This review explores how current breast cancer treatment could change our understanding of the biology of breast cancer tumour dormancy, and summarizes relevant experimental models to date. Current knowledge gaps are highlighted and potential areas of future research are identified.

Cancer, 2001

BACKGROUND. The current study examines the fate of occult metastatic cells detected in bone marrow (BM) at primary diagnosis and evaluates whether persistently positive findings support the prognostic influence of these cells in patients with Stage I-III (International Union Against Cancer) breast carcinoma. METHODS. The authors analyzed BM aspirates, at the time of primary diagnosis and after a median interval of 19 months (range, 7-67 months), from 89 patients who were free of recurrence. The presence of cytokeratin (CK) positive cells was assessed with the monoclonal anti-CK antibody A45-B/B3. Patients were observed prospectively for a median of 41 (range, 12-78) months after the first aspiration. RESULTS. At the time of primary diagnosis, 24 of 89 patients (27%) presented with occult metastatic cells in the BM. Of the same 89 patients, 25 (28%) had a positive BM finding at the time of the second BM analysis. Among those patients with an initially negative BM finding, 15 patients (17%) had occult metastatic cells at time of the second BM aspiration, whereas 10 patients (11%) had a persistently positive BM finding. Patients with a persistently negative BM status (n ϭ 50) had a significantly better overall survival than patients with a positive BM status at the time of the second BM aspiration (n ϭ 25), both by univariate analysis (P ϭ 0.045, log-rank) and multivariate analysis (P ϭ 0.034, Cox regression). CONCLUSIONS. In many patients with primary breast carcinoma, minimal residual disease can be detected by follow-up examination of the BM. This finding is prognostically relevant and provides reason to include BM monitoring in future clinical trials. Cancer 2001;92:46 -53.

Frontiers in Molecular Biosciences, 2014

PLoS ONE, 2012

Background: Disseminated tumor cells (DTCs) in the bone marrow may exist in a dormant state for extended periods of time, maintaining the ability to proliferate upon activation, engraft at new sites, and form detectable metastases. However, understanding of the behavior and biology of dormant breast cancer cells in the bone marrow niche remains limited, as well as their potential involvement in tumor recurrence and metastasis. Therefore, the purpose of this study was to investigate the tumorigenicity and metastatic potential of dormant disseminated breast cancer cells (prior to activation) in the bone marrow.

Nature Medicine, 2013

Tumor recurrence represents a major clinical challenge. Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors. This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence. Screening for this innate response predicted accurately in which mice recurrence would occur. Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete. By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured. These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment.

Medicina

The report addresses the role of the hazard function in the analysis of disease-free survival data in breast cancer. An investigation on local recurrences after mastectomy provided evidence that uninterrupted growth is inconsistent with clinical findings and that tumor dormancy could be assumed as working hypothesis to understand the clinical course of the disease. Additionally, it was deemed that the lag-time between primary tumor removal and tumor recurrence is dynamically dependent on the subclinical metastasis development within the host-tumor system and, therefore, may be informative about the biology of the disease. Accordingly, the hazard function, which estimates the event risk pattern through the time, was adopted to analyze survival data. The multipeak pattern of the hazard function suggested that the process metastasis development has discontinuous features. A new paradigm of breast cancer metastatic development was proposed, involving the notions of tumor homeostasis, tu...

Pathology research international, 2010

Brain metastasis, an important cause of cancer morbidity and mortality, occurs in at least 30% of patients with breast cancer. A key event of brain metastasis is the migration of cancer cells through the blood-brain barrier (BBB). Although preventing brain metastasis is immensely important for survival, very little is known about the early stage of transmigration and the molecular mechanisms of breast tumor cells penetrating the BBB. The brain endothelium plays an important role in brain metastasis, although the mechanisms are not clear. Brain Microvascular Endothelial Cells (BMECs) are the major cellular constituent of the BBB. BMECs are joined together by intercellular tight junctions (TJs) that are responsible for acquisition of highly selective permeability. Failure of the BBB is a critical event in the development and progression of several diseases that affect the CNS, including brain tumor metastasis development. Here, we have delineated the mechanisms of BBB impairment and b...

British Journal of Cancer

BACKGROUND: Recurrence after >5-year disease-free survival affects one-fifth of breast cancer patients and is the clinical manifestation of cancer cell reactivation after persistent dormancy. METHODS: We investigated cellular dormancy in vitro and in vivo using breast cancer cell lines and cell and molecular biology techniques. RESULTS: We demonstrated cellular dormancy in breast cancer bone metastasis, associated with haematopoietic stem cell (HSC) mimicry, in vivo competition for HSC engraftment and non-random distribution of dormant cells at the endosteal niche. Notch2 signal implication was demonstrated by immunophenotyping the endosteal niche-associated cancer cells and upon coculture with sorted endosteal niche cells, which inhibited breast cancer cell proliferation in a Notch2-dependent manner. Blocking this signal by in vivo acute administration of the γ-secretase inhibitor, dibenzazepine, induced dormant cell mobilisation from the endosteal niche and colonisation of visceral organs. Sorted Notch2 HIGH breast cancer cells exhibited a unique stem phenotype similar to HSCs and in vitro tumour-initiating ability in mammosphere assay. Human samples confirmed the existence of a small Notch2 HIGH cell population in primary and bone metastatic breast cancers, with a survival advantage for Notch2 HIGH vs Notch2 LOW patients. CONCLUSIONS: Notch2 represents a key determinant of breast cancer cellular dormancy and mobilisation in the bone microenvironment.

