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Challenges and Opportunities in Breast Cancer

Challenges and Opportunities in Breast Cancer

Dr. Gerald J. Mizejewski

Abstract

Growth Inhibitory Peptide (GIP) is an alpha-fetoprotein (AFP) derived peptide found during human pregnancy, which gradually disappears following childbirth in both the woman and the newborn. Following a stress-induced conformational change in the AFP molecule, GIP is exposed on the protein surface from a concealed occult site on the unfolded full-length AFP. The exposed 34-amino acid GIP peptide then targets, blocks, and suppresses malignant growth in the mammalian body. In the present report, GIP has been demonstrated to inhibit cell growth in vitro in nine different types of cancers including breast, prostate, and ovarian among others. GIP can further assist in preventing blood clotting, arresting growth via the cytoplasmic growth cycle, suppressing tumor blood vessel angiogenesis, and inhibiting circulating cancer cell metastasis. In further studies, GIP has been reported to suppress cancer growth in 38 of 60 different cancer cell culture lines. The growth suppressed human breast cancer cell lines included MCF-7, T-47D, Bt-547, MDA-MB-231, MDA-MB-435, in addition to mouse mammary tumor implants and xenografts. Thus, GIP was found to suppress and inhibit cancer growth in both in vitro and in vivo preclinical studies.

Arun Holenarasipur Narasannaiah

Abstract

Background: Among the various methods in minimizing Limb Lymphoedema following ALND in Breast cancer, Axillary reverse mapping is a novel approach. Attempt to preserve the ARM node without threatening Oncological safety is a further step.

Aim: To identify Blue ARM Node, intra operatively whether harbors metastases or not, defined by Radioactivity comparing with Histo pathological Examination.

Materials and Method: The 30 cases of Breast cancer patients undergoing surgery along with Axillary dissection were considered for Double dye technique of ARM study with Radio colloid injection in subareolar region and 3ml of 5% methylene blue to the Arm,1 hour before starting surgery. At Axillary dissection, level I and level II nodal clearance done and the blue thin, tortuous lymphatics entering axilla are identified are followed medially, where blue nodes are usually identified below inferior to Axillary vein. The Blue nodes are considered belonging to upper limb called ARM node, whose radioactivity is recorded invivo, are dissected and sent for Histo pathological Examination.

Results: The identification rate of blue lymphatics is about 77% (26 cases out of 30), the location of blue ARM node (70% identification rate, 21 out of 30 cases) were within 2cms inferior to Axillary vein lateral to Latissimus dorsi pedicle. The Radioactivity of the Blue ARM node more the 10% of the count at Subareolar region considered as Cross over Node (Blue+Hot) is observed among 2 patients, which confirmed with histopathologicaly positive for metastases, but rest of 19 (95.3%) Blue ARM node with less than 10% radioactivity (Blue +Cold), were Histopathologicaly Negative for metastases. Among 21 Blue ARM nodes, 2 nodes were metastatic amounting to 9.4% cases having cross over Lymphatics, identified by radioactivity.

Conclusion: The Double dye Axillary Reverse Mapping study is a valuable armamentarium for the surgeons, during Breast Cancer surgery undergoing Axillary Lymphnode dissection to preserve uninvolved ARM Lymph node, thereby avoid Limb lymphedema without compromising Oncological safety.

Christos Markopoulos, MD, PhD, FEBS, CEBS

Abstract

The clinical management of invasive breast cancer has changed during the last decade with the use of molecular-based multigene assays (MGAs).They are increasingly used to gain additional prognostic and predictive information and guide adjuvant treatment decisions. Since 2004, several MGAs have become available but, four of them are the most widely used in clinical practice: the OncotypeDX® Breast Recurrence Score, the 70-gene signature MammaPrint®, the Prosigna® (PAM50) and the EndoPredict® (EP/EPclin Scores) assay. However, MGAs are not all the same and they do not provide interchangeable information. They differ in terms of the technological platform used for their development, the number and specific genes assessed, and the patient populations in which they were validated. Furthermore, although they are all validated for providing prognostic information, not all of them are supported with data from prospective randomised trials confirming the clinical value of their use in chemotherapy treatment decisions in certain groups of breast cancer patients; in this regard, so far there are published data only for OncotypeDX and MammaPrint, whilst PAM-50 (Prosigna) and EndoPredict assays are currently not supported by entirely prospective randomized trials evaluating their predictive value of chemotherapy benefit. As such, inclusion of these MGAs in major international treatment guidelines differs in indications for their use in clinical practice as prognosticators only or as predictors of chemotherapy benefit as well. Use of MGAs in clinical decision making can lead to de-escalation of chemotherapy recommendations and thus save a large number of patients from unnecessary side effects and decrease the cost of breast cancer treatment to National Health systems. This review provides an overview of the four most widely used MGAs in clinical practice, including basic information on their development and validation, as well as recent data on the information they can provide.

Fatimata MBAYE, Nada AGENDEY, and Mbacké SEMBENE

Abstract

Breast tumors are a frequent cause of medical consultations. Although these tumors are mainly benign, they can become malignant or cancerous. This study aimed to elucidate the involvement of genetic alterations in the C-MYC oncogene in breast tumorigenesis in Senegalese females. After PCR, the epidemiological and molecular profiles of 45 samples, including 19 controls (C) from healthy individuals and 11 benign (BT) and 15 cancerous (MT) samples from patients with tumors, were determined. Mutations were determined using Mutation Surveyor software, and their pathogenicity was assessed using SIFT, Polyphen-2, Mutpred2, SNAP2, PANTER-PSEP, PROVEAN, PhD-SNP, SNP&GO, MUpro, and I-mutant prediction tools. At the epidemiological level, the average ages of the BT and MT groups were 21 and 49.76 years, respectively, and the average ages at menarche were 14.14 and 14.58 years, respectively, with a high frequency of adenofibromas (53.85%) in the BT group and only infiltrating ductal carcinomas (100%) found in the MT group. The stages (III and IV) and grade of SBR were specific to the MT group 76.47% and 58.82%, respectively. At the molecular level, four mutations were identified, all of which were heterozygous and novel, and three of which were non-synonymous. One of the mutations (c.115 T > TC; p.Tyr39His) was recurrent (frequency = 26.67%, 4/15 in the MT group; and 10.53%, 2/19 in the C group) and the other two (c.113 T > TC; p.Phe38Ser and c.117 C > CT) were exclusive to the C group, with the same frequency of 5.26% (1/19). No mutations were found in the BT group. The p.Phe38Ser and p.Tyr39His mutations were described as deleterious and can cause cancer according to the prediction tools. Overall, these mutations can be considered as variants of interest and are the subject of PCR screening for breast cancer prevention.

