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Invasive Lobular Carcinoma: Biology, Treatment, and Future Directions for Research
1. Rachel C. Jankowitz, MD
Associate Professor of Medicine
Perelman School of Medicine
Department of Medicine
Division of Hematology-Oncology
11/13/2019
Invasive Lobular Carcinoma: Biology,
Treatment, and Future Directions for
Research
3. ILC • Discohesive growth pattern:
single-file infiltration of tumor
cells through breast tissue due
to hallmark molecular loss of E-
cadherin (cell-cell adhesion)
• More occult on mammography;
can be diagnosed at later
stages
• Increased multifocality and
bilaterality
• Unusual pattern of metastatic
spread: GI tract, ovaries, orbit
David Dabbs, Pathologist, Magee
Womens Hospital, “Breast Pathology”
Elsevier, 2012
4. - ILC would rank as
6th most common
cancer in women
(30,000 cases/ year)
ILC Incidence
- ILC represents “only” 5-15% of all breast cancer
- Understudied as a breast cancer subtype
5. ILC Incidence
Li CI, Anderson BO, Daling JR, Moe RE. Trends in Incidence Rates of Invasive Lobular and Ductal Breast Carcinoma. JAMA.
2003;289(11):1421–1424. doi:10.1001/jama.289.11.1421
Proportional Increase in ILC vs. IDC
6. n=127
n=490
Molecular Portrait of ILC
CDH1 (E-cadherin) loss:
Mutation, LOH, or protein down-regulation in >95% of
ILC
ER+/LumA:
ILC: 94% ER-positive
83% Luminal A
IDC: 66% ER-positive
41% Luminal A
-Alterations in PI3K pathway
-Amplifications in ESR1, ERBB2 and MDM4
-Increased rates of HER2/HER3 mutations in ILC
-FGFR4 overexpression in metastatic ER+ and
enriched in ILC
Ciriello et al, (TCGA), Cell 2015
Cao at al, Cancer Letters, 2019
Levine et al. npj, 2019
7. ILC Characteristics
1) Arpino et al BCR 2004 (IDC : 45,169; ILC: 4,140) (Retrospective population –based analysis)
2) Pestalozzi BC, J Clin Oncol 2008; 26: 3006–3014 (IDC: 8,607; ILC: 767) (International Breast Cancer Study Group Trial,
IBCSG)
Factor p
Age (older) 0.02
Nodal status n.s.
Grade (lower) <0.01
ER (+) <0.01
Size (larger) <0.01
Vessel invasion <0.01
Menopausal status n.s.
Adjuvant therapy n.s.
Local treatment
(mastectomies)
<0.01
Better prognostic markers?
8. Outcome in ILC Might be Time-dependent
- Limited data on outcome differences between IDC and ILC
Pestalozzi et al, JCO, 2008
-Increased risk of late recurrence and inferior long-term outcomes for
patients ILC versus IDC
6 yr conversion point
16% lower risk
for DFS
54% higher risk
for DFS
767
8,607
OS
9. Metzger et al., SABCS 2012.
Differential Response to Endocrine
Therapy in Patients with ILC
10. Preclinical Studies in Oesterreich lab
(UPitt/UPMC)
MCF-7 (IDC)
- MM-134 ILC cells are partially resistant 4-hydroxytamoxifen, and in absence of estrogen ligand, tam is a
partial agonist
Sikora MJ, Cooper KL, Bahreini A, Luthra S, Wang G, Chandran UR, Davidson NE, Dabbs DJ, Welm AL, Oesterreich S. Invasive lobular carcinoma cell lines are
characterized by unique estrogen-mediated gene expression patterns and altered tamoxifen response. Cancer Res. 2014 Mar 1; 74(5):1463-74. PMID: 24425047.
MDA-MB-134 (ILC)
11. Treatment for Invasive Lobular
Carcinoma (ILC)
Currently: no ILC-specific treatment
recommendations
Emphasizes importance of research and
clinical trials for patients with ILC
12. Ongoing Studies
Pre-operative Trials for Newly Diagnosed
Patients
» TBCRC 037: ILC-specific
» PELOPS: Enriched for ILC
Trial for Patients with Metastatic ILC
» ROLO
» GELATO
13. A Neoadjuvant Window Trial of Endocrine
Response in Women with Invasive
Lobular Carcinoma; TBCRC 037
Funding: Komen Career Catalyst Research Grant , AstraZeneca
14. First prospective study specific to lobular cancer. A collaborative
effort across institutions to study an uncommon breast cancer subtype.