International Journal of Molecular Sciences

Metastasis, a multistep process during which tumor cells disseminate to secondary organs, represents the main cause of death for cancer patients. Metastatic dormancy is a late stage during cancer progression, following extravasation of cells at a secondary site, where the metastatic cells stop proliferating but survive in a quiescent state. When the microenvironmental conditions are favorable, they re-initiate proliferation and colonize, sometimes years after treatment of the primary tumor. This phenomenon represents a major clinical obstacle in cancer patient care. In this review, we describe the current knowledge regarding the genetic or epigenetic mechanisms that are activated by cancer cells that either sustain tumor dormancy or promote escape from this inactive state. In addition, we focus on the role of the microenvironment with emphasis on the effects of extracellular matrix proteins and in factors implicated in regulating dormancy during colonization to the lungs, brain, and...

PloS one, 2013

Probability of recurrence in patients with estrogen receptor (ER)-positive breast cancer remains constant for long periods. We compared tumor burden impact on late versus early recurrence in our cohort with long-term follow-up. Five hundred and ninety five patients diagnosed with ER-positive breast cancer between 1989 and 2001 were classified into three groups: early recurrence within 5 years, late recurrence after 5 years, and no recurrence. We identified prognostic factors among the groups using logistic regression analysis. At median follow-up of 11.7 years, among 595 ER-positive women, 98 (16.4%) had early recurrence and 58 (9.7%) had late recurrence. On multivariate analysis, higher nodal stage (N0 vs. N2, odds ratio [OR] 3.189; N0 vs. N3, OR 9.948), higher histologic grade (grade 1 vs. grade 2, OR 3.896; grade 1 vs. grade 3, OR 5.945), age >35 years (OR 0.295), and receiving endocrine therapy (OR 0.293) affected early recurrence. Compared to no recurrence, receiving endocri...

Breast Cancer Research, 2013

Introduction: Recurrence risk in breast cancer varies throughout the follow-up time. We examined if these changes are related to the level of expression of the proliferation pathway and intrinsic subtypes. Methods: Expression of estrogen and progesterone receptor, Ki-67, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR) and cytokeratin 5/6 (CK 5/6) was performed on tissue-microarrays constructed from a large and uniformly managed series of early breast cancer patients (N = 1,249). Subtype definitions by four biomarkers were as follows: luminal A

Scientific Reports

Both gamma rays and atmospheric pressure plasma are known to have anticancer properties. While their mechanism actions are still not clear, in some contexts they work in similar manner, while in other contexts they work differently. So to understand these relationships, we have studied Myoglobin protein after the treatment of gamma rays and dielectric barrier discharge (DBD) plasma, and analyzed the changes in thermodynamic properties and changes in the secondary structure of protein after both treatments. The thermodynamic properties were analyzed using chemical and thermal denaturation after both treatments. We have also studied the action of gamma rays and DBD plasma on myoglobin in the presence of osmolytes, such as sorbitol and trehalose. For deep understanding of the action of gamma rays and DBD plasma, we have analyzed the reactive species generated by them in buffer at all treatment conditions. Finally, we have used molecular dynamic simulation to understand the hydrogen peroxide action on myoglobin with or without osmolytes, to gain deeper insight into how the osmolytes can protect the protein structure from the reactive species generated by gamma rays and DBD plasma. Cancer is a complex disease that holds the ability to metastasize into different organs of the body, which results in the increase of cancer. Cancer cases worldwide are predicted to almost double in the next 20-40 years 1, 2. A huge proportion of cancer patients suffer deterioration for years or spans later 3, 4 causing a therapeutic challenge. For the clinical management of cancer, radiation remains by far the most utilized treatment for patients with localized malignant tumors, and it is applied in a course of multiple fractions for several weeks to decrease the toxicity in normal cell 5-7. Low and high linear energy transfer (LET) radiations are using for radiation therapy to efficiently kill the tumor cells at minimum dose, in order to control the toxicity towards normal cells 8. Gamma rays, X-rays, and charged particles are the utmost types of radiation delivered by a machine outside the body, or irradiated through radioactive material placed near to the cancer cells/tissue in the body for cancer treatment. However, ionizing radiations are also used in agriculture, pharmaceutical, and other technological processes, rather than treatment of biological systems. Among all other ionizing radiations, Gamma ray use is more economical and effective, because of its easy availability and penetration power 9. Moreover, the change in structural, morphological, and biological systems depends on the strength and duration of exposure of gamma doses. Over the last few years, non-thermal atmospheric pressure (NTP) plasma has been studied as the alternative to ionizing radiations for cancer treatments. Plasma medicine is a new field that uses NTP plasma for a diversity of medical applications 10-12 , such as sterilization 12 , wound healing 13 , blood coagulation 14, 15 , and cancer treatment 16. NTP plasma interacts with the oxygen,

New Journal of Physics, 2021

We describe a viscocapillary instability that can perturb the spherical symmetry of cellular aggregates in culture, also called multicellular spheroids. In the condition where the cells constituting the spheroid get their necessary metabolites from the immediate, outer microenvironment, a permanent cell flow exists within the spheroid from its outer rim where cells divide towards its core where they die. A perturbation of the spherical symmetry induces viscous shear stresses within the tissue that can destabilise the aggregate. The proposed instability is viscocapillary in nature and does not rely on external heterogeneities, such as a pre-existing pattern of blood vessels or the presence of a substrate on which the cells can exert pulling forces. It arises for sufficiently large cell–cell adhesion strengths, cell-renewal rates, and metabolite supplies, as described by our model parameters. Since multicellular spheroids in culture are good model systems of small, avascular tumours, ...

