1,945 results
The Great Immune Escape: Understanding the Divergent Immune Response in Breast Cancer Subtypes.
Cancer Discov. 2023 Jan 9;13(1):23-40. doi: 10.1158/2159-8290.CD-22-0475.
PMID: 36620880
Free PMC article.
Review.Abstract
Breast cancer, the most common type of cancer affecting women, encompasses a collection of histologic (mainly ductal
and lobular) and molecular subtypes exhibiting diverse clinical
presentation, disease trajectories, treatment options, and outcomes.
Immunotherapy has revolutionized treatment for some solid tumors but has shown limited promise for breast cancers. In this review, we summarize recent advances in our understanding of the complex interactions between tumor and immune cells in subtypes of breast cancer at the cellular and microenvironmental levels. We aim to provide a perspective on opportunities for future immunotherapy agents tailored to specific features of each subtype of breast cancer. Significance: Although there are currently over 200 ongoing clinical trials testing immunotherapeutics, such as immune-checkpoint blockade agents, these are largely restricted to the triple-negative and HER2+ subtypes and primarily focus on T cells. With the rapid expansion of new in vitro, in vivo, and clinical data, it is critical to identify and highlight the challenges and opportunities unique for each breast cancer subtype to drive the next generation of treatments that harness the immune system.
Immunotherapy has revolutionized treatment for some solid tumors but has shown limited promise for breast cancers. In this review, we summarize recent advances in our understanding of the complex interactions between tumor and immune cells in subtypes of breast cancer at the cellular and microenvironmental levels. We aim to provide a perspective on opportunities for future immunotherapy agents tailored to specific features of each subtype of breast cancer. Significance: Although there are currently over 200 ongoing clinical trials testing immunotherapeutics, such as immune-checkpoint blockade agents, these are largely restricted to the triple-negative and HER2+ subtypes and primarily focus on T cells. With the rapid expansion of new in vitro, in vivo, and clinical data, it is critical to identify and highlight the challenges and opportunities unique for each breast cancer subtype to drive the next generation of treatments that harness the immune system.
- PMCID: PMC9833841
- DOI: 10.1158/2159-8290.CD-22-0475
©2022 American Association for Cancer Research.
Fibrosis and cancer: A strained relationship.
Biochim Biophys Acta Rev Cancer. 2020 Apr;1873(2):188356. doi: 10.1016/j.bbcan.2020.188356. Epub 2020 Mar 5.
PMID: 32147542
Free PMC article.
Review.
Abstract
Tumors are characterized by extracellular matrix (ECM) deposition,
remodeling, and cross-linking that drive fibrosis to stiffen the stroma
and promote malignancy. The stiffened stroma enhances tumor cell
growth, survival and migration and drives a mesenchymal transition. A
stiff ECM also induces angiogenesis, hypoxia and compromises anti-tumor
immunity. Not surprisingly, tumor aggression and poor patient prognosis
correlate with degree of tissue fibrosis and level of stromal stiffness.
In this review, we discuss the reciprocal interplay between tumor
cells, cancer associated fibroblasts (CAF), immune cells and ECM
stiffness in malignant transformation and cancer aggression. We discuss
CAF heterogeneity and describe its impact on tumor development and
aggression focusing on the role of CAFs in engineering the fibrotic
tumor stroma and tuning tumor cell tension and modulating the immune
response. To illustrate the role of mechanoreciprocity in tumor
evolution we summarize data from breast cancer and pancreatic ductal
carcinoma (PDAC) studies, and finish by discussing emerging
anti-fibrotic strategies aimed at treating cancer. Keywords:
CAF; Cancer; ECM; Fibrosis; Mechanoreciprocity.
Mammary gland development.
Wiley Interdiscip Rev Dev Biol. 2012 Jul-Aug;1(4):533-57. doi: 10.1002/wdev.35.
PMID: 22844349
Free PMC article.
Review.
Abstract
The mammary gland develops through several distinct stages. The
first transpires in the embryo as the ectoderm forms a mammary line that
resolves into placodes. Regulated by epithelial–mesenchymal
interactions, the placodes descend into the underlying mesenchyme and
produce the rudimentary ductal structure of the gland present at birth.