Masami Okamoto

Abstract

When traction forces are generated in the cells underlying extracellular matrix (ECM) including artificial scaffolds, the cells feel essentially stiffness of the surrounding microenvironment and respond to applied forces and exert forces in the matrix, in which the traction forces can change cellular morphology and cytoskeletal structure. To date, analysis of cell morphology, including quantitative measurements such as cytoplasm roundness, cytoplasm elongation factor, nuclear elongation factor, ratio nuclear area to cytoplasm area ratio (AN/AC), nuclear dimension, and nuclear height, has been widely used in cancer diagnostics and hematology. Increasing evidence suggests that the extracted morphological features such as cell area and the length of major and minor axes, could also be used to analyze the dynamic changes of cells in diseases of the nervous system and cellular stress related phenomena. Furthermore, multivariate analyses of morphological data suggest that quantitative cytology may be a useful adjunct to conventional tests for the selection of new substances.

Thus, understanding the interaction between the microenvironment and cancer cells via cellular morphology is a critical subject to tackle the metastatic spread of cancer cells and its many associated issues. In this topic, the cellular morphological parameters and functional characteristics of cancer cells are summarized.

Gustavo Febles De León, Andrés Dell´Acqua, and Andrea Cristiani

Abstract

Objective: to analyze whether ultrasonography with fine-needle aspiration cytology of an axillary suspicious node, in patients with breast cancer, could help to differentiate between patients with low involvement of the axilla (up to 2 nodes with macrometastasis) of those with high involvement of the axilla (more than 2 lymph nodes with macrometastasis).

Material and methods: A total of 115 consecutive patients with breast cancer (up to 5 cm in diameter), with clinically negative axilla and pathologically positive axilla. All patients underwent preoperative axillary ultrasound and ultrasound-guided fine-needle aspiration cytology was performed in patients with suspicious nodes. In all patients with positive cytology, lymphadenectomy was performed. In all patients with negative ultrasound and cytology, sentinel lymph node biopsy was performed, and when it was positive, lymphadenectomy was performed. The number of pathological lymph nodes was evaluated after lymphadenectomy.

Results: A total of 61 patients had positive axillary ultrasound and cytology. In 42 of them (69%), there were more than 2 pathological lymph nodes. There were 54 patients with negative axillary ultrasound and cytology. In 49 of them (90%), there were only 1 or 2 pathological lymph nodes. Axillary ultrasound and fine-needle aspiration cytology were able to identify 42 of the 47 patients (89%) with more than 2 pathological lymph nodes.

Conclusion: ultrasound and ultrasound-guided fine-needle aspiration citology was able to identify, in a preoperative stage, those patients with high axillary involvement (more than 2 lymph nodes with macrometastasis). The latter are the patients who would benefit from lymphadenectomy of the axilla, ignoring the sentinel lymph node biopsy stage.

Brian Kawahara and Pradip K. Mascharak

Abstract

Drug resistance to conventional chemotherapeutics is a great impediment to cancer therapy. A major part of this problem arises from rapid metabolism of the drugs by cytochrome P450 class of enzymes before they reach their targets or at the target itself. Inhibition of such enzymatic deactivation of the drugs could offer partial rescue and make chemotherapy more effective. Site specific delivery of exogenous carbon monoxide has been shown to inhibit cytochrome P450 enzymes and resurrect sensitivity to chemotherapeutics already available in the market. Successful design for application of such CO delivery will thus be extremely desirable to patients particularly in poor countries where the antibody-based or nanodrug therapies, discovered recently, are too expensive for the general population. The potential of such carbon monoxide-induced cytochrome P450 inhibition to improve drug sensitization to conventional chemotherapeutics in breast cancer therapy has been discussed in this account.

Rémy Salmon
 

Abstract

The number of breast cancers is rising world wide: 2088000 in 2018 and 2833000 estimated in 2040 i.e. an 35%increase. This increase in number will concern mainly the LMIC (Low and middle Income Countries), like sub- saharian Africa where the rising control of malaria, HIV and tuberculosis is associated with a longer life and consequently an increase in the number of cancers. Facing these disparities how can we avoid to increase the gap between the patients living in rich countries and those living in the LMIC. Actually the number of cases does not correspond to the TNM classification. Technical and biological progress as well as Artificial Intelligence ( IA) developments allows more and more targeted approachs in all the aspects of breast cancer management. At the same time costs are dramatically increasing and ours Health systems are greatly concerned by the present and future costs.

Elke Smeers, Huget Désiron, Elke Van Hoof, Jeroen Mebis, Lode Godderis, and Angelique de Rijk

Abstract

Background: Women of working age who are diagnosed with breast cancer often experience a decline in their ability to work during and after treatment. A hospital-based tailored intervention is needed to restore their labour participation by bridging the gap between the healthcare setting and the workplace. The aim of this intervention is to restore the labour participation and, guided by an occupational therapist, to enhance the quality of life of BC patients during their return-to-work process. This paper mainly focusses on describing that intervention, including the research protocol to evaluate its feasibility and participant’s perceptions.

Materials and Methods: The development of the BRIDGE intervention has yielded a roadmap that describes the individual patient’s path to return to work and includes tools for professionals. The Template for Intervention Description and Replication (TIDieR) guidelines were used to systematically describe the intervention. A feasibility study – designed as mimic RCT – was used as protocol for this study.

