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04-21-2011, 02:35 PM
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#1
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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TDM-1 works (on cell lines) even if already resistant to herceptin/lapatinib!!
Trastuzumab-DM1 causes tumor growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in vivo
Mark Barok , Minna Tanner , Katri Koninki and Jorma Isola
Breast Cancer Research 2011, 13:R46doi:10.1186/bcr2868
Published: 21 April 2011
Abstract (provisional)
Introduction
Trastuzumab is widely used for the treatment of HER2-positive breast cancer. Despite encouraging clinical results, a significant fraction of patients are, or become refractory to, the drug. To overcome this, trastuzumab DM1 (T-DM1), a newer, more potent drug has been introduced. We tested the efficacy and mechanisms of action of T-DM1 in nine HER2-positive breast cancer cell lines in vitro and in vivo. The nine cell lines studied included UACC-893, MDA-453 and JIMT-1, which are resistant to both trastuzumab and lapatinib.
Methods
AlamarBlue cell-proliferation assay was used to determine the growth response of breast cancer cell lines to trastuzumab and T-DM1 in vitro. Trastuzumab- and T-DM1-mediated antibody-dependent cellular cytotoxicity (ADCC) was analysed by measuring the lactate dehydrogenase released from the cancer cells as a result of ADCC activity of peripheral blood mononuclear cells. Severe Combined Immunodeficient (SCID) mice were inoculated with trastuzumab-resistant JIMT-1 cells to investigate the tumour inhibitory effect of T-DM1 in vivo. The xenograft samples were investigated using histology and immunohistochemistry.
Results
T-DM1 was strongly growth inhibitory on all investigated HER2-positive breast cancer cell lines in vitro. T-DM1 also evoked antibody-dependent cellular cytotoxicity (ADCC) similar to that of trastuzumab. Outgrowth of JIMT-1 xenograft tumors in SCID mice was significantly inhibited by T DM1. Histologically, the cellular response to T-DM1 consisted of apoptosis and mitotic catastrophe, the latter evidenced by increased number of cells with aberrant mitotic figures and giant multinucleated cells.
Conclusions
Our results suggest mitotic catastrophe as a previously undescribed mechanism of action of T-DM1. T DM1 was found effective even on breast cancer cell lines with moderate HER2 expression levels and cross-resistance to trastuzumab and lapatinib (MDA-453 and JIMT-1).
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04-21-2011, 02:49 PM
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#2
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Senior Member
Join Date: Feb 2006
Location: Southern, CA
Posts: 2,511
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Re: TDM-1 works (on cell lines) even if already resistant to herceptin/lapatinib!!
More exciting news on T-DM1. I just wish they would hurry up and approve T-DM1 for those of us that need it.
Thanks for sharing this news Lani!
Chelee
__________________
DX: 12-20-05 - Stage IIIA, Her2/Neu, 3+++,Er & Pr weakly positive, 5 of 16 pos nodes.
Rt. MRM on 1-3-06 -- No Rads due to compromised lungs.
Chemo started 2-7-06 -- TCH - - Finished 6-12-06
Finished yr of wkly herceptin 3-19-07
3-15-07 Lt side prophylactic simple mastectomy. -- Ooph 4-05-07
9-21-09 PET/CT "Recurrence" to Rt. axllia, Rt. femur, ilium. Possible Sacrum & liver? Now stage IV.
9-28-09 Loading dose of Herceptin & started Zometa
9-29-09 Power Port Placement
10-24-09 Mass 6.4 x 4.7 cm on Rt. femur head.
11-19-09 RT. Femur surgery - Rod placed
12-7-09 Navelbine added to Herceptin/Zometa.
3-23-10 Ten days of rads to RT femur. Completed.
4-05-10 Quit Navelbine--Herceptin/Zometa alone.
5-4-10 Appt. with Dr. Slamon to see what is next? Waiting on FISH results from femur biopsy.
Results to FISH was unsuccessful--this happens less then 2% of the time.
7-7-10 Recurrence to RT axilla again. Back to UCLA for options.
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04-21-2011, 04:10 PM
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#3
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Senior Member
Join Date: Sep 2009
Location: Kensington, CT
Posts: 394
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Re: TDM-1 works (on cell lines) even if already resistant to herceptin/lapatinib!!
Lani,
This is exciting news. when I went to Memorial Sloan for a 2nd opinion, the oncologist mentioned this as a possibility for brain mets (he's not convinced that it doesn't x the bbb). I sure do wish it is true.