Subsequent stages of development—pubertal growth, pregnancy, lactation,
and involution—occur postnatally under the regulation of hormones.
Puberty initiates branching morphogenesis, which requires growth hormone
(GH) and estrogen, as well as insulin-like growth factor 1 (IGF1), to
create a ductal tree that fills the fat pad. Upon pregnancy, the
combined actions of progesterone and prolactin generate alveoli, which
secrete milk during lactation. Lack of demand for milk at weaning
initiates the process of involution whereby the gland is remodeled back
to its prepregnancy state. These processes require numerous signaling
pathways that have distinct regulatory functions at different stages of
gland development. Signaling pathways also regulate a specialized
subpopulation of mammary stem cells that fuel the dramatic changes in
the gland occurring with each pregnancy. Our knowledge of mammary gland
development and mammary stem cell biology has significantly contributed
to our understanding of breast cancer and has advanced the discovery of
therapies to treat this disease.
Nipple-sparing and skin-sparing mastectomy: Review of aims, oncological safety and contraindications.
Breast. 2017 Aug;34 Suppl 1(Suppl 1):S82-S84. doi: 10.1016/j.breast.2017.06.034. Epub 2017 Jun 30.
PMID: 28673535
Free PMC article.
Review.
Abstract
Skin-sparing (SSM) and nipple-sparing (NSM) mastectomies are
relatively new conservative surgical approaches to breast cancer. In SSM
most of the breast skin is conserved to create a pocket that
facilitates immediate breast reconstruction with implant or autologous
graft to achieve a quality cosmetic outcome. NSM is closely similar
except that the nipple-areola complex (NAC) is also conserved.
Meta-analyses indicate that outcomes for SSM and NSM do not differ from
those for non-conservative mastectomies. Recurrence rates in the NAC
after NSM are acceptably low (0-3.7%). Other studies indicate that NSM
is associated with high patient satisfaction and good psychological
adjustment. Indications are carcinoma or DCIS that require mastectomy
(including after neoadjuvant chemotherapy). NSM is also suitable for
women undergoing risk-reducing bilateral mastectomy. Tumor not less than
2 cm from the NAC is recommended, but may be less important than no
evidence of nipple involvement on mandatory intraoperative nipple margin
assessment. A positive margin is an absolute contraindication for
nipple preservation. Other contraindications are microcalcifications
close to the subareolar region and a positive nipple discharge.
Complication rates are similar to those for other types of
post-mastectomy reconstructions. The main complication of NSM is NAC
necrosis, however as surgeon experience matures, frequency declines.
Factors associated with complications are voluminous breast, ptosis,
smoking, obesity, and radiotherapy. Since the access incision is small,
breast tissue may be left behind, so only experienced breast surgeons
should do these operations in close collaboration with the plastic
surgeon. For breast cancer patients requiring mastectomy, NSM should be
the option of choice.
Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.
Lancet. 2014 Jul 12;384(9938):164-72. doi: 10.1016/S0140-6736(13)62422-8. Epub 2014 Feb 14.
PMID: 24529560
Review.