Results: prepared by a phase 0 (indication phase), the five phases of the intervention are as follows: exploration; comparison; preparation; goal-setting and action planning; realisation and evaluation. An overview of the procedures involved, including the stakeholders in each phase and the materials to be used, is also presented. Results of the mimic RCT are currently analysed and prepared for publication.

Conclusions: This five-phase BRIDGE intervention is performed by an OT and targets patients in paid work who have been diagnosed with BC. It aims to bridge the gap between the healthcare setting and the workplace.

Yuko Takao, Yuriko Katagiri, Rie Sugihara, Shumtarou Matsushima, Hidetaka Watanabe, Nobutaka Iwakuma, Miki Yamaguchi, Fumitaka Fujita, and Uhi Toh

Abstract

Background: For post-neoadjuvant chemotherapy patients with breast cancer, sentinel lymph node biopsy (SLNB) was recommended using the dual-tracer mapping technique (radioisotope plus blue dye) or placing a biopsy clip into the positive node at diagnosis and identifying it at the time of surgery due to SLN identification rates were lower and false negative rates were greater for patients with local advanced BC than those of patients with early-stage BC in the absence of NAC. Our previous clinical trial has indicated that the real-time ICG fluorescence (RT-ICG) imaging technique could improve the diagnostic sensitivity and detection accuracy for SLNB.

Methods: The SLNs was detected by conventional procedures of blue-dye (Indigo carmine) plus 99mTc radioisotope (dual-tracer) and combined with concurrent RT-ICG technique. The positivity of each single SN by each single tracer (blue dye, ICG, or radioisotope alone) was counted and identified, respectively. 51 enrolled cN1patients after NAC are required to undergo SNB followed by completion axillary lymph node dissection (CND). The identification rate and false negative rate of each single tracer and their summation (triple tracer) were calculated by comparing the results of the SLNB and the histopathology of the resection specimens of CND. 

Results: post-neoadjuvant patients, the identification rate and false negative rate of each single procedure for SLNB was 84.3% and 5.9% when used Indigo Carmine blue, 94.1% and 0 when used ICG fluorescence, 92.2% and 3.9% when used RI, respectively. In contrast, the total calculation of triple tracer showed that identification rate reached to 96.1% and false negative rate was 0, respectively. 

Conclusions: Our results suggested that the multitracer technique combining blue dye, ICG, and radioisotope is effective method for detection of SLNs in post-neoadjuvant cN+ BC pts. The identification rate and false negative rate of SLNB might be improved by this multiple tracer mapping technique, particularly for patients with ypN(+) after NAC. It is considered that the multi-tracer can complement each other for what was not able to be traced and detected by the single tracer with one mapping material, and that result in totally the improvement of identification rate of SLNB.

Keeley D Newsom, David Xiang, Alan Yang, Libby R Copeland-Halperin, Anna Weiss, and Justin M Broyles

Abstract

Lymphedema is one of the most feared complications of breast cancer treatment. The objective of this article is to review the basic workup, staging, and diagnostic criteria for lymphedema and to discuss non-surgical and surgical treatments, with a focus on breast-cancer related lymphedema. Non-surgical treatment consists of intensive physical therapy including manual lymphatic drainage via massage, daily compression wraps, and exercises to prevent scarring and increase mobility. Surgical intervention is considered when non-surgical treatment is ineffective or more recently as a preventive measure. Surgical interventions, used once lymphedema has developed, include 1) lympho-venous bypass, which is the anastomosis of lymphatic vessels distal to the site of dermal backflow to neighboring venules to shunt lymphatic drainage away from the area of lymphatic injury; 2) vascularized lymph node transplant, in which lymph nodes are harvested from a donor site with their supporting artery and vein and transferred to the affected recipient site; and 3) debulking procedures including liposuction and direct excision. Preventive surgical interventions include 1) lymphatic microsurgical preventive healing approach, known as LYMPHA, which also utilizes lympho-venous anastomoses but at the time of lymph node dissection to anastomose lymphatic channels transected during lymph node dissection with adjacent veins to preserve lymphatic drainage of the arm; and 2) axillary reverse mapping, which involves tracer or dye injection within the ipsilateral arm before axillary surgery so that the breast surgeons are able to delineate nodal drainage and therefore attempt to spare nodes specific to arm tissue provided they are not the sentinel lymph node. Patient selection is critical for these procedures, and requires a multi-disciplinary approach.

Jane Perlmutter, Susie Brain, Thelma Brown, Deborah Collyar, Amy Delson, Diane Heditsian, Barbara LeStage, Bev Parker, Susan Samson, Joan Venticinque, and Jeff Matthews

Abstract

The innovative I-SPY Breast Trial is presented as an example of an unusually patient-centric clinical trial that has been significantly impacted by extensive advocate involvement. In the introduction we briefly define what we mean by patient-centric trials and describe the overall structure, goals, and evolution of I-SPY. We then describe: 1) the roles and philosophy of advocate involvement; 2) attributes of the trial design that make it especially patient-centric; and 3) educational material and communications approaches aimed at empowering and supporting trial participants. For each section, in addition to describing I-SPY practices, we provide aspirational suggestions that could enhance I-SPY and/or other clinical trials. Embedding advocates into every aspect of clinical trial design and operations, empowering trial participants with excellent patient educational material and incorporating and learning from patient-reported outcomes serves as a model approach to achieve more patient-centric clinical trials.

Elke Smeers, Huget Désiron, Angelique de Rijk, Elke Van Hoof, Jeroen Mebis, Lode Godderis

Abstract

Background: International research indicates that patients’ needs for return-to-work (RTW) support should be addressed and integrated within the curative healthcare process and as early as possible in the treatment process. Using intervention mapping, a hospital based RTW intervention, named BRIDGE (Bridging health care and workspace), was developed with an emphasis on bridging the gap between healthcare and the workplace.

The aims of this evaluation were (a) to determine whether BRIDGE contributes to restoring participation and increasing quality of life for BC patients during their RTW process; and (b) to identify the needs and experiences of patients and healthcare professionals during this transmural intervention process. This paper describes the quantitative and qualitative evaluation of the intervention.