Breast Cancer Research

Background: Obesity is associated with an increased risk of breast cancer recurrence and cancer death. Recurrent cancers arise from the pool of residual tumor cells, or minimal residual disease (MRD), that survives primary treatment and persists in the host. Whether the association of obesity with recurrence risk is causal is unknown, and the impact of obesity on MRD and breast cancer recurrence has not been reported in humans or in animal models. Methods: Doxycycline-inducible primary mammary tumors were generated in intact MMTV-rtTA;TetO-HER2/neu (MTB/TAN) mice or orthotopic recipients fed a high-fat diet (HFD; 60% kcal from fat) or a control low-fat diet (LFD; 10% kcal from fat). Following oncogene downregulation and tumor regression, mice were followed for clinical recurrence. Body weight was measured twice weekly and used to segregate HFD mice into obese (i.e., responders) and lean (i.e., nonresponders) study arms, and obesity was correlated with body fat percentage, glucose tolerance (measured using intraperitoneal glucose tolerance tests), serum biomarkers (measured by enzyme-linked immunosorbent assay), and tissue transcriptomics (assessed by RNA sequencing). MRD was quantified by droplet digital PCR. Results: HFD-Obese mice weighed significantly more than HFD-Lean and LFD control mice (p < 0.001) and had increased body fat percentage (p < 0.001). Obese mice exhibited fasting hyperglycemia, hyperinsulinemia, and impaired glucose tolerance, as well as decreased serum levels of adiponectin and increased levels of leptin, resistin, and insulin-like growth factor 1. Tumor recurrence was accelerated in HFD-Obese mice compared with HFD-Lean and LFD control mice (median relapse-free survival 53.0 days vs. 87.0 days vs. 80.0 days, log-rank p < 0.001; HFD-Obese compared with HFD-Lean HR 2.52, 95% CI 1.52-4.16; HFD-Obese compared with LFD HR 2.27, 95% CI 1.42-3.63). HFD-Obese mice harbored a significantly greater number of residual tumor cells than HFD-Lean and LFD mice (12,550 ± 991 vs. 7339 ± 2182 vs. 4793 ± 1618 cells, p < 0.001). Conclusion: These studies provide a genetically engineered mouse model for study of the association of diet-induced obesity with breast cancer recurrence. They demonstrate that this model recapitulates physiological changes characteristic of obese patients, establish that the association between obesity and recurrence risk is causal in nature, and suggest that obesity is associated with the increased survival and persistence of residual tumor cells.

2021

Background Breast cancer mortality is principally due to tumor recurrence, which can occur following extended periods of clinical remission that may last decades. While clinical latency has been postulated to reflect the ability of residual tumor cells to persist in a dormant state, this hypothesis remains unproven since little is known about the biology of these cells. Consequently, defining the properties of residual tumor cells is an essential goal with important clinical implications for preventing recurrence and improving cancer outcomes. Methods To identify conserved features of residual tumor cells, we modeled minimal residual disease using inducible transgenic mouse models for HER2/neu and Wnt1-driven tumorigenesis that recapitulate cardinal features of human breast cancer progression, as well as human breast cancer cell xenografts subjected to targeted therapy. Fluorescence-activated cell sorting was used to isolate tumor cells from primary tumors, residual lesions followin...

Pharmaceutics

Photodynamic therapy (PDT) is an alternative modality to conventional cancer treatment, whereby a specific wavelength of light is applied to a targeted tumor, which has either a photosensitizer or photochemotherapeutic agent localized within it. This light activates the photosensitizer in the presence of molecular oxygen to produce phototoxic species, which in turn obliterate cancer cells. The incidence rate of breast cancer (BC) is regularly growing among women, which are currently being treated with methods, such as chemotherapy, radiotherapy, and surgery. These conventional treatment methods are invasive and often produce unwanted side effects, whereas PDT is more specific and localized method of cancer treatment. The utilization of nanoparticles in PDT has shown great advantages compared to free photosensitizers in terms of solubility, early degradation, and biodistribution, as well as far more effective intercellular penetration and uptake in targeted cancer cells. This review ...

Cancers, 2011

This article brings mathematical modeling to bear on the reconstruction of the natural history of prostate cancer and assessment of the effects of treatment on metastatic progression. We present a comprehensive, entirely mechanistic mathematical model of cancer progression accounting for primary tumor latency, shedding of metastases, their dormancy and growth at secondary sites. Parameters of the model were estimated from the following data collected from 12 prostate cancer patients: (1) age and volume of the primary tumor at presentation; and (2) volumes of detectable bone metastases surveyed at a later time. This allowed us to estimate, for each patient, the age at cancer onset and inception of the first metastasis, the expected metastasis latency time and the rates of growth of the primary tumor and metastases before and after the start of treatment. We found that for all patients: (1) inception of the first metastasis occurred when the primary tumor was undetectable; (2) incepti...