Kris....
__________________
06/08/09 - 55, IDC, IIIA, ER+/PR-/HER+++
Nottingham 6/9 - Grade 2 5.2cm, several nodes
06/23/09 - Neoadjuvant - TCH Herceptin til June
10/07/09 - Finished Chemo
10/27/09 - Mastectomy RB
Path Report: RB No residual tumor pCR,
2 of 15 pos - .5mm largest micromets
12/18/09 - Radiation started (28)
02/05/10 - Finished Radiation
01/11/10 - Started Femara
06/22/10 - Finished Herceptin.. My son's 22nd BD. Hope it's a sign! Hoping for the best.
11/15/10 - Started Walter Reed BC Vaccine trial at
1/04/11 - Sibley Mem. Had to withdraw due to met
01/23/11 - Stage IV - Brain Met 1.6cm 1.7cm
02/03/11 - Gamma Knife (2 fracts to minmize necrosis)
03/01/11 - Gamma Knife
6/11 - Necrosis
7/11 - Necrosis stopped & Tumor progression
8/11 = Now think it's really necrosis
9/11 - Avastin every two weeks -- It's working!! Necrosis is shrinking.
12/11 - Necrosis gone AVASTIN worked.
12/11 - Bone &CT found
Oct '10 - Ran Hartford 1/2 Marathon to Thank Dr. Slamon for Herceptin!
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04-21-2011, 04:23 PM
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#4
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Senior Member
Join Date: Jan 2010
Location: Matakana which is one hour north of Auckland, New Zealand.
Posts: 89
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Re: TDM-1 works (on cell lines) even if already resistant to herceptin/lapatinib!!
Thats what i want to find out. Does T-DM1 cross the blood brain barrier. Does anyone out there know?
I have to wait another 4 weeks for my brain MRI and I'll find out what further treatment is needed.
Thanks for the post Lani.
Regards Jacqui
__________________
Oct 2009 Masectomy 6 cm Tumor . Sentinal node biopsy , Node Positive . Her2 + er/pr -.
Nov 2009 X3 Taxane and Herceptin, X3 FEC
March 2010 25 Rads
March 2010 continued on Herception untill 16 Dec 2010
May 2010 Ultra Sound .... ALL CLEAR... NED
August 2010 started vaccine trial University of Washington
7th Dec 2010 finished vaccine trial
20th Dec 2010 Port removed
3rd Feb no longer ned brain mets
23r Feb start VMAT radiation
August 2011 two new mets to brain and others starting to grow again !!!!
August start tykerb and xeloda
Dec 1 MRI all small brain mets gone. Largest shrunk by 50% only three small ones to go 17mm,8mm,6mm. Mets on there way out. Yeah
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04-21-2011, 07:40 PM
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#5
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Senior Member
Join Date: Oct 2005
Posts: 3,519
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Re: TDM-1 works (on cell lines) even if already resistant to herceptin/lapatinib!!
Kris, my onc believes it's possible too. He's in the camp that believes the bbb is much more "leaky" than other camps of oncs and researchers have professed over the years. He thinks T-DM1 will help treat my brain.
Jaqui, I don't think we are there yet to know for sure. Have you talked to your onc about starting Tykerb/Xeloda?
__________________
Brenda
NOV 2012 - 9 yr anniversary
JULY 2012 - 7 yr anniversary stage IV (of 50...)
Nov'03~ dX stage 2B
Dec'03~ Rt side mastectomy, Her2+, ER/PR+, 10 nodes out, one node positive
Jan'04~ Taxotere/Adria/Cytoxan x 6, NED, no Rads, Tamox. 1 year, Arimadex 3 mo., NED 14 mo.
Sept'05~ micro mets lungs/chest nodes/underarm node, Switched to Aromasin, T/C/H x 7, NED 6 months - Herceptin only
Aug'06~ micro mets chest nodes, & bone spot @ C3 neck, Added Taxol to Herceptin
Feb'07~ Genetic testing, BRCA 1&2 neg
Apr'07~ MRI - two 9mm brain mets & 5 punctates, new left chest met, & small increase of bone spot C3 neck, Stopped Aromasin
May'07~ Started Tykerb/Xeloda, no WBR for now
June'07~ MRI - stable brain mets, no new mets, 9mm spots less enhanced, CA15.3 down 45.5 to 9.3 in 10 wks, Ty/Xel working magic!