Method: The mixed-method design of this study assessed quantitative outcome measures on patient level (perceived Quality of life), number of days on sick leave, relapse and experience with RTW support; and on healthcare worker level (days of duration of the RTW guided process, perception of satisfaction with RTW support and time spent by the occupational therapist and the multidisciplinary team). Semi structured interviews were used to evaluate qualitative measures on patient level, focus-group discussion was used to collect healthcare providers’ perceptions.

Results: Of all eligible patients (n =179), 79 accepted to participate. Randomisation attributed 43 participants to the intervention group (IG) and 36 to the control group (CG). The outcomes showed that patients felt respected and empowered in their choices and actions regarding their professional career and that health care providers perceive the intervention as valuable support for their patients.

Conclusions: The BRIDGE intervention is highly appreciated both by HCPs and BC patients. Improvements can be made by elaborating the thoughtful follow-up which enables the BCM to stay in touch, to enable indication of the right moment for each patient to engage in the RTW process. It also would reinforce insights for the BCM to provide the type of service that fits patients’ and all other stakeholders’ needs. On the other hand, HCPs are not comfortable with the content as well as the potential impact. More emphasis on the thoughtful follow-up is needed to motivate HCPs to align with the idea of the BRIDGE intervention.

Joyce Ayugi, Dr., George Ndagijimana, Dr., Stanley Luyima, Dr., and David Lagoro Kitara

Abstract

Background: Breast Cancer is one of the most common cancers that occur universally among women. The disability-adjusted life years lost by women to breast cancer globally are more than any other cancer. Breast cancer occurs in women worldwide after puberty with increasing rates in later life. Improvements in breast cancer survival began in the 1980s in countries where early detection programs combined with different modes of treatment to eradicate the invasive form of the disease are practiced. Recent data show a higher prevalence of breast cancer among women in Northern Uganda compared to the rest of the country.

This study aimed to determine factors associated with breast cancer awareness, breast self-examination, clinical breast examination, and other modalities for screening and early breast cancer detection among adult women in Gulu Main Market.

Methods: We conducted a cross-sectional study in Gulu’s Main Market in 2020. We recruited Ninety-eight adult women for the study using a random sampling method. The questionnaire had an internal validity of Cronbach’s α=0.72, and a local IRB approved the study. We used SPSS version 26.0 for data analysis, and a p-value less than 0.05 was considered significant.

Results: Most participants were 20-29 years 41(41.8%), married 44(44.9%), monthly incomes of more than one million shillings 51(52.2%), Acholi 81(82.7%), Catholics 46(46.9%), vendors 75(76.5%), work duration in the Market (1-10 years) 64(65.4%), primary level of education 39(39.8%), and had 1-2 pregnancies 37(37.8%). The independent factors associated with breast cancer awareness, breast self-examination, and clinical breast examination were vendor (primary occupation) (β=-0.130, t=-2.979, p=0.004), work duration in the Main Market (1-10 years) (β=-0.186, t=-2.452, p=0.016), and the highest level of education (β=-0.091, t=-2.506, p=0.014).

Conclusions: Breast cancer awareness and downstaging practices among adult women in Gulu’s Main Market are thought-provoking. Women with better socioeconomic status (higher education level, moderate work duration in the Market, and vendors) in Gulu Main Market were more likely aware and practiced breast cancer downstaging activities. There is a need to strengthen publicity on breast cancer-related knowledge for lower-income occupational groups and those with lower educational levels to understand better the importance of conducting early breast cancer detection activities.

Mandeep Singh, Sonal Prakash, Supinder Kaur, Neha Sharma, Deepak Jha, Chandrakant S Pandav, and Frank Hoffman

Abstract

Introduction: Breast cancer is the most common cancer in women around the world, including India. The peak incidence in India is occurring between the ages of 45 -49 years. The solution to problem lies in early detection. The two important methodologies are tactile examination and radiological assessment in form of Mammography. This study explores the concept of enabling and training visually impaired women known as Medical Tactile Examiners with enhanced tactile sense to perform Tactile Breast Examination (TBE) for early detection of Breast Cancer.

Material & Method: A total 1338 women were enrolled. Tactile Breast Examination included intensive and meticulous examination of every cm of breast by three different touch pressures using specialized strips to guide the visually impaired. It was preceded by recording information around lifestyle habits, pregnancy, lactation, menstruation, family history, etc. The radiological assessment included Ultrasound for women less than 40 years and Mammogram for 40 years and above. Data generated was statistically analyzed.

Results: 2.6% of 1338 women were doing routine breast screening; 16% had Body Mass Index > 30; 3% were into substance abuse; 7% experienced menstrual irregularities; 16% were nulliparous; 15% of the parous women had insufficient lactation. 5% had family history of Hereditary Breast and Ovarian Cancer and 4% had previous history     of Breast Cancer. Tactile Breast Examination findings were normal in 756/1338 (56.5%), amongst which 8/756 (1%) had radiology reports with BIRADS 4 (suspicious for malignancy) findings. Medical Tactile Examiners during the process of TBE identified palpable breast alterations in 582/1338 (43.5%) of the cases, amongst which 29/582 (5%) were identified as BIRADS 4. The statistical analysis suggests Tactile Breast Examination having a high sensitivity (78.3%) and a very high negative predictive value (98.9%)

Conclusion: The process of Tactile Breast Examination by visually impaired appears apt for breast screening as it detects almost any aberration both benign and malignant in breast which is amenable to human touch and misses out in just 1% changes which can be malignant. It has the potential to become vocational avenue for visually impaired women.

Maseabata Ramathebane Lineo Maja, Mopa Sooro, Molungoa Sello, Motselisi Mokhethi, and Kabelo Mputsoe

Abstract

Background: It has been estimated that, more than 60% of the new breast cancer cases and 70% of related deaths will be seen in Low-Middle Income Countries in the coming 20 years. In Lesotho, out of 228 women, 177 had heard about breast cancer while 72.9% had heard of breast cancer screening. Given limited treatment facilities and options in Lesotho, many patients die soon after diagnosis, before they are able to access treatment; to date this cannot be quantified. Another challenge that affects breast cancer management is treatment and travel-related costs, particularly for those not living close to the medical centre. Most patients are coming with advanced disease stage and are sent home for home-based care, some of which could have been prevented with early screening.