Breast Cancer Research, 2011

Breast cancer stem cells (CSCs) are increasingly thought to play a major role in breast cancer growth and the formation of metastases. CSCs have hierarchical potential to undergo self-renewal along with yielding daughter cells that result in the formation of bulk tumor cells, while maintaining a self-replicating potential [1]. CSCs appear to make up a small minority of most tumors, while in others (for example, melanoma) they may comprise up to 25% of the total mass [2]. Epithelial-to-mesenchymal transition (EMT), a process fi rst noted during embryogenesis, guides the trans formation of non-mobile epithelial-like cells into mobile, mesenchymal-like cells that have the potential to travel to distant anatomical sites within the developing embryo (Figure 1). Th is naturally occurring process has also been observed during tumor formation, and may lead to the development of metastatic growth. Th e process can be reversed through mesenchymal-to-epithelial transition (MET), where migratory cells become anchored at distant sites and lose their migratory potential. Embryonic signaling pathways, such as the Notch, Hedge hog (Hh), Wnt, and transforming growth factor (TGF)-β pathways, are essential for stem cell signaling during embryogenesis [3]. Th ese pathways play critical roles in normal tissue development and maintenance, and are also involved in the tight regulation of EMT. Deregulation of embryonic signaling pathways has been widely reported in human cancers, including breast, pancreatic, and lung [4-6]. Th is observation has led to the evaluation of these pathways as potential targets for a new generation of anti-cancer drugs. Th is review examines current fi ndings and perspectives on the interplay between CSCs, embryonic signaling pathways, and EMT/MET in breast tumor growth and metastasis. Breast cancer stem cells Th e cell-of-origin for breast CSCs has yet to be determined, but may be the result of malignant trans for mation of normal stem/progenitor cells [7]. Th e long life span of stem/progenitor cells makes them more susceptible to the accumulation of DNA mutations. Th e capacity to replicate and produce multiple progeny also makes stem and progenitor cells likely candidates for tumor cells-oforigin [8].

Cells, 2021

Surgery remains an essential therapeutic approach for most solid malignancies. Although for more than a century accumulating clinical and experimental data have indicated that surgical procedures themselves may promote the appearance and progression of recurrent and metastatic lesions, only in recent years has renewed interest been taken in the mechanism by which metastasizing of cancer occurs following operative procedures. It is well proven now that surgery constitutes a risk factor for the promotion of pre-existing, possibly dormant micrometastases and the acceleration of new metastases through several mechanisms, including the release of neuroendocrine and stress hormones and wound healing pathway-associated immunosuppression, neovascularization, and tissue remodeling. These postoperative consequences synergistically facilitate the establishment of new metastases and the development of pre-existing micrometastases. While only in recent years the role of the peripheral nervous sy...

Cancers, 2021

Major progress has been achieved to treat cancer patients and survival has improved considerably, even for stage-IV bone metastatic patients. Locomotive health has become a crucial issue for patient autonomy and quality of life. The centerpiece of the reflection lies in the fracture risk evaluation of bone metastasis to guide physician decision regarding physical activity, antiresorptive agent prescription, and local intervention by radiotherapy, surgery, and interventional radiology. A key mandatory step, since bone metastases may be asymptomatic and disseminated throughout the skeleton, is to identify the bone metastasis location by cartography, especially within weight-bearing bones. For every location, the fracture risk evaluation relies on qualitative approaches using imagery and scores such as Mirels and spinal instability neoplastic score (SINS). This approach, however, has important limitations and there is a need to develop new tools for bone metastatic and myeloma fracture...

Laboratory Investigation, 2020

In patients with breast cancer, primary chemotherapy often fails due to survival of chemoresistant breast cancer stem cells (BCSCs) which results in recurrence and metastasis of the tumor. However, the factors determining the chemoresistance of BCSCs have remained to be investigated. Here, we profiled a series of differentially expressed microRNAs (miRNAs) between parental adherent breast cancer cells and BCSC-mimicking mammosphere-derived cancer cells, and identified hsa-miR-27a as a negative regulator for survival and chemoresistance of BCSCs. In the mammosphere, we found that the expression of hsa-miR-27a was downregulated, and ectopic overexpression of hsa-miR-27a reduced both number and size of mammospheres. In addition, overexpression of hsa-miR-27a sensitized breast cancer cells to anticancer drugs by downregulation of genes essential for detoxification of reactive oxygen species (ROS) and impairment of autophagy. Therefore, enhancing the hsa-miR-27a signaling pathway can be a potential therapeutic modality for breast cancer.

Biology, 2020

Cancer recurrence has remained a significant challenge, despite advances in therapeutic approaches. In part, this is due to our incomplete understanding of the biology of cancer stem cells and the underlying molecular mechanisms. The phenomenon of differentiation and dedifferentiation (phenotypic switching) is not only unique to stem cells but it is also observed in several other organisms, as well as evolutionary-related microbes. Here, we propose the use of a primitive eukaryotic unicellular organism, Acanthamoeba castellanii, as a model to study the molecular mechanisms of cellular differentiation and dedifferentiation.

Oncogene, 2016

Autophagy is a highly conserved self-degradative process that has a key role in cellular stress responses and survival. Recent work has begun to explore the function of autophagy in cancer metastasis, which is of particular interest given the dearth of effective therapeutic options for metastatic disease. Autophagy is induced upon progression of various human cancers to metastasis and together with data from genetically engineered mice and experimental metastasis models, a role for autophagy at nearly every phase of the metastatic cascade has been identified. Specifically, autophagy has been shown to be involved in modulating tumor cell motility and invasion, cancer stem cell viability and differentiation, resistance to anoikis, epithelial-to-mesenchymal transition, tumor cell dormancy and escape from immune surveillance, with emerging functions in establishing the pre-metastatic niche and other aspects of metastasis. In this review, we provide a general overview of how autophagy modulates cancer metastasis and discuss the significance of new findings for disease management.