METHODS Abstract Background:
Pathological complete response has been proposed as a surrogate
endpoint for prediction of long-term clinical benefit, such as
disease-free survival, event-free survival (EFS), and overall survival
(OS). We had four key objectives: to establish the association between
pathological complete response and EFS and OS, to establish the
definition of pathological complete response that correlates best with
long-term outcome, to identify the breast cancer subtypes in which
pathological complete response is best correlated with long-term
outcome, and to assess whether an increase in frequency of pathological
complete response between treatment groups predicts improved EFS and OS.Methods:
We searched PubMed, Embase, and Medline for clinical trials of
neoadjuvant treatment of breast cancer. To be eligible, studies had to
meet three inclusion criteria: include at least 200 patients with
primary breast cancer treated with preoperative chemotherapy followed by
surgery; have available data for pathological complete response, EFS,
and OS; and have a median follow-up of at least 3 years. We compared the
three most commonly used definitions of pathological complete
response--ypT0 ypN0, ypT0/is ypN0, and ypT0/is--for their association
with EFS and OS in a responder analysis. We assessed the association
between pathological complete response and EFS and OS in various
subgroups. Finally, we did a trial-level analysis to assess whether
pathological complete response could be used as a surrogate endpoint for
EFS or OS.Findings:
We obtained data from 12 identified international trials and 11
955 patients were included in our responder analysis. Eradication of
tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was
better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44,
95% CI 0·39-0·51; ypT0/is ypN0: 0·48, 0·43-0·54) and OS (0·36,
0·30-0·44; 0·36, 0·31-0·42) than was tumour eradication from the breast
alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55-0·66; OS 0·51, 0·45-0·58). We
used the ypT0/is ypN0 definition for all subsequent analyses. The
association between pathological complete response and long-term
outcomes was strongest in patients with triple-negative breast cancer
(EFS: HR 0·24, 95% CI 0·18-0·33; OS: 0·16, 0·11-0·25) and in those with
HER2-positive, hormone-receptor-negative tumours who received
trastuzumab (EFS: 0·15, 0·09-0·27; OS: 0·08, 0·03, 0·22). In the
trial-level analysis, we recorded little association between increases
in frequency of pathological complete response and EFS (R(2)=0·03, 95%
CI 0·00-0·25) and OS (R(2)=0·24, 0·00-0·70).Interpretation:
Patients who attain pathological complete response defined as ypT0
ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is
greatest in aggressive tumour subtypes. Our pooled analysis could not
validate pathological complete response as a surrogate endpoint for
improved EFS and OS.
Breast brachytherapy.
Brachytherapy. 2021 Sep-Oct;20(5):976-983. doi: 10.1016/j.brachy.2020.10.011. Epub 2021 Jan 19.
PMID: 33353845
Review.
Abstract
Accelerated partial breast irradiation with brachytherapy is a
treatment method with a very low risk profile. In fact, accelerated
partial breast irradiation brachytherapy has been proven in randomized
trials to have fewer late side effects than whole-breast irradiation.
Notably, Grade 3 late side effects are extremely rare, and excellent to
good cosmetic results are observed in well over 90% of patients. In this
article, published side effects of breast brachytherapy are reviewed
and appropriate management discussed.
Tailoring therapies--improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015.
Ann Oncol. 2015 Aug;26(8):1533-46. doi: 10.1093/annonc/mdv221. Epub 2015 May 4.
PMID: 25939896
Free PMC article.Abstract
The 14th St Gallen International Breast Cancer Conference (2015)
reviewed substantial new evidence on locoregional and systemic therapies
for early breast cancer. Further experience has supported the adequacy
of tumor margins defined as 'no ink on invasive tumor or DCIS' and the
safety of omitting axillary dissection in specific cohorts. Radiotherapy
trials support irradiation of regional nodes in node-positive disease.
Considering subdivisions within luminal disease, the Panel was more
concerned with indications for the use of specific therapies, rather
than surrogate identification of intrinsic subtypes as measured by
multiparameter molecular tests. For the treatment of HER2-positive
disease in patients with node-negative cancers up to 1 cm, the Panel
endorsed a simplified regimen comprising paclitaxel and trastuzumab
without anthracycline as adjuvant therapy. For premenopausal patients
with endocrine responsive disease, the Panel endorsed the role of
ovarian function suppression with either tamoxifen or exemestane for
patients at higher risk. The Panel noted the value of an LHRH agonist
given during chemotherapy for premenopausal women with ER-negative
disease in protecting against premature ovarian failure and preserving
fertility. The Panel noted increasing evidence for the prognostic value
of commonly used multiparameter molecular markers, some of which also
carried prognostic information for late relapse. The Panel noted that
the results of such tests, where available, were frequently used to
assist decisions about the inclusion of cytotoxic chemotherapy in the
treatment of patients with luminal disease, but noted that threshold
values had not been established for this purpose for any of these tests.
Multiparameter molecular assays are expensive and therefore unavailable
in much of the world. The majority of new breast cancer cases and
breast cancer deaths now occur in less developed regions of the world.