Aim: The aim of study is to determine challenges faced by breast cancer patients, the cost to the health system and the opportunities this may bring to the country.

Methods: A quantitative cross-sectional, prospective and retrospective study was conducted on 45 breast cancer patients who were initiated chemotherapy at the only cancer treatment centre in Lesotho; Senkatana oncology clinic located at the Botshabelo complex in Maseru.

Results: The majority of patients were facing challenges of arranging transport to the doctor (83.3%, n=15), of being far from the healthcare facilities even if transportation was available (77.8%, n=14), paying for healthcare (83.3%, n=15), paying for transport (77.8%, n=14) and paying for diagnostic test (88.9%, n=16) in all ages. Majority of patients who presented for care and treatment late faced challenges more than those who presented earlier. Diagnostic and monitoring laboratory test constituted 64.5% of total direct medical costs followed by 24.7 % from chemotherapy.

Conclusion: The challenges faced by breast cancer patients are of financial and practical nature and they get higher for patients who presented at advanced stage for care and treatment. In order to improve breast cancer care and treatment outcome at lower costs efforts for breast cancer awareness need to be intensified so that patients presented early at the health centers. In term of direct medical cost, the largest cost came from the diagnostic and monitoring laboratory tests.

Anita Gadgil, MS, Radhika Srinivasan, MD, PhD, Surita Kantharia, MD, and Partha Basu, MD, PhD

Abstract

Breast cancer tops the list of female cancers both in incidence and mortality. Eastern and south Asian countries have seen a very significant 86%-89% rise in age standardized incidence. Currently 5-year survival of breast cancer in low- and middle-income countries is only 40-60%. There is an urgent need to reduce delays in diagnosis of breast cancer and establish effective referral pathways to improve the observed low survival. Existing literature describes reasons for such delays in breast cancer management extensively, yet does not propose solutions to disrupt this status quo.

Pre-diagnostic delays and diagnostic delays are interdependent due to overlapping socioeconomic and cultural barriers to seeking health, and accessing and accepting care. Non-availability of diagnostic tests or trained human resource and out of pocket expenditure complicate these delays. Present article highlights probable solutions to mitigate these problems with an emphasis on resource limited settings.

Early diagnosis of breast cancer essentially involves reducing the delays in triple assessment of symptomatic patients in the context of limited resources. Clinical breast examination, use of ultrasonography and fine needle aspiration biopsy which are possible to organize at secondary level can mitigate some of the delays. Newer technologies like portable ultrasound devices, use of artificial intelligence, cartridge based real time receptor assay can further reduce the diagnostic delay. Many pilot studies and interventions using newer point of care tests are in progress to establish their role against gold standard investigations in clinical practice.

Delay in diagnosis cannot be mitigated by providing standalone solutions. Robust pathways with provision of green corridor for referrals, task shifting of patient navigation to various grassroot level health care workers, developing contextual practice guidelines, recognising challenges and weaknesses of cancer control system, and realizing importance of equitable distribution of health resources can strengthen the cancer control strategies and mitigate the delays in breast cancer diagnosis.

Robert Charles Burton

Abstract

In Australia and many other high and middle-income countries diagnosis of the most curable stages of breast cancer, early breast cancer (EBC), in women by population based mammographic screening began after 1990. In many of these same and other high and middle-income countries administering adjuvant endocrine and chemotherapy after surgical complete resection of EBC (adjuvant therapy) also began in the 1990s. Some populations then underwent declines in breast cancer mortality that were recorded in population-based Cancer Registries that were attributed to either mammographic screening and/or adjuvant therapy. In only a few populations, for example, in the State of Victoria Australia from 1986-2019 long term trends in the incidence of breast cancer stages at diagnosis have been recorded by the population-based Victorian Cancer registry (VCR). These long-term stage trends have shown that advanced stages of breast cancer have increased or remained stable in those populations, so mammographic screening could not have directly caused the recorded declines in breast cancer mortality in their population-based Cancer Registries. In contrast in Victoria Australia adjuvant therapy use can explain all the recorded mortality decline.

Nitin Telang

Abstract

Background: Progression of early stage breast cancer to advanced stage metastatic disease represents a major cause of death in women. The Luminal A breast cancer subtype exhibits acceptable response to Chemo-endocrine and targeted therapy. However, these treatment options are associated with intrinsic/acquired therapy resistance and emergence chemo-resistant cancer initiating stem cell population, and resultant progression to advanced stage metastatic disease. These limitations emphasize an unmet need for the development of reliable models for cancer stem cells that facilitate identification of efficacious therapeutic alternatives. Documented human consumption, low systemic toxicity, preclinical cancer growth inhibitory efficacy and stem cell targeting efficacy of natural products, such as dietary phytochemicals and nutritional herbs, provide mechanistic leads for these agents as testable therapeutic alternatives. 

Objectives: The objectives of the present review are to i.) Provide a systematic discussion of published evidence relevant conceptual background of conventional/targeted therapy and nutritional herbs as testable alternatives, ii.) Growth inhibitory efficacy of nutritional herbs in a cellular model for the Luminal A breast cancer, iii.) Breast cancer stem cell biology and stem cell models for therapy-resistant breast cancer, and iv.) Future research directions.

Conclusions: Collectively, all the elements discussed in the present review validate mechanism-based experimental approaches to identify and prioritize potential therapeutic alternatives.

Future Research: This review provides a rationale for investigations on patient-derived tumor samples that may minimize extrapolation of the preclinical data for their clinical relevance and translatability.