The FEBS journal, 2018

Macro-autophagy is an ancient and highly conserved self-degradative process that plays a homeostatic role in normal cells by eliminating organelles, pathogens, and protein aggregates. Autophagy, as it is routinely referred to, also allows cells to maintain metabolic sufficiency and survive under conditions of nutrient stress by recycling the by-products of autophagic degradation, such as fatty acids, amino acids, and nucleotides. Tumor cells are more reliant than normal cells on autophagy for survival in part due to their rapid growth rate, altered metabolism, and nutrient-deprived growth environment. How this dependence of tumor cells on autophagy affects their progression to malignancy and metastatic disease is an area of increasing research focus. Here, we review recent work identifying critical functions for autophagy in tumor cell migration and invasion, tumor stem cell maintenance and therapy resistance, and cross-talk between tumor cells and their microenvironment.

Ear, Nose & Throat Journal, 2013

We describe an unusual case of breast cancer metastatic to the middle ear in a 71-year-old woman. The metastasis was the initial sign of disseminated disease 20 years after the patient had undergone a quadrantectomy for her primary disease. Computed tomography (CT) demonstrated the presence of an intratympanic mass with a soft-tissue density that was suggestive of chronic inflammation. The patient underwent a canal-wall-down tympanoplasty. When a brownish mass was found around the ossicles, a mastoidectomy with posterior tympanotomy was carried out. However, exposure of the tumor was insufficient, and therefore the posterior wall of the ear canal had to be removed en bloc. Some tumor was left on the round window membrane so that we would not leave the patient with a total hearing loss. Our case highlights the limitations of CT and magnetic resonance imaging in differentiating inflammatory and neoplastic lesions.

Cancers

The molecular receptor status of breast cancer has implications for prognosis and long-term metastasis. Although metastatic luminal B-like, hormone-receptor-positive, HER2−negative, breast cancer causes brain metastases less frequently than other subtypes, though tumor metastases in the brain are increasingly being detected of this patient group. Despite the many years of tried and tested use of a wide variety of anti-hormonal therapeutic agents, there is insufficient data on their intracerebral effectiveness and their ability to cross the blood-brain barrier. In this review, we therefore summarize the current state of knowledge on anti-hormonal therapy and its intracerebral impact and effects on the blood-brain barrier in breast cancer.

Cancer, 2004

between 1927 and 1987. The median follow-up period was 12.3 years. Distant disease-free survival (DDFS) was determined for women who did not receive systemic therapy. V and M were obtained from log-linear plots of DDFS. RESULTS. No significant difference in tumor size at presentation was observed among women age Ͻ 40 years, women ages 40-70 years, and women age Ͼ 70 years (P ϭ 0.86), whereas significantly fewer women age Ͼ 70 years presented with positive lymph nodes compared with younger women (P ϭ 0.05). In women with negative lymph node status, there was a higher DDFS rate among patients ages 40-70 years (81% at 10 years) compared with patients age Ͼ 70 years (65% at 10 years; P ϭ 0.018). There was no significant age-related difference among women with lymph node-positive disease (P ϭ 0.2). For example, the 10-year DDFS rate for women ages 40-70 years was 33%, compared with 38% for women age Ͼ 70 years. Among those with lymph node-negative disease, V was 3% per year for women ages 40-70 years as well as women age Ͼ 70 years. Among women with lymph node-negative disease, M was 0.20 for patients ages 40-70 years and 0.35 for patients age Ͼ 70 years. In women with positive lymph node status, both V (11% per year vs. 10% per year) and M (0.70 vs. 0.65) were similar in both age groups. CONCLUSIONS. Fewer women age Ͼ 70 years had lymph node involvement at presentation. However, when this finding was taken into account, the authors found no evidence that breast carcinoma was more indolent in women age Ͼ 70 years. These results support the use of similar diagnostic and therapeutic efforts for elderly women and younger women, with modification for elderly women based only on comorbidity. Cancer 2004;100:1807-13.

British Journal of Cancer, 2005

There has been much uncertainty as to whether metastasis requires mutation at the time of spread. Here, we use clinical data to calculate the probability of the spread of melanoma and breast cancer cells. These calculations reveal that the probability of the spread of cancer cells is relatively high for small tumours (B1 event of spread for every 500 cells for melanomas of 0.1 mm) and declines as tumours increase in size (B1 event of spread for every 10 8 cells for melanomas of 12 mm). The probability of spread of breast cancer cells from the lymph nodes to the periphery is B1 event of spread for every 10 8 cells in the nodal masses, which have a mean diameter of 5 mm, while the probability of spread of cancer cells from the breast to the periphery when the primary masses are 5 mm is also B1 event of spread for every 10 8 cells. Thus, the occurrence of an event of spread from the breast to the lymph nodes appears not to increase the propensity of the progeny of those cells to spread from the lymph nodes to the periphery. These values indicate that the spread of human breast cancer and melanoma cells is unlikely to occur by a mechanism requiring mutation at the time of spread.

BMC Cancer

Background Cells in every epithelium can be roughly divided in three compartments: stem cell (SC) compartment, transient amplifying cell (TA) compartment and terminally differentiated (TD) compartment. Maturation of stem cells is characterized by epithelial stromal interaction and sequential maturational movement of stem cell’s progeny through those compartments. In this work we hypothesize that providing an artificial stroma, which murine breast cancer metastatic cells can infiltrate, will induce their differentiation. Methods BALB/c female mice were injected with 106 isogenic 4T1 breast cancer cells labeled with GFP. After 20 days primary tumors were removed, and artificial ε-PCL implants were implanted on the contralateral side. After 10 more days mice were sacrificed and implants along with lung tissue were harvested. Mice were divided in four groups: tumor removal with sham implantation surgery (n = 5), tumor removal with ε-PCL implant (n = 5), tumor removal with VEGF enriched ...