Aug'07~ MRI - brain mets shrunk half, NO NEW BRAIN METS!!, TMs stable @ 9.2
Oct'07~ PET/CT & MRI show NED
Apr'08~ scans still show NED in the head, small bone spot on right iliac crest (rear pelvic bone)
Sept'08~ MRI shows activity in brain mets, completed 5 fractions/5 consecutive days of IMRT to zap the pesky buggers
Oct'08~ dropped Xeloda, switched to tri-weekly Herceptin in combo with Tykerb, extend to tri-monthly Zometa infusion
Dec'08~ Brain MRI- 4 spots reduced to punctate size, large spot shrunk by 3mm, CT of torso clear/pelvis spot stable
June'09~ new 3-4mm left cerrebellar spot zapped with IMRT targeted rads
Sept'09~ new 6mm & 1 cm spots in pituitary/optic chiasm area. Rx= 25 days of 3D conformal fractionated targeted IMRT to the tumors.
Oct'09~ 25 days of low dose 3D conformal fractionated targeted IMRT to the bone mets spot on rt. iliac crest that have been watching for 2 years. Added daily Aromasin back into treatment regimen.
Apr'10~ Brain MRI clear! But, see new small spot on adrenal gland. Change from Aromasin back to Tamoxifen.
June'10~ Tumor markers (CA15.3) dropped from 37 to 23 after one month on Tamoxifen. Continue to monitor adrenal gland spot. Remain on Tykerb/Herceptin/Tamoxifen.
Nov'10~ Radiate positive mediastinal node that was pressing on recurrent laryngeal nerve, causing paralyzed larynx and a funny voice.
Jan'11~ MRI shows possible activity or perhaps just scar tissue/necrotic increase on 3 previously treated brain spots and a pituitary spot. 5 days of IMRT on 4 spots.
Feb'11~ Enrolled in T-DM1 EAP in Denver, first treatment March 25, 2011.
Mar'11~ Finally started T-DM1 EAP in Denver at Rocky Mountain Cancer Center/Rose on Mar. 25... hallelujah.
"I would rather be anecdotally alive than statistically dead."
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04-21-2011, 08:20 PM
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#6
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Senior Member
Join Date: Oct 2008
Posts: 88
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Re: TDM-1 works (on cell lines) even if already resistant to herceptin/lapatinib!!
Lani -
This is incredible news. You are such a blessing to us!
- 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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04-21-2011, 08:31 PM
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#7
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Senior Member
Join Date: May 2006
Posts: 3,142
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Re: TDM-1 works (on cell lines) even if already resistant to herceptin/lapatinib!!
This is really great news for all of us.
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04-22-2011, 02:26 AM
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#8
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Senior Member
Join Date: Feb 2009
Posts: 1,526
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Re: TDM-1 works (on cell lines) even if already resistant to herceptin/lapatinib!!
Thanks Lani
You always post news that cheers us up!
I agree with Chelee, the sooner you girls get it in the States the sooner we have a chance of getting it across the pond!!
Ellie
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04-22-2011, 04:14 PM
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#9
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Senior Member
Join Date: Sep 2005
Location: Central Coast, CA
Posts: 3,207
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Re: TDM-1 works (on cell lines) even if already resistant to herceptin/lapatinib!!
Interesting phrase - especially when applied to a cancer cell!!!!!
__________________
Chris in Scotts Valley
June 2002 extensive hi grade DCIS (pre-cancer-stage 0, clean sentinal node) Mastectomy/implant - no chemo, rads. "cured?"
9/2004 Diag: Stage IV extensive liver mets (!) ER/PR- Her2+++
10/04-3/05 Weekly Taxol/Carboplatin/Herceptin , complete response!
04/05 - 4/07 Herception every 3 wks, Continue NED
04/07 - recurrence to liver - 2 spots, starting tykerb/avastin trial
06/07 8/07 10/07 Scans show stable, continue on Tykerb/Avastin
01/08 Progression in liver
02/08 Begin (TDM1) trial
08/08 NED! It's Working! Continue on TDM1
02/09 Continue NED
02/10 Continue NED. 5/10 9/10 Scans NED 10/10 Scans NED
12/10 Scans not clear....4/11 Scans suggest progression 6/11 progression confirmed in liver
07/11 - 11/11 Herceptin