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06-22-2012, 06:01 AM
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#1
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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I strongly recommend you read this article (even if you have to struggle a bit)
http://www.plosone.org/article/info%...l.pone.0039626
incredible advance in understanding and fabulous results even in Stage IV even with brain mets or leptomeningeal mets, whether ER+ or ER-
Hope this speeds up drug development and testing and leads to both cure/prevention!
Open Access
RESEARCH ARTICLE
Multiorgan Metastasis of Human HER-2+ Breast Cancer in Rag2−/−;Il2rg−/− Mice and Treatment with PI3K Inhibitor
Patrizia Nanni1, Giordano Nicoletti2, Arianna Palladini1, Stefania Croci1, Annalisa Murgo1, Marianna L. Ianzano1, Valentina Grosso1, Valeria Stivani1, Agnese Antognoli1, Alessia Lamolinara3, Lorena Landuzzi2, Emmanuelle di Tomaso4, Manuela Iezzi3, Carla De Giovanni1*, Pier-Luigi Lollini5
1 Section of Cancer Research, Department of Experimental Pathology, University of Bologna, Bologna, Italy, 2 Rizzoli Orthopedic Institute, Bologna, Italy, 3 Aging Research Centre, “G. D'Annunzio” University, Chieti, Italy, 4 Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts, United States of America, 5 Department of Hematology and Oncological Sciences, University of Bologna, Bologna, Italy
Abstract
In vivo studies of the metastatic process are severely hampered by the fact that most human tumor cell lines derived from highly metastatic tumors fail to consistently metastasize in immunodeficient mice like nude mice. We describe a model system based on a highly immunodeficient double knockout mouse, Rag2−/−;Il2rg−/−, which lacks T, B and NK cell activity. In this model human metastatic HER-2+ breast cancer cells displayed their full multiorgan metastatic potential, without the need for selections or additional manipulations of the system. Human HER-2+ breast cancer cell lines MDA-MB-453 and BT-474 injected into Rag2−/−;Il2rg−/− mice faithfully reproduced human cancer dissemination, with multiple metastatic sites that included lungs, bones, brain, liver, ovaries, and others. Multiorgan metastatic spread was obtained both from local tumors, growing orthotopically or subcutaneously, and from cells injected intravenously. The problem of brain recurrencies is acutely felt in HER-2+ breast cancer, because monoclonal antibodies against HER-2 penetrate poorly the blood-brain barrier. We studied whether a novel oral small molecule inhibitor of downstream PI3K, selected for its penetration of the blood-brain barrier, could affect multiorgan metastatic spread in Rag2−/−; Il2rg−/− mice. NVP-BKM120 effectively controlled metastatic growth in multiple organs, and resulted in a significant proportion of mice free from brain and bone metastases. Human HER-2+ human breast cancer cells in Rag2−/−;Il2rg−/− mice faithfully reproduced the multiorgan metastatic pattern observed in patients, thus allowing the investigation of metastatic mechanisms and the preclinical study of novel antimetastatic agents.
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06-22-2012, 10:51 AM
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#2
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Senior Member
Join Date: Feb 2009
Posts: 1,526
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Re: I strongly recommend you read this article (even if you have to struggle a bit)
Hi Lani
Once again many thanks for the info. I have struggled through it a couple of times to try to grasp fully the implications. Does this mean they already have a drug that works very very well and could progress to human trials soon? Does this mean that it would be effective equally against hormone positive and negative tumours? Is there a realistic chance that this is our cure!
Thanks
Ellie
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06-22-2012, 11:23 AM
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#3
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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Re: I strongly recommend you read this article (even if you have to struggle a bit)
No, we don't even know if this drug is safe and effective in humans yet.
But the great news is for the first time they have what seems like a reasonable model of metastatic her2+ breast cancer--it is the metastases that kill, not the primary tumor. And they have a drug which crosses the blood brain barrier.
They may find they have to combine say herceptin, TDM-1 and/or pertuzumab with a PI3K inhibitor (as it is the PI3K pathway which often is responsible for antiher2 therapy resistance). For some it may end up being herceptin, TDM-1 and/or pertuzumab plus a Hsp90 inhibitor or plus an mTor inhibitor. But we have drugs in all these classes either in Stage II/III trials or already approved and now a way to see in real time and using human tumors (and in some cases the patients own immune system transplanted into the same mice) what works in what cases.