British Journal of Cancer

Background Breast cancer (BC) metastasis, which often occurs in bone, contributes substantially to mortality. MicroRNAs play a fundamental role in BC metastasis, although microRNA-regulated mechanisms driving metastasis progression remain poorly understood. Methods MiRome analysis in serum from BC patients was performed by TaqMan™ low-density array. MiR-662 was overexpressed following MIMIC-transfection or lentivirus transduction. Animal models were used to investigate the role of miR-662 in BC (bone) metastasis. The effect of miR-662-overexpressing BC cell conditioned medium on osteoclastogenesis was investigated. ALDEFLUOR assays were performed to study BC stemness. RNA-sequencing transcriptomic analysis of miR-662-overexpressing BC cells was performed to evaluate gene expression changes. Results High levels of hsa-miR-662 (miR-662) in serum from BC patients, at baseline (time of surgery), were associated with future recurrence in bone. At an early-stage of the metastatic disease,...

Cancers

Gene expression profiling has revolutionized our understanding of cancer biology, showing an unprecedented ability to impact patient management especially in breast cancer. The vast majority of breast cancer gene expression signatures derive from the analysis of the tumor bulk, an experimental approach that limits the possibility to dissect breast cancer heterogeneity thoroughly and might miss the message hidden in biologically and clinically relevant cell populations. During disease progression or upon selective pressures, cancer cells undergo continuous transcriptional changes, which inevitably affect tumor heterogeneity, response to therapy and tendency to disseminate. Therefore, metastasis-associated signatures and transcriptome-wide gene expression measurement at single-cell resolution hold great promise for the future of breast cancer clinical care. Seen from this perspective, transcriptomics of circulating tumor cells (CTCs) represent an attractive opportunity to bridge the k...

2019

PurposeFor patients with early-stage breast cancer, prediction of the risk of metastatic relapse is of crucial importance. Existing predictive models rely on agnostic survival analysis statistical tools (e.g. Cox regression). Here we define and evaluate the predictive ability of a mechanistic model for the time to metastatic relapse.MethodsThe data consisted of 642 patients with 21 clinicopathological variables. A mechanistic model was developed on the basis of two intrinsic mechanisms of metastatic progression: growth (parameterα) and dissemination (parameterμ). Population statistical distributions of the parameters were inferred using mixed-effects modeling. A random survival forest analysis was used to select a minimal set of 5 covariates with best predictive power. These were further considered to individually predict the model parameters, by using a backward selection approach. Predictive performances were compared to classical Cox regression and machine learning algorithms.Res...

Trends in cancer, 2022

Metastasis is an intricate process whereby tumor cells migrate from the primary tumor, survive in the circulation, seed distal organs, and proliferate to create metastatic foci. CD8+ T cells can detect and eliminate tumor cells. Research on CD8+ T cell-dependent antitumor immunity has classically focused on its role in the primary tumor. There is increasing evidence, however, that CD8+ T cells have unique antimetastatic functions in various steps of the metastatic cascade. Here, we review the mechanisms whereby CD8+ T cells control metastatic lesions. We discuss their role in each step of metastasis, metastatic dormancy, and metastatic clonal evolution as well as the consequent clinical repercussions.

Breast Cancer Research, 2004

Introduction Information on the metastasis process in breast cancer patients undergoing primary tumour removal may be extracted from an analysis of the timing of clinical recurrence. Methods The hazard rate for local-regional and/or distant recurrence as the first event during the first 4 years after surgery was studied in 1173 patients undergoing mastectomy alone as primary treatment for operable breast cancer. Subset analyses were performed according to tumour size, axillary nodal status and menopausal status. Results A sharp two-peaked hazard function was observed for node-positive pre-menopausal patients, whereas results from node-positive post-menopausal women always displayed a single broad peak. The first narrow peak among pre-menopausal women showed a very steep rise to a maximum about 8-10 months after mastectomy. The second peak was considerably broader, reaching its maximum at 28-30 months. Postmenopausal patients displayed a wide, nearly symmetrical peak with maximum risk at about 18-20 months. Peaks displayed increasing height with increasing axillary lymph node involvement. No multi-peaked pattern was evident for either pre-menopausal or post-menopausal node-negative patients; however, this finding should be considered cautiously because of the limited number of events. Tumour size influenced recurrence risk but not its timing. Findings resulting from the different subsets of patients were remarkably coherent and each observed peak maintained the same position on the time axis in all analysed subsets. Conclusions The risk of early recurrence for node positive patients is dependent on menopausal status. The amount of axillary nodal involvement and the tumour size modulate the risk value at any given time. For pre-menopausal node-positive patients, the abrupt increase of the first narrow peak of the recurrence risk suggests a triggering event that synchronises early risk. We suggest that this event is the surgical removal of the primary tumour. The later, broader, more symmetrical risk peaks indicate that some features of the corresponding metastatic development may present stochastic traits. A metastasis development model incorporating tumour dormancy in specific micro-metastatic phases, stochastic transitions between them and sudden acceleration of the metastatic process by surgery can explain these risk dynamics.