All 3 study medications are common breast cancer treatments. The
trial aims to study mechanisms of response and resistance specifically in
ILC tumors.
Tumor sequencing & pathology studies before & after medications will
be critical to inform future treatment of patients with ILC.
TBCRC 037
15. TBCRC
037: Trial
Enrollment
By Site- A
True Team
Effort!!
Site Enrolled Activation Date
Pittsburgh 24 8/24/15
MD Anderson 7 11/1/16
Mayo 13 12/9/16
Washington 11 1/27/17
UAB 10 4/4/17
Montefiore 2 7/7/19
UNC 10 12/6/17
UCSF 10 8/3/18
U Chicago 2 2/21/19
Baylor 3 3/15/19
UPenn 0 pending
Total 92
16.
17. • Window Phase: To evaluate the difference in anti-
proliferative activity of letrozole versus tamoxifen
in patients with ILC and IDC, calculated by the
fold-change in percent of Ki67 from baseline and
Day 15 research biopsy samples.
• Treatment Phase: To evaluate the pathologic
complete response (pCR) of endocrine therapy
plus palbociclib and of endocrine therapy alone in
breast cancer patients diagnosed with HR-
positive breast cancer.
PELOPS AIMS
18. Phase II study of Crizotinib in
E-cadherin negative lobular breast
and diffuse gastric cancers
Version 1.2 13/02/2019
19. BACKGROUND
Pre-clinical data: E-cadherin
• E-cadherin is a cell adhesion molecule
• E-cadherin loss is the signature of lobular breast cancer and
diffuse gastric cancer
Bajrami et al., Cancer Discovery 2018
20. TRIAL DESIGN
A Single arm phase II study
Parallel recruitment to breast & gastric cohorts:
Previously treated
advanced lobular breast
cancer
(N=29)
Crizotinib 250mg bd + Fulvestrant
500mg IM
q 28 days (plus loading dose at
D15) until progression
Previously treated
advanced diffuse
gastric cancer
(N=29)
Crizotinib 250mg bd
until progression
21. AssessinG the Efficacy of carboplatin and ATEzolizumab in
metastatic Lobular breast cancer
NCT03147040
22. Immune related subtype ILC
Definition of IR-
subtype in TCGA data
IR-subtype has more
lymphocytic infiltration
Adapted from: TCGA Cell 2015 Michaut,..,Linn,.., Wessels,.., Bernards Sci. Rep. 2016
Strong effect platinum in
IR-subtype in vitro
23. Conclusions
• ILC: unique patient, pathologic, and molecular characteristics
• ILC incidence has risen disproportionately to IDC incidence
• Critical need to understand response/resistance mechanisms
to hormonal breast cancer therapies in ILC tumors, as
increased risk of late recurrence versus IDC
• Ongoing trials in early-stage and metastatic ILC will inform
biomarker identification and development of ILC-tailored
treatments in the future
24. Acknowledgements
Funding: Komen Career Catalyst Research
Grant, AstraZeneca
Lobular Breast Cancer Alliance (LBCA)
Steffi Oesterreich
Priscilla McAuliffe
Nancy Davidson
Brenda Kurland
Beth Clark
Ruth Modzelewski
Jennifer Xavier
CRS: Lucia Borasso, Rometa Pollard , Brenda
Lee Steele, Trisha Schneider
Participating study patients in TBCRC 037
o Mayo- Tina Hieken
o MDACC- Isabelle Bedrosian
o UAB- Erica Stringer-Reasor
o Washington- Hannah Linden
o Montefiore-Joseph Sparano
o UNC-Kristalyn Gallagher
o UCSF- Rita Mukhtar
o U Chicago-Jennifer Tseng
o Baylor- Julie Rani Nangia, Mothaffar
Rimawi, Alastair Thompson
o UPenn- Amy Clark, Angela DeMichele
Editor's Notes
1
Invasive lobular carcinoma is chronically understudied as a breast cancer subtype. Although it represents only 5-15% of all breast cancer, numerically, if it was an independent cancer in women, it would still be more common than non-hodgkin’s lymphoma or melanoma, and the incidence has shown to be rising
By contrast , rates of IDC increased only slightly during this same time period. Consequently this led to an increase in the proportion of invasive breast cancers with a lobular component from 9.5% in 1987 to 15.6% over this time period.