Vijay Sharma

Abstract

The biological behaviour of breast cancer is remarkably heterogeneous and it is essential to have tools which can provide the necessary risk stratification to plan clinical management. Breast cancer prediction and prognosis needs to be holistic, and account for multiple levels of organisation. The histological classification and grading of the tumour itself presents valuable predictive and prognostic information. Hormone receptor status remains a mainstay, but roles may emerge for assessment of the intrinsic molecular subtype, for a molecular subclassification of triple negative carcinomas, and for whole genome sequencing. The recent discovery that antibody drug conjugates are effective in patients with weak HER-2 protein expression has led to the definition of the HER-2 low group.

There has been a proliferation in predictive and prognostic models, numbering over 900, but the majority are at high risk of bias and tend to perform less well when applied to populations beyond the development cohort. The Nottingham Prognostic Index is a notable exception. Of the molecular risk stratification tools currently available, Oncotype Dx is the most widely recommended and used, but the question as to which test is superior remains unanswerable with current data. There is growing interest in omics-based approaches from which a number of biomarkers are being developed.

It is well established that the microenvironment of the tumour is key to the tumour’s behaviour. Some components contain and destroy the cancer, whereas others are co-opted by the tumour and aid in its progression; the current evidence is reviewed, including the current status of tumour infiltrating lymphocyte assessment and immune checkpoint inhibition in breast cancer. The use of the liquid biopsy to achieve early detection of tumours and to manage tumour evolution is receiving intense attention; approaches include circulating tumour cells and circulating tumour DNA. Specific assessment of tumour giant cells may also provide the ability to anticipate tumour evolution. The influence of the gut microbiome on breast cancer is an intriguing development which requires further intensive study. There is a paucity of biomarkers in the setting of hereditary breast cancer. The use of polygenic risk scores in this setting is an interesting development requiring further study.

The greatest challenge of all is to pull from such complexity key decision nodes that are clear enough to guide treatment decisions without losing the depth and richness of the information that underlies them. Seeking and finding this balance has been and will continue to be the holy grail of all endeavours in this field.

Tommaso Susini, MD, PhD, Irene Renda, Milo Giani, Vania Vezzosi, Gianna Baroni, and Simonetta Bianchi

Abstract

Background: Collagen type XI, alpha 1 (COL11A1) is a minor component of extracellular matrix and its overexpression is associated with tumoral progression and poorer outcome in several human cancers; data on breast cancer are promising but scarce. FGD3 expression has been shown to be a strong independent prognostic factor in breast cancer. The aim of our study was to investigate whether COL11A1 expression correlates with other classic pathologic prognostic factors including FGD3 expression, as well as with clinical outcome, to evaluate its potential use as prognostic factor in breast cancer patients.

Methods: We evaluated by immunohistochemistry COL11A1 expression and we studied the relationship between this protein expression and traditional breast cancer prognostic factors, FGD3 expression, as well as with patients’ outcome.

Results: We found that higher stromal COL11A1 expression was associated with higher tumour grade (G3) (p = 0.001), higher Ki67 proliferation index (p = 0.006), more advanced AJCC stage (p = 0.031) and lower FGD3 expression (p = 0.039). In a case-control analysis, we observed that patients with high-COL11A1 had a higher risk of recurrence (OR = 2.0) and of dying of the disease (OR = 2.0). Patients with high-COL11A1-expressing tumours had shorter disease-free survival and overall survival (difference not significant). There was a linear positive correlation between COL11A1 expression on epithelial tumoral cells and surrounding stromal cells (r = 0.247, p = 0.04).

Conclusion: Our findings suggest that COL11A1 may represent a marker of aggressiveness in invasive breast cancer and that its detection warrants further study on larger series to evaluate its possible use in clinical practice.

Puschel K, Paz S, Fowler M, Vescovic Z, Fuentes I, Sanchez C, and Acevedo F

Abstract

Background: Breast cancer is the leading cause of death from cancer among women in Latin America. Most Latin American countries started national mammogram screening programs a decade ago. The implementation level and effects of screening programs in Latin America have not been evaluated.

Aim: To evaluate the association between screening programs implementation and breast cancer mortality in selected North American and European countries compared to a group of Latin American countries with national screening programs.

Methods: The study applied an ecological design with secondary data from official national and international sources. Join point regression analysis was conducted to describe the trends in mortality rates in a group of five Latin American countries (Brazil, Chile, Colombia, Costa Rica and Mexico) with five Non-Latin American countries (Canada, Spain, Sweden, United Kingdom and the United States of America). The association between screening and mortality rates was explored using correlation and linear regression. National cancer plans were assessed to describe screening strategies among selected countries.

Results: A significant reduction in standardized breast cancer mortality rates was observed in all Non-Latin American countries with an Average Annual Percent Change (AAPC) of -2.00 (p<.05, 95%CI [-3.33, -0.70]) for the period 2010-2020. In contrast, Latin American countries reported a significant increase in the AAPC of +1.38 (p<.05, 95%CI [0.86,1.76]) in breast cancer mortality rates for the period 2010-2020. For Latin American countries, with screening rates below 50%, there was no correlation between screening and mortality rates for the period 1985-2020 (r = -0.17, p = .78). For non-Latin American countries, with screening rates over 70%, the linear regression model explained significantly 55% of the variance in mortality rates (R2aj =.55, F (5,14) = 5.69, p = .005), with a negative and significant effect of mammogram screening on mortality rates (β = -0.14, p = .01). The National Plans analysis revealed an opportunistic screening model for Latin American countries and an organized-systematic model in Non-Latin American countries.

Conclusion: There is an association between the level of implementation of screening programs and mortality rates from breast cancer. Latin American countries should transform their opportunistic strategy into an organized-systematic model.

Donfeng Wu and Seongho Kim

Abstract

Aims: Accurate estimation of the three key parameters (sensitivity, time duration in disease-free state and sojourn time in preclinical state) in cancer screening are critical. Likelihood method with a new link function was applied to the Health Insurance Plan of Greater New York (HIP) breast cancer screening data, to estimate the onset age of preclinical state and the sojourn time in the preclinical state for breast cancer.

Materials and Methods: A new link function to model sensitivity as a function of time in the preclinical state and the sojourn time was adopted. Markov Chain Monte Carlo simulations were used to obtain posterior samples and make inference on the three key parameters. Maximum likelihood estimate was also used for comparison.