Frontiers in Oncology, 2021

Metastasis and relapse account for the great majority of cancer-related deaths. Most metastatic lesions are micro metastases that have the capacity to remain in a non-dividing state called “dormancy” for months or even years. Commonly used anticancer drugs generally target actively dividing cancer cells. Therefore, cancer cells that remain in a dormant state evade conventional therapies and contribute to cancer recurrence. Cellular and molecular mechanisms of cancer dormancy are not fully understood. Recent studies indicate that a major cellular stress response mechanism, autophagy, plays an important role in the adaptation, survival and reactivation of dormant cells. In this review article, we will summarize accumulating knowledge about cellular and molecular mechanisms of cancer dormancy, and discuss the role and importance of autophagy in this context.

Breast Cancer Research and Treatment, 2011

Purpose: Produce an improved web-based calculator by using published mathematical models of cancer lethality to accurately predict the risk of breast carcinoma death in each of 15 years after diagnosis and the impact of various treatment choices. The SNAP method of the published binary biological model of cancer metastasis uses information on tumor size, nodal status, and other prognostic factors to accurately estimate of breast cancer lethality at 15 years after diagnosis. By combining these 15-year-lethality estimates with data on the breast cancer hazard function, breast cancer lethality was estimated at each of the 15 years after diagnosis. A web-based calculator was then created to visualize the estimated lethality with and without a range of adjuvant therapy options at any of the 15 years after diagnosis, and incorporate conditional survival information for any years survived since diagnosis. NIH population data was used to estimate non-breast-cancer chance of death. The accuracy of the calculators was tested against two large breast carcinoma datasets: 12,327 patients seen at two academic hospitals and 435,694 patients from the SEER national dataset. The calculators were found to be highly accurate and specific, with ability to stratify patients into groups differing by as little as a 2% risk of death and to account for tumor size, nodal status, histology, grade, age, and hormone receptor status. Our calculators, available at www.cancermath.net, improve on existing calculators by more finely and accurately stratifying patients according to risk of death, and displaying more detailed mortality forecasts. Validation of outcome calculator. LIST OF AL 36 TABLE and Figure 2's shown below: All patients after 1987, parameters for the outcome calculator, see TABLE I. TABLE and Figure 2a: Verification on the SEER dataset. Patients grouped by 10% predicted lethality bins TABLE and Figure 2b: Verification on the SEER dataset. Patients grouped by 5% predicted lethality bins TABLE and Figure 2c: Verification on the SEER dataset. Patients grouped by 2% predicted lethality bins TABLE and Figure 2d: Verification on the SEER dataset. Patients grouped by 1% predicted lethality bins TABLE and Figure 2e: Verification on the SEER dataset. Patients grouped by 10% predicted lethality percentiles TABLE and Figure 2f: Verification on the SEER dataset. Patients grouped by 5% predicted lethality percentiles TABLE and Figure 2g: Verification on the SEER dataset. Patients grouped by 10 mm tumor size bins TABLE and Figure 2h: Verification on the SEER dataset. Patients grouped by 5 mm tumor size bins TABLE and Figure 2i: Verification on the SEER dataset. Patients grouped by 10% tumor size percentiles TABLE and Figure 2j: Verification on the SEER dataset. Patients grouped by lymph nodes positivity status TABLE and Figure 2k: Verification on the SEER dataset. Patients grouped by number of positive lymph nodes TABLE and Figure 2l: Verification on the SEER dataset. Patients grouped by tumor grade TABLE and Figure 2m: Verification on the SEER dataset. Patients grouped by estrogen and progesterone receptor TABLE and Figure 2n: Verification on the SEER dataset Patients grouped by histological type TABLE and Figure 2o: Verification on the SEER dataset. Permutations of 10 mm tumor size bins and number of positive lymph nodes TABLE and Figure 2p: Verification on the SEER dataset. Permutations of 10 mm tumor size bins and tumor grade TABLE and Figure 2q: Verification on the SEER dataset. Permutations of 10 mm tumor size bins and ER/PR receptor TABLE and Figure 2r: Verification on the SEER dataset. Permutations of 10 mm tumor size bins and histological type TABLE and Figure 2s: Verification on the SEER dataset. Permutations of number of positive lymph nodes and EER/PR receptor status TABLE and Figure 2t: Verification on the SEER dataset. Permutations of tumor grade and ER/PR status TABLE and Figure 2u: Verification on the SEER dataset. Permutations of tumor grade and histological type TABLE and Figure 2v: Verification of the SNAP method on the SEER dataset. Grouped by race TABLE and Figure 2w: Verification of the SNAP method on the SEER dataset Grouped by sex TABLE and Figure 2x: Verification of the SNAP method on the SEER dataset Grouped by age TABLE and Figure 2aa: Verification on the Partners dataset. Patients grouped by 10% predicted lethality bins TABLE and Figure 2bb: Verification on the Partners dataset. Patients grouped by 5% predicted lethality bins TABLE and Figure 2cc: Verification on the Partners dataset. Patients grouped by 2% predicted lethality bins TABLE and Figure 2dd: Verification on the Partners dataset. Patients grouped by 10% predicted lethality %'s TABLE and Figure 2ee: Verification on the Partners dataset. Patients grouped by 5% predicted lethality %'s TABLE and Figure 2ff: Verification on the Partners dataset. Patients grouped by 10 mm tumor size bins TABLE and Figure 2gg: Verification on the Partners dataset. Patients grouped by 5 mm tumor size bins TABLE and Figure 2hh: Verification on the Partners dataset. Patients grouped by 10% tumor size percentiles TABLE and Figure 2ii: Verification on the Partners dataset. Patients grouped by number of positive lymph nodes TABLE and Figure 2ijj: Verification on the Partners dataset. Patients grouped by tumor grade TABLE and Figure 2ikk: Verification on the Partners dataset. Patients grouped by ER receptor status TABLE and Figure 2ill: Verification on the Partners dataset. Patients grouped by histological type TABLE and Figure 2mm: Verification on the Partners dataset. Permutations of 10 mm tumor size bins and tumor grade TABLE and Figure 2mm: Verification on the Partners dataset. Permutations of age TABLE and Figure 2mm: Verification on the Partners dataset. Permutations of HER2 status '0-2%' 27741 '4.64% (0.6%)' '1.31% (0%)' '-3.34%' '2-4%' 47188 '5.4% (0.4%)' '3.14% (0%)' '-2.26%' '4-6%' 44332 '6.73% (0.4%)' '5.21% (0%)' '-1.52%' '6-8%' 39381 '8.64% (0.5%)' '7.26% (0%)' '-1.38%' '8-10%' 32236 '10.9% (0.6%)' '9.3% (0%)' '-1.6%' '10-12%' 30558 '11.69% (0.6%)' '11.32% (0%)' '-0.37%' '12-14%' 24561 '14.54% (0.7%)' '13.38% (0%)' '-1.16%' '14-16%' 20951 '15.55% (0.8%)' '15.39% (0%)' '-0.16%' '16-18%' 17789 '18.21% (0.9%)' '17.4% (0%)' '-0.81%' '18-20%' 15324 '19.82% (1%)' '19.44% (0%)' '-0.38%' '20-22%' 13866 '21.51% (1.1%)' '21.47% (0%)' '-0.04%' '22-24%' 11076 '23.38% (1.3%)' '23.47% (0%)' '0.08%' '24-26%' 10274 '25.69% (1.4%)' '25.42% (0%)' '-0.28%' '26-28%' 8858 '25.2% (1.4%)' '27.52% (0%)' '2.32%' '28-30%' 6990 '30% (1.8%)' '29.48% (0%)' '-0.51%' '30-32%' 6804 '29.16% (1.7%)' '31.52% (0%)' '2.36%' '32-34%' 5520 '33.27% (2.1%)' '33.53% (0%)' '0.27%' '34-36%' 4994 '32.51% (2%)' '35.5% (0%)' '2.99%' '36-38%' 4111 '34.51% (2.5%)' '37.56% (0%)' '3.04%' '38-40%' 3697 '40.02% (2.6%)' '39.48% (0%)' '-0.54%' '40-42%' 3064 '40.22% (2.8%)' '41.52% (0%)' '1.3%' '42-44%' 2803 '40.08% (2.9%)' '43.47% (0%)' '3.39%' '44-46%' 2132 '40.71% (3.2%)' '45.52% (0.1%)' '4.81%' '46-48%' 1913 '41.97% (3.5%)' '47.45% (0.1%)' '5.48%' '48-50%' 1489 '48.61% (4.3%)' '49.45% (0.1%)' '0.84%' '50-52%' 1341 '50.42% (4.2%)' '51.37% (0.1%)' '0.95%' '52-54%' 1152 '47.58% (4.5%)' '53.32% (0.1%)' '5.74%' '54-56%' 934 '50.26% (5.2%)' '55.42% (0.1%)' '5.16%' '56-58%' 712 '51.78% (5.8%)' '57.42% (0.1%)' '5.64%' '58-60%' 546 '56.06% (6.1%)' '59.64% (0.1%)' '3.58%' '60-62%' 424 '57.45% (8.2%)' '61.47% (0.1%)' '4.01%' '62-64%' 340 '44.15% (7%)' '63.47% (0.1%)' '19.32%' '64-66%' 220 '45.69% (8.5%)' '65.35% (0.1%)' '19.66%' 'Weighted Mean Error'