Invasive lobular breast cancer, or ILC, represents about 10% of all breast cancer. This slide shows a molecular analysis of ILC cells by the TCGA. It shows that ILC is characterized by loss of E-cadherin, which leads to loss of cell-cell adhesion. This contributes to the unusual growth and metastasis pattern of ILC. We know that the the majority of ILC tumors are strongly ER –positive, and thus patients should theoretically have good outcomes with hormonal therapies that target the estrogen receptor and tumor growth that is mediated by binding binding to the the estrogen receptor.
Pittsburgh: CNA study in ILC: frequent ESR1 CN gain or amplification associated with recurrence, frequent ERBB2 amplification (19%), and MDM4 amplification
This discrepancy could result
from tissue heterogeneity, but could also reflect low level amplifications
detected by sensitive Nanostring technologies that do not cause
high level overexpression. Such low-level gene amplifications might
reflect genomic instability, and might not be consequential with regard
to the biological consequence of overexpression of the gene that has
undergone CN changes. Here MDM4 amplification was
shown to be associated with endocrine resistance, while TP53 driver
mutations were predominantly early events during metastatic evolution
[42,43].
Our data suggests that MDM4 overexpression in wt TP53 primary
ILC tumors may reduce apoptosis, enhance progression through the cell
cycle and ultimately contribute to tumor proliferation, implicating it as
a novel therapeutic target. The development of small molecules that can
target the interaction of TP53 and MDM4 and induce a TP53-dependent
cell cycle arrest and/or apoptosis have previously been described [48];
however, it remains largely unclear whether blocking the binding of MDM proteins to TP53 compromises their TP53-independent functions.
While no such agents are currently in clinical development, small molecules
specifically targeting the function of MDM4 could potentially
hold promise for a subgroup of ILC patients in the future. Given the high
frequency of MDM4 CN alterations in ILC reported herein, it will be
important to determine the value of such targeted agents and their
potential combination with endocrine therapy for ILC patients with
MDM4 CNA.
In conclusion, our CNA study of 70 primary ILC specimens has revealed
clinically relevant gains and amplifications in ESR1, that are
associated with disease recurrence, frequent ERBB2 amplifications
often in the absence of clinical IHC scores, and frequent MDM4 amplifications.
Further, our functional studies suggest that MDM4 may
contribute to ILC progression through both TP53-dependent and independent
mechanisms. We believe our findings provide a molecular
foundation to further explore the development and progression of ILC,
ultimately providing vital insights that may lead to personalized
treatment for patients with this understudied subtype of breast cancer
Minimal data on response to endocrine therapy and outcome specific to ILC reported, but some studies suggest that the relative outcomes of ILC and IDC may be time dependent (significant early advantage in DFS and OS for ILC, followed by a significant late advantage for IDC after 6 and 10 years, respectively) (pestalozzi)
Additionally, we saw 2012 at the San Antonio Breast Cancer Symposium, Dr. Metzger presented data showing increased relative effectiveness of letrozole compared with tamoxifen for patients with ILC in comparison to IDC in an analysis of the BIG 1-98 trial. This data suggested that somehow patients with ILC were responding differently to these commonly used hormonal therapies than other patients with HR-positive breast cancer.
On the left, in MCF-7 invasive ductal carcinoma cells, estrogen increases growth (shown in the black line). You can see that tamoxifen and fulvestrant both compete with this growth
In the absence of estrogen ligand, tamoxifen does not cause any change, but fulvestrant decreases growth minimally below baseline
On the right is the ILC cell line, MDA-MB-134. Addition of estrogen increases cell growth similarly to the IDC cell line, shown in the black line. Addition of ICI or fulvestrant does appear to inhibit ILC growth in this model.