Again, I still feel serial bone marrow will also be helpful in this pursuit, but
this is a great leap forward in finding out how her2+ breast cancer develops (perhaps it takes both mutations AND loss/loss of function of B,T, and NK cells), how to best treat each of its subtypes, how to block its usual modes of escape and how to correctly dose and how long to treat with these agents.
This is really different from the NodSCID mice they have used before and the her2 transfected cell lines (extremely artificial constructs which may in no way behave like the real thing).
I expect it will speed things up remarkably--at least I hope so!
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06-22-2012, 01:23 PM
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#4
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Senior Member
Join Date: Feb 2009
Posts: 1,526
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Re: I strongly recommend you read this article (even if you have to struggle a bit)
Thanks Lani for your very comprehensive reply.It is encouraging that we may already have these drugs so we don't need to 'reinvent the wheel'. Hopefully some drug consortium will now view this as a very good investment and pursue it's development
Ellie
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06-22-2012, 04:03 PM
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#5
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Senior Member
Join Date: Jan 2012
Location: Boulder Colorado as of January 2013
Posts: 389
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Re: I strongly recommend you read this article (even if you have to struggle a bit)
I agree with Lani that this model will allow the pharmaceutical industry to have a map to test drugs. This is like having a map where there never was one before; a English/foreign language dictionary; or a pH meter to test for acidity. Without a good diagnostic system it is a guessing game. This is an extremely important break through. Hopefully this will shorten time to development of new treatments.
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06-22-2012, 09:05 PM
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#6
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Senior Member
Join Date: May 2011
Location: Denver, CO
Posts: 1,427
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Re: I strongly recommend you read this article (even if you have to struggle a bit)
Thanks Lani!
It's exciting to see developments like this.
__________________
Amy
_____________________________
4/19/11 Diagnosed invasive ductal carcinoma in left breast; 2.3 cm tumor, 1 axillary lymph node, weakly ER+, HER2+++
4/29/11 CT scan shows suspicious lesions on liver and lungs
5/17/11 liver biopsy
5/24/11 liver met confirmed--Stage IV at diagnosis
5/27/11 Begin weekly Taxol & Herceptin for 3 months (standard of care at the time of my DX)
7/18/11 Switch to weekly Abraxane & Herceptin due to Taxol allergy
8/29/11 CT scan shows no new lesions & old lesions shrinking
9/27/11 Finish Abraxane. Start Herceptin every 3 weeks. Begin taking Arimidex
10/17/11--Brain MRI--No Brain mets
12/5/11 PET scan--Almost NED
5/15/12 PET scan shows progression-breast/chest/spine (one vertebra)
5/22/12 Stop taking Arimidex; stay on Herceptin
6/11/12 Started Tykerb and Herceptin on clinical trial (w/no chemo)
9/24/12 CT scan--No new mets. Everything stable.
3/11/13 CT Scan--two small new possible mets and odd looking area in left lung getting larger.
4/2/13--Biopsy of suspicious area in lower left lung. Mets to lung confirmed.
4/30/13 Begin Kadcyla/TDM-1
8/16/13 PET scan "mixed," with some areas of increased uptake, but also some definite improvement, so I'll stay on TDM-1/Kadcyla.
11/11/13 Finally get hormone receptor results from lung biopsy of 4/2/13. My cancer is no longer ER positive.
11/13/13 PET scan mixed results again. We're calling it "stable." Problems breathing on exertion.
2/18/14 PET scan shows a new lesion and newly active lymph node in chest, other progression. Bye bye TDM-1.
2/28/14 Begin Herceptin/Perjeta every 3 weeks.
6/8/14 PET "mixed," with no new lesions, and everything but lower lungs improving. My breathing is better.
8/18/14 PET "mixed" again. Upper lungs & one spine met stable, lower lungs less FDG avid, original tumor more avid, one lymph node in mediastinum more avid.
9/1/14 Begin taking Xeloda one week on, one week off. Will also stay on Herceptin and Perjeta every three weeks.
12/11/14 PET Scan--no new lesions, and everything looks better than it did.
3/20/15 PET Scan--no new lesions, but lower lung lesions larger and a bit more avid.
4/13/15 Increasing Xeloda dose to 10 days on, one week off.
7/1/15 Scan "mixed" again, but suggests continuing progression. Stop Xeloda. Substitute Abraxane every 3 weeks starting 7/13.