Breast Cancer Research and Treatment, 2002

Purpose. To gather information on the natural history of breast cancer from the time-distribution of deaths of patients undergoing mastectomy alone. Patients and methods. A total of 1173 patients, who entered controlled clinical trials carried out at the Milan Cancer Institute and underwent radical or modified radical mastectomy without any adjuvant therapy for operable breast cancer, were examined. The risk of death at a given time after surgery was studied utilizing the deathspecific hazard rate. The risk distribution was assessed relative to tumor size, axillary lymph node involvement, and menopausal status. Results. The hazard rate for death presented an early peak at about the 3rd-4th year after surgery and a second late peak near the 8th year. The double-peaked pattern was almost completely generated by N+ patients, while N− patients did not show relevant structures. Pre-menopausal patients showed an initial mortality wave covering about 6 years, with maximum height at the 4th year, followed by a peak 8 years after surgery, while post-menopausal patients showed an early high mortality surge peaking at the 3rd year, followed by a modest increase at the 8th year. Detailed analysis revealed that post-menopausal patients with early mortality had significantly larger tumors and higher nodal involvement, while no special trait characterized the corresponding pre-menopausal patients. Moreover, patients of the late mortality peak were more likely to have suffered early local-regional or contra-lateral recurrence or to be pre-menopausal patients recurring anywhere at the second recurrence peak. Conclusion. The double-peaked hazard curve confirmed the occurrence of discontinuous features in the natural history of breast cancer for patients undergoing mastectomy. Indeed, the mortality pattern maintained definite signs of the previous double-peaked structure of recurrences. However, death events did not parallel the corresponding recurrence events and, moreover, pre and post-menopausal patients revealed dissimilar survival after recurrence, at least for early deaths. These findings, showing disconnection of mortality pattern from recurrence pattern for subsets of patients, suggest that parameters other than those influencing the recurrence risk may determine the survival of recurred patients.