However, the addition of tamoxifen shows only partial inhibition of growth in these cells, illustrated by the green arrow the red line with the open squares- this line does not go to baseline.
Additionally, treatment with tamoxifen alone without estrogen ligand actually yields increased growth of cells, functioning as a partial agonist in this cell line
With that background, we developed a neoadjuvant window of opportunity trial for patients with newly diagnosed ILC.
Eligible patients will include postmenopausal women with a diagnosis of ILC measuring at least 1cm radiographically/clinically
After enrollment participants will undergo a research core biopsy for immunohistochemical analysis and correlative studies. They will then be randomized to a 21 day treatment period of tamoxifen, anastrozole, or fulvestrant. At the time of definitive surgery, a second core biopsy will be obtained from the surgical specimen for repeat immunohistochemical and correlative studies. Subjects receiving further neoadjuvant endocrine therapy would have to be agreeable to a second research core biopsy after the 21 day study window period. We want to determine the change from baseline to post-treatment Ki67 values in ILC tumor tissue after 21-27 days of preoperative treatment with commonly used breast cancer hormonal therapies.
Ki67 is the growth/proliferation rate of the tumor.
Ki67 reduction in the preoperative setting has been shown in many trials to be predictive of long-term patient outcome and risk of relapse.
Hypothesis: Ki67 will be reduced most in patients treated with fulvestrant, followed by those treated with anastrozole, and least in those treated with tamoxifen
Women who have been diagnosed with Stage 1 – 3 invasive lobular breast cancer (ILC) who have not yet had surgery to remove their tumor may be eligible to participate in a clinical trial. This trial is open to all ER+ and/or PR+ HER2- patients (ductal or lobular), however it is being enriched with lobular breast cancer patients to promote a better understanding of how ILC might respond differently to these therapies.
Name of the Trial: Palbociclib and Endocrine Therapy for Lobular Breast Cancer Preoperative Study (PELOPS).
Who might qualify? Patients with stage 1 – 3 estrogen and/or progesterone positive, HER2 negative breast cancer, with a minimum 1.5cm tumor, who have not yet had surgery to remove their tumor may qualify for the study. This study is open to both premenopausal and postmenopausal patients. Patients with Lobular Breast Cancer are being recruited specifically to form a key cohort for evaluation.
Where can patients enroll? As of August 2019, this trial is currently enrolling patients in Boston MA; Brewer ME, Stamford CT, Providence RI; Nashville TN, Houston, TX. Check the trial listing at Clinicaltrials.gov for updates and location contacts.
What happens in this study? This trial has two parts.
1) First, patients will be randomly assigned to one of four groups. Each group will receive a different commonly prescribed breast cancer endocrine therapy medications (Tamoxifen or Letrozole) for two weeks prior to their surgery. These medications are all proven to be effective therapies against breast cancer, and are typically given to patients at the end of their treatment for five years. Giving these medications before surgery will allow researchers to analyze the effect of each medication on the tumor to learn which medication might be most effective to treat lobular breast cancer.
2) Patients with estrogen positive breast cancer frequently receive endocrine therapy medications (such as Tamoxifen or Letrozole) for five years after completing their surgery and completing any other necessary treatments. In this study, patients will receive either standard endocrine therapy alone or endocrine therapy plus Palbociclib, a CDK 4/6 inhibitor drug that is currently used to treat some types of more advanced breast cancer.
How to learn more about whether participating in this clinical trial is right for you.
Read more about the trial at the ClinicalTrials.gov
Discuss this trial with your doctor. Questions to ask your doctor from the National Institutes of Health can help
Principle Investigator and Responsible Researcher:
Otto Metzger, MD, Dana-Farber Cancer Institute Boston, MA ometzger@partners.org 617 632-3352
Sponsors and Collaborators Dana-Farber Cancer Institute, Pfizer ClinicalTrials.gov identifier (NCT number): NCT02764541
The Lobular Breast Cancer Alliance shares information about ongoing clinical trials for patients with lobular breast cancer for educational purposes only. LBCA does not sponsor or run the clinical trials, and the scientific validity and safety of the trials is the responsibility of the trial investigators. Patients should always discuss their participation in any clinical trial directly with their doctor and learn more by contacting the clinical trial coordinators listed above directly. Learn more about participating in clinical trials.