Results: The onset age of the preclinical state has a wide range for breast cancer; the peak onset age was 65.07 years (95% credible interval [C.I.], 55.76 to 73.02). The mean sojourn time was 2.00 years (95% C.I., 0.85 to 2.95). The 95 % C.I. for the sojourn time was 0.16 to 5.53 years. Sensitivity at onset of the preclinical state was 0.75 (95% C.I., 0.54 to 0.88); and sensitivity at the end of the preclinical state was 0.84 (95% C.I., 0.67 to 0.88).   

Conclusion: The HIP study was the oldest breast cancer mass screening. The estimates reflect key parameters in those days with lower screening sensitivity. However, it is helpful to know other parameters in the planning for future breast cancer screening.

Nayla Robledo, MD, Maria Jose Chico, MD, Maria Paz Swiecicki, MD, Maria Contos, MD, Karina Alejandra Pesce, MD, PhD, and Pamela Causa Andrieu, MD

Abstract

We present and discuss a case report of a 70-year-old patient with a primary carcinoma in accessory breast tissue in the anterior chest wall.

Accessory breast tissue has a reported incidence of 0.3% to 6% in the general population, resulting from an incomplete involution of the mammary milk line. It usually presents as a palpable mass. The most frequent localization of accessory breast tissue and its possible pathologies is the armpit, although it can occur in the inframammary region and rarely on thighs, perineum, groin, or vulva.

The diagnosis is mainly clinical, but imaging findings may be helpful to confirm the suspicion because they are similar to breast cancer within the breast. Ultrasound is the most useful radiological method to evaluate these lesions and guide the suspected diagnosis together with the clinical presentation.

Treatment should be performed under the same principles as breast cancer, both surgical and systemic therapies. The prognosis of accessory breast carcinoma may be poor in cases with delayed diagnosis compared to native breast cancer.

Gargi Sharma, DNB, Tejinder Kataria, MD, DNB, Deepak Gupta, MD, Venkatesan Kaliyaperumal, PHD, Shyam Singh Bisht, MD, and Sorun Shishak, MD

Abstract

Introduction: There has been a trend towards de-escalation in the management of axilla over the last two decades in the form of shift from axillary lymph node dissection to sentinel lymph node dissection in early stage breast cancer. This de-escalation has main advantage in terms of reducing the incidence of lymphedema without compromising the local control. However, when it comes to axillary radiation, there is lack of consensus regarding its use . In this context we reviewed our prospectively maintained data base for axillary recurrences, without radiation to axilla in axillary node positive patient cohort.

Materials and methods: The data of breast cancer patients treated at Medanta, Cancer Institute from 2010 till 2020 was analyzed by querying the electronic health records. Minimum follow up was 2 years after completion of radiation treatment. During follow up, patients were assessed clinically and underwent yearly mammogram, bi-annual ultrasound abdomen and annual chest X-Ray. In case of clinically palpable or suspicious lymph nodes in axilla, a histopathological confirmation was required. The axilla was not irradiated intentionally except in very few cases where the decision was individualized as per surgical and pathological findings after discussion in the tumour board meeting.

Results: Of the 2400 breast cancer patients treated from 2010-2020, final analysis included 1422 patients as per the inclusion criteria. Pathological node positive cases were 827(58.15%). Of which 446/827(53.9%) had N1, 283/827(34.2%) were N2 and 98/827(11.8%) were with N3 disease status. 69.19% patients had undergone axillary dissection. A total of 35 patients received axillary radiation, 7 of them had early stage disease, underwent sentinel lymph node biopsy and were treated before 2013, and rest of them had advanced local disease, post axillary dissection with high axillary burden and presence of high risk features. None (0%) of the patients developed ipsilateral axillary relapse.

Conclusion: The results of this study are a step further in the de-escalation of axillary management in terms of radiation, and provide robust data in support of omitting the axillary radiation for breast cancer patients even when sentinel node biopsy shows (1-2) positive nodes for early stage breast disease and in locally advanced breast disease when adequate axillary dissection (even with heavy axillary node burden) has been performed.

Haim Werner, PhD

Abstract

The insulin-like growth factor-1 hormonal axis has emerged in recent years as a promising therapeutic target in oncology. Empirical support to this view was provided by pre-clinical studies showing that insulin-like growth factor-1 receptor expression and activation constitute fundamental prerequisites for breast cancer development. Unfortunately, the vast majority of phase III clinical trials using monoclonal antibodies against the receptor have been disappointing. As a result of these negative outcomes there is an urgent need to identify predictive biomarkers that may identify potential responders. The present review article is aimed at providing an overview of the role of the insulin-like growth factor-1 axis in breast cancer. Circulating insulin-like growth factor-1 constitutes a risk factor for a number of malignancies, including breast cancer, and various members of the insulin-like growth factor-1 system are produced by the tumoral cells or by stromal cells. In addition, we provide evidence that the mechanism of action of insulin-like growth factor-1 involves interactions with the estrogen receptor as well as with the breast cancer gene-1. Finally, lifestyle factors that are related to insulin-like growth factor-1, such as obesity, have been suggested to have an effect on breast cancer.

Soumya Sonalika, Sushree Sangita Mishra, Subhashree Mahapatro, and Devasmita Sahoo

Abstract

Introduction: Breast cancer is a global health concern, accounting for significant morbidity and mortality among women. The fragile ill prepared healthcare systems in low- & middle-income countries need to address these challenges find solutions with their limited resources.

Objectives: Through a critical examination of the literature, this article aims to contribute to a better understanding of breast cancer and to stimulate further research in this field.

Methods & Analysis: This review article provides an in-depth analysis of the current state of breast cancer research, focusing on advancements in diagnosis, treatment, and prevention, as well as the challenges and future directions.

Conclusion: Emerging technologies, such as AI, 3D bioprinting, and nanotechnology, hold promise for addressing the challenges like management of metastatic disease, global disparities in outcomes, and the need for a better understanding of breast cancer etiology and revolutionizing breast cancer care.