10/28/15 PET scan shows dramatic improvement everywhere. All lesions except lower lungs have resolved; lower lungs noticeably improved.
12/18/15 Last Abraxane. Continue on Herceptin and Perjeta alone beginning 1/8/16.
1/27/16 PET scan shows cancer is stable.
5/11/16 PET scan shows uptake in some areas that were resolved on the last two scans.
6/3/16 Begin Kadcyla and Tykerb combination
6/5 - 6/23 Horrible diarrhea from K&T together. Got pneumonia.
7/15/16 Begin Kadcyla only every 3 weeks.
9/6/16 Begin radiation therapy on right lung lesion that caused the pneumonia.
10/3/16 Last of 12 radiation treatments to right lung.
11/4/16 Huffing and puffing, low O2, high heart rate, on tiniest bit of exertion. Diagnosed as radiation pneumonitis. Treated with Prednisone.
11/11/16 PET scan shows significant improvement to radiated part of right lung BUT a bunch of new lung lesions, and the bone met is getting worse.
11/22/16 Begin Eribulin and Herceptin. H every 3 weeks. E two weeks on, one week off.
3/6/17 Scan shows progression in lungs. Bone met a little better.
3/23/17 Lung biopsy. Tumor sampled is ER-, PR+ (5%), HER2+++. Getting Herceptin and Perjeta as a maintenance treatment.
5/31/17 Port placement
6/1/17 Start Navelbine & Tykerb
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06-23-2012, 03:17 PM
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#7
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Senior Member
Join Date: Sep 2009
Location: Los Angeles
Posts: 76
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Re: I strongly recommend you read this article (even if you have to struggle a bit)
Lani,
Thanks so much for this and for all the research that you've brought to this group. I appreciate you a lot!
Idelle
__________________
Idelle Davidson
Co-author (with Dr. Dan Silverman at UCLA) of "Your Brain After Chemo: A Practical Guide to Lifting the Fog and Getting Back Your Focus" (Da Capo Lifelong Books, 2009). Amazon. www.YourBrainAfterChemo.com.
ER/PR negative/HER-2 positive
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06-24-2012, 01:49 PM
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#8
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Senior Member
Join Date: May 2006
Location: California
Posts: 668
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Re: I strongly recommend you read this article (even if you have to struggle a bit)
Dear Lani,
Thank you so much for the info.
__________________
1994 - rt brst, .lump, underarm node dissection,chemo+rad 1.2 cms, Grade 3.
28 nodes neg
Er,Pr, Positive HER2 status unknown
2003- Recur to rt lung.July 16 ( B-Day!)
Her2+++ Er,Pr, Negative
2003 - Aug04--Navelbine + Herceptin
2004- 2007--NED - Herceptin, only
2007 Feb-April Xeloda added to hereceptin
2007-May Back on Navelbine+Herceptin
2008-Feb-Mar 15 Ses Rad to Rt. Lung
2008- Oc 17 Add Tykerb to Herceptin
2009- June-- Discont Tykerb
2009 July 7--Current Taxol + Herceptin
2009 Dec--Discontinued treatment due to progression. Looking into cyberknife.
2010-Aug Accepted to TDM1, no SE, except liver count went up.
2010-2011 September got kicked out of the trial, due to a small spot found on lung.
2011- 2012 September thru early 2013 on Herceptin
2013- March Bone density shows small spot on 5th rib.
2013 - April 4th appt with onc. will post after discussing course of treatment.
2013-March-April Cyber knife to brain and radiation to rib. Chest --base line before chemo-CT-Scan stable for lung issue. CA2729 Normal.
2013 April Herceptin- TDMI
2013 Sept Herceptin + Perjeta . CA2729 within normal range. Brain and Pet scans October 31st. will post results.
2013 October Brain MRI- mixed response. Will see Onc/rad on Halloween.
2013 October/November Brain-MRI nothing new. Repeat MRI next year in May.
2013 December Continue Herceptin and Perjeta. Stable at the moment.
2014 February Brain MRI -clear!
2014 January Added Taxotere to Perjeta+Herceptin.
2014 March Stopped chemo-chest ct-scan next.
2014- March Scans shows tumor's larger, CA2729 higher. Discontinue Herceptin.