In these areas, less expensive pathology tests may provide valuable
information. The Panel recommendations on treatment are not intended to
apply to all patients, but rather to establish norms appropriate for the
majority. Again, economic considerations may require that less
expensive and only marginally less effective therapies may be necessary
in less resourced areas. Panel recommendations do not imply unanimous
agreement among Panel members. Indeed, very few of the 200 questions
received 100% agreement from the Panel. In the text below, wording is
intended to convey the strength of Panel support for each
recommendation, while details of Panel voting on each question are
available in supplementary Appendix S2, available at Annals of Oncology
online.
How to Navigate the Treatment Spectrum from Multimodality Therapy to Observation Alone for ductal carcinoma in situ.DCIS
Surg Oncol Clin N Am. 2023 Oct;32(4):663-673. doi: 10.1016/j.soc.2023.05.011. Epub 2023 Jun 15.
PMID: 37714635
Review.
Current guidance concordant care recommends surgical
intervention for all patients with DCIS, followed by radiation and/or
endocrine therapy for some. Adjuvant therapies after surgical excision have reduced recurrence rates but not breast cancer mortality. .. …Abstract
DCIS detection has increased dramatically since the introduction
of screening mammography. Current guidance concordant care recommends
surgical intervention for all patients with DCIS, followed by radiation
and/or endocrine therapy for some. Adjuvant therapies after surgical
excision have reduced recurrence rates but not breast cancer mortality.
Given the lack of evidence of current treatment regimens and the
morbidity associated with these treatments, there is concern that DCIS
is over-treated. Active surveillance may be a favorable alternative for
selected patients and is currently being investigated through four
international clinical trials.
Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011.
Ann Oncol. 2011 Aug;22(8):1736-47. doi: 10.1093/annonc/mdr304. Epub 2011 Jun 27.
PMID: 21709140
Free PMC article.
Abstract
The 12th St Gallen International Breast Cancer Conference (2011)
Expert Panel adopted a new approach to the classification of patients
for therapeutic purposes based on the recognition of intrinsic
biological subtypes within the breast cancer spectrum. For practical
purposes, these subtypes may be approximated using clinicopathological
rather than gene expression array criteria. In general, systemic therapy
recommendations follow the subtype classification. Thus, 'Luminal A'
disease generally requires only endocrine therapy, which also forms part
of the treatment of the 'Luminal B' subtype. Chemotherapy is considered
indicated for most patients with 'Luminal B', 'Human Epidermal growth
factor Receptor 2 (HER2) positive', and 'Triple negative (ductal)'
disease, with the addition of trastuzumab in 'HER2 positive' disease.
Progress was also noted in defining better tolerated local therapies in
selected cases without loss of efficacy, such as accelerated radiation
therapy and the omission of axillary dissection under defined
circumstances. Broad treatment recommendations are presented,
recognizing that detailed treatment decisions need to consider disease
extent, host factors, patient preferences, and social and economic
constraints.
Precision surgery and avoiding over-treatment.
Eur J Surg Oncol. 2017 May;43(5):938-943. doi: 10.1016/j.ejso.2017.02.003. Epub 2017 Feb 11.
PMID: 28238520
Review.
Abstract
Over-diagnosis and over-treatment are consequences of greater
awareness about breast cancer, more intensive screening, and the
resultant identification of more cases of breast cancer that are low or
ultralow risk. This area represents an important opportunity to optimize
the delivery of appropriate targeted therapy for breast cancer
patients. Despite the evolution of breast cancer care over the last few
decades and our ability to tailor treatment to biology, a one-size fits
all approach is still prevalent in the local and regional management of
and screening for breast cancer, failing to reflect the unique biology
and tumor characteristics of each patient. In this review, we explore
how we can use new tools to better define tumor biology and also how we
can change current clinical practices based on already available data.
Every surgeon should be knowledgeable about how to craft personalized
breast cancer care in the areas of systemic therapy, adjuvant radiation
therapy, management of ductal carcinoma in situ (DCIS), precision
surgery, and breast cancer screening.
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