Tags:
Advocacy, Clinical Trials, ILC Research
Women who have been diagnosed with Stage 1 – 3 invasive lobular breast cancer (ILC) who have not yet had surgery to remove their tumor may be eligible to participate in a clinical trial. This trial is open to all ER+ and/or PR+ HER2- patients (ductal or lobular), however it is being enriched with lobular breast cancer patients to promote a better understanding of how ILC might respond differently to these therapies.
Name of the Trial: Palbociclib and Endocrine Therapy for Lobular Breast Cancer Preoperative Study (PELOPS).
Who might qualify? Patients with stage 1 – 3 estrogen and/or progesterone positive, HER2 negative breast cancer, with a minimum 1.5cm tumor, who have not yet had surgery to remove their tumor may qualify for the study. This study is open to both premenopausal and postmenopausal patients. Patients with Lobular Breast Cancer are being recruited specifically to form a key cohort for evaluation.
Where can patients enroll? As of August 2019, this trial is currently enrolling patients in Boston MA; Brewer ME, Stamford CT, Providence RI; Nashville TN, Houston, TX. Check the trial listing at Clinicaltrials.gov for updates and location contacts.
What happens in this study? This trial has two parts.
1) First, patients will be randomly assigned to one of four groups. Each group will receive a different commonly prescribed breast cancer endocrine therapy medications (Tamoxifen or Letrozole) for two weeks prior to their surgery. These medications are all proven to be effective therapies against breast cancer, and are typically given to patients at the end of their treatment for five years. Giving these medications before surgery will allow researchers to analyze the effect of each medication on the tumor to learn which medication might be most effective to treat lobular breast cancer.
2) Patients with estrogen positive breast cancer frequently receive endocrine therapy medications (such as Tamoxifen or Letrozole) for five years after completing their surgery and completing any other necessary treatments. In this study, patients will receive either standard endocrine therapy alone or endocrine therapy plus Palbociclib, a CDK 4/6 inhibitor drug that is currently used to treat some types of more advanced breast cancer.
How to learn more about whether participating in this clinical trial is right for you.
Read more about the trial at the ClinicalTrials.gov
Discuss this trial with your doctor. Questions to ask your doctor from the National Institutes of Health can help
Principle Investigator and Responsible Researcher:
Otto Metzger, MD, Dana-Farber Cancer Institute Boston, MA ometzger@partners.org 617 632-3352
Sponsors and Collaborators Dana-Farber Cancer Institute, Pfizer ClinicalTrials.gov identifier (NCT number): NCT02764541
The Lobular Breast Cancer Alliance shares information about ongoing clinical trials for patients with lobular breast cancer for educational purposes only. LBCA does not sponsor or run the clinical trials, and the scientific validity and safety of the trials is the responsibility of the trial investigators. Patients should always discuss their participation in any clinical trial directly with their doctor and learn more by contacting the clinical trial coordinators listed above directly. Learn more about participating in clinical trials.
Tags:
Advocacy, Clinical Trials, ILC Research
Crizotinib is a small molecule inhibitor of ALK/ROS1 and MET which is licensed in lung cancer
Crizotinib and foretinib are effective in E-cadherin deficient GEMM and PDX mouse models:
Crizotinib is a small molecule inhibitor of ALK/ROS1 and MET which is licensed in lung cancer
Crizotinib and foretinib are effective in E-cadherin deficient GEMM and PDX mouse models:
ROLO: Targeted Therapy Trial for Advanced ILC
The ROLO trial is a targeted therapy clinical trial in the United Kingdom for patients with advanced or metastatic lobular breast cancer.
Name of the trial: ROLO– A phase 2 study for advanced lobular breast cancer NCT03620643
Eligible patients: Citizens of the United Kingdom with advanced or metastatic lobular breast cancer
Summary: The ROLO trial will test the effectiveness of Crizotinib combined with the drug Fulvestrant in patients with E-cadherin defective, ER+ advanced or metastatic lobular breast cancer. Crizotinib is manufactured by Pfizer and already approved by the FDA to treat a type of lung cancer.