Omobolaji O. Ayandipo, Anuoluwapo O. Ajao, Naomi A. Olagunju, Oluwasanmi A. Ajagbe, Adegbolahan J. Fakoya, and Gbolahan Obajimi

Abstract

Background: Breast cancer subtypes are often used as therapeutic and prognostic measures; however, it is unclear whether there is an association between molecular subtypes and site-specific metastasis. Our study aimed to evaluate the relationship between molecular subtypes and developing metastasis in specific sites.

Methods: We selected 118 breast cancer patients with immunohistochemistry confirmed molecular subtype diagnosed in 2020 and 2021 at the Department of Surgery, University College Hospital, Ibadan. We classified the molecular subtypes into four categories, HR+/HER2-, HR-/HER2+, HR+/HER2+, and triple negative (HR-/HER2-). The different sites of metastasis of interest were lungs, liver, brain, and bone. We used the chi-square test to determine the proportions and significance of the subtypes based on the different sites assessed.

Results: According to our study, 45.50%, 18.20%, and 36.40% of patients presented with lungs, liver, and other (multiple organs and contralateral breast) metastasis respectively. Additionally, HR+/HER2- and TNBC patients developed metastasis at a higher rate and account for a combined 90.10% of all metastases (the site-specific distribution was even between both subtypes).

Conclusion: Overall, while there are limitations in our study based on sample size, our data shows that some molecular subtypes are associated with a higher risk of metastasis. Additionally, while not significant in our study, breast cancer subtypes are associated with different metastatic sites.

Masami Okamoto

Abstract

Metastasis is one of the greatest challenges in cancer treatment today. Normal mammary epithelial cells are optimally supported by interaction with a soft matrix (microenvironment) with elastic modulus of about 800 Pa. However, after transformation, breast tissue becomes progressively stiffer and tumour cells become significantly more contractile and hyper-responsive to matrix elasticity. In addition, importantly, the cancer cells penetrate into blood vessel and enter the circulation during metastasis. The modulus of fluid such as blood or mucus has very low stiffness of around 50 Pa. For this reason, the critical association between cancer cell phenotype and the change of matrix rigidity with an order of magnitude smaller should be emphasizing. This review highlights the current understanding of epithelial-mesenchymal transition and cancer stem cells in metastasis, and identified importance for investigation on artificial extracellular matrix with different viscoelastic properties, which is required to mimics in vivo microenvironment. The substrate damping coefficient (tand) as potential physical parameter emerged the important linkage to cellular motility, cancer stemness, and epithelial-mesenchymal transition induction. Although further investigation is required to clarify the efficacy of environmental stimuli (tand) for tumors exhibiting stem cell-like properties, this review indicates that the cancer cells incubated on softer substrate might lead to express cancer stem cell biomarkers exhibiting high expression.

Casimir Adjoe

Abstract

For most rural dwellers, breast cancer is a death sentence. While the concern and discourses of health practitioners and professionals, researchers and analysts may focus on medical attention and the creation of awareness, defined as a deliverance from ‘ignorance’, the personal experience of victims of breast cancer and the members of the community in which they are embedded have a different take. Their focus is more on the origins of the illness and its management in waiting for the ultimate inevitable fate. The paper uses the approach of personal experience and Guttenplan’s categories of consciousness/experiencing, attitude/attitudinizing, and act/action/activity to undertake a somewhat longitudinal examination to investigate the anatomy of the decision-making processes involved in such incidents –  socio-cultural and socio-economic -involving personal and family perspectives, facts/experiencing, beliefs, critical decision-making processes and conclusions attendant with the course of management of the disease through a case study. It concludes that the outlook as currently enacted on what creates and causes delayed medical attention may need to be more critically reviewed. It recommends that the acceptance of seeking medical attention for perceived ‘death sentence’ diseases such as breast cancer should first tackle the certainty of ‘cure’ and the solidarity with victims to ‘fight’ and ‘defeat’ the disease rather than on awareness creation based on unexamined and unsupported assumptions of ‘ignorance’ of victims and their communities that make the efforts to tackle the breast cancer menace in Africa not as effective as they could be.

Heloisa Resende, Vinícius Q Aguiar, Luiz F P Jacob, Angélica L C A Renó, Ana P Cunha, Biazi Ricieri Assis Viviane L Pereira, Leticia B Tureta, Layza V Eler, Matheus H Oliveira, Matheus R Montenegro, Lucas R Pereira, Felipe S Teixeira, and Igor C Soares

Abstract

Breast cancer is the most common female neoplasm in Brazil accounting for 73.610 new cases a year. The organization of public health system is a critical point to provide diagnosis and treatment for these patients, considering that 75% of the population is covered by public health system (Sistema Único de Saúde, SUS). Waiting time for diagnosis procedures and treatment has been used to evaluate accessibility to the health system and can guide governmental strategies to improve them. A retrospective study was conducted by assessing medical records of all patients registered at a High Complexity Oncology Assistance Unit (Unidade de Alta Complexidade em Oncologia, UNACON). The patients registered in the period from October 2021 to September 2022 were included.  The medical report was used to collect epidemiological, clinicopathologic data, and main waiting times for diagnosis procedures and treatment. There were registered 143 patients, mean age was 57.6 years (SD±12,6). Symptoms detected cancer was the majority with 112 patients (86,8%). Median waiting times:  1-from breast abnormalities self-perception to first image exam was 60 days; 2-waiting time from the exam to core biopsy was 41,5 days; 3-waiting time from the biopsy to report liberation of biopsy was 11.0 days; 4-waiting time from biopsy report to first visit at oncologic care unit was 31.0 days; 4-waiting time from the oncologic care unit first visit to first treatment was 55.0 days; 5-waiting time from the breast biopsy to treatment beginning was 97.0 days. Our study demonstrates long waiting time from diagnosis to first treatment (above 60 days as established by Brazilian law) and long waiting time spending with each step of journey from the breast abnormalities self-detected to treatment beginning. Integration among basic, secondary and high complexity units, and clear strategies to guide patients with self-detected symptoms are points to be target.