2014 April Perjeta+ Halaven
2014 April CA2729 went down 60 points after one cycle. Cough does not want to go away.
2014 June Continue on Perjeta + Halaven-- no more cough. Stable
2014 June Back on Herceptin + abraxane
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06-24-2012, 03:22 PM
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#9
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Senior Member
Join Date: Jan 2012
Location: Boulder Colorado as of January 2013
Posts: 389
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Re: I strongly recommend you read this article (even if you have to struggle a bit)
NVP-BKM120 was used at 50 mg/kg for the mice. For a 132 pound (60 kg) woman, this would scale to 3 gm per dose, four dose per week. I hope this is not too expensive and does not have any side effects at these doses. Also, it might be some time before it gets to clinical trials. TDM-1 and Pertuzumab are available for now, and these are good front line systems. If the new drug can be brought to market and is less expensive and has fewer side effects, this will be a great step forward. The mere fact that both a test model and a drug have made this progress should be inspirational for the people on this web, both the women with HER+, their family members, and their friends.
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06-24-2012, 11:40 PM
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#10
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Senior Member
Join Date: Oct 2008
Posts: 88
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Re: I strongly recommend you read this article (even if you have to struggle a bit)
Once again / Lani YOU Rock! Feels like
you r an angel!
Thanks - Kim
__________________
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Dx Stage 3C 2005, triple +, tons of lymph nodes as well. FEC, surgery, TCH, rads, herceptin 1 year. And, Aromasin.
2007 - recurrence to medistinal lymph node, Abraxene and Herceptin - took it down 50%
2008 - on Arimidex/Herceptin - stable lymph node.
2009 - stable on Arimidex/Herceptin
2010 - lymph node progression and liver mets.
2010 - went on Gemzar, Navelbine, Herceptin - Navelbine and Herceptin took liver mets down. lymph node slightly progressed.
2010 - did Xeloda & Tykerb - MAJOR progression in liver in only 6 weeks.
Dec 2010 - present - Ixempra/Avastin/Herceptin/Fasoldex - regressing
June 2012 - chemo break
Sept 19, 2012 - start t-dm1. Chose this over going back on Ixempra.
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06-26-2012, 11:13 AM
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#11
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Senior Member
Join Date: Sep 2005
Location: Naples FL
Posts: 1,744
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Re: I strongly recommend you read this article (even if you have to struggle a bit)
Thanks so much, Lani!!! You are amazing! I printed this so I can read it later, with my companion dictionary!!!
__________________
 Suzan W.
age 54 at diagnosis
5/05 suspicious mammogram-left breast
5/05 biopsy-invasive lobular carcinoma with LCIS,8mm tumor,stage 1 grade 2, ER+ PR+ Her2+++
6/14/05 bilateral mastectomy, node neg. all scans neg.
Oncotype DX-high risk
8/05-10/05 4 rounds A/C
10/05 -10/06 1 yr. herceptin
arimidex-5 years
2/14/08 started daily self administered injections..FORTEO for severe osteoporosis
7/28/09 BRCA 1 negative BRCA2 POSITIVE
8/17/09 prophylactic salpingo-oophorectomy
10/15/10 last FORTEOinjection
RECLAST infusion(ostoeporosis)
6/14/10 5 year cancerversary!
8/2010-18%increase in bone density!
no further treatments
Oncologist says, "Go do the Happy Dance"
I say,"What a long strange trip its been"
'One day at a time'
6-14-2015. 10 YEAR CANCERVERSARY!
7-16 to 9-16. Extensive (and expensive) dental work done to save teeth. Damage from osteoporosis and chemo and long term bisphosphonate use
6-14-16. 11 YEAR CANCERVERSARY!!
7-20-16 Prolia injection for severe osteoporosis
2 days later, massive hive outbreak. This led to an eventual dx of Chronic Ideopathic Urticaria, an auto-immune disease from HELL.
6-14-17 12 YEAR CANCERVERSARY!!
still suffering from CIU. 4 hospitilizations in the past year
as of today, 10-31-17 in remission from CIU and still, CANCER FREE!!!
6-14-18 13 YEAR CANCERVERSARY!! NED!!
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06-26-2012, 02:37 PM
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#12
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Senior Member
Join Date: May 2012
Posts: 31
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Re: I strongly recommend you read this article (even if you have to struggle a bit)
Hi,
I just want to cry this disease has me confused. Right now I have 6 rounds of TCH with Herceptin as well as Herceptin every week between the TCH. Triple Positive, 1 cm tumor no node envolvement. Should I be taking the TCH? What is the prognosis of this early stage? I just don't know.
Thanks,
Mary Jo
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