Why is this Trial Important: This trial will test whether an existing FDA approved drug will be an effective targeted therapy for Lobular Breast Cancer.
Background: This trial will test whether Crizotinib can target an alteration in the CDH1 gene that is commonly seen in lobular breast cancer. The defect in the CDH1 gene causes a loss of a protein called E-cadherin, which then allows lobular breast cancer cells to grow abnormally. Cells with defective CDH1 genes can continue to survive, but not when a protein called ROS-1 is defective or missing. Cells cannot survive when both E-cadherin and ROS-1 are not functional. Crizotinib acts to inactivate ROS-1. In cells in the laboratory, Crizotinib inactivated ROS-1 and killed E-cadherin defective cells. The ROLO trial will test if the same effect is seen in humans.
Clinical Trial location: London, England (This trial is only accepting patients from the United Kingdom)
How to learn more about whether participating in this trial is right for you: Send inquiries to ROLO.trial@rmh.nhs.uk
The Lobular Breast Cancer Alliance shares information about ongoing clinical for lobular breast cancer. LBCA does not sponsor or run the clinical trials, and the scientific validity and safety of the trials is the responsibility of the trial investigators. Learn more by contacting the clinical trial coordinators listed above directly.
Patients should always discuss their participation in any clinical trial directly with their doctor – these Questions to Ask your Doctor may help. Learn more about participating in clinical trials. Learn about other lobular breast cancer clinical trials and studies.
Tags:
Clinical Trials, ILC Research, Metastasis
GELATO: Immunotherapy Clinical Trial for ILC Mets
The GELATO clinical trial is a lobular breast-cancer specific immunotherapy trial investigating the response to an immunotherapy + chemotherapy medication combination. This phase 2 trial is open to metastatic lobular breast cancer patients and is being conducted in the Netherlands.
Name of the trial: GELATO (AssessinG Efficacy of Carboplatin and ATezOlizumab in Metastatic Lobular Breast Cancer). NCT03147040
Goal of this Trial: This clinical trial (recruiting patients as of August 2018) aims to discover if a combination of chemotherapy and an immunotherapy medication is effective in lobular breast cancer patients. Additionally, this trial hopes to discover if there are any markers that correlate with response to this combination of medications.
Background: There are recent studies indicating that tumors in a subset of patients with lobular breast cancer express many immune cell markers, and/or are infiltrated by immune cells, and thus might be responsive to therapies targeting the immune system (Ciriello et al, PMID:26451490; Michaut et al, PMID:26729235; Desmedt et. al, PMID:29471435; Du, et. al, PMID: 29739984).
Clinical Trial location: The trial is currently being conducted in the Netherlands (locations in Amsterdam, Groningen, Maastricht, Rotterdam.)
Eligible patients: Patients with metastatic lobular breast cancer who are residents of the Netherlands. The trial coordinator may consider others who can speak Dutch and have a place to stay during the early part of the trial.
For more information regarding the clinical trial, please contact the Principal Investigator Marleen Kok, MD at +3120512 ext 9111 or m.kok@nki.nl and review the trial listing on the ClinicalTrials.gov website.
The Lobular Breast Cancer Alliance shares information about ongoing clinical for lobular breast cancer. LBCA does not sponsor or run the clinical trials, and the scientific validity and safety of the trials is the responsibility of the trial investigators. Learn more by contacting the clinical trial coordinators listed above directly.
Patients should always discuss their participation in any clinical trial directly with their doctor – these Questions to Ask your Doctor may help. Learn more about participating in clinical trials. Learn about other lobular breast cancer clinical trials and studies.
Tags:
Clinical Trials, ILC Research, Metastasis
Metastatic lobular breast carcinoma
Loss or aberrant staining of E-cadherin
Progression after endocrine treatment (ER+)
Maximum 2 lines of chemotherapy
WHO performance status 0 or 1
LDH < 2x ULN
Anti-PD(L)1 in combination with carboplatin can be effective in ILC
This effect might be more pronounced in the IR ILC’s
Addition of carboplatin can modulate the tumor microenvironment to enhance the anti-cancer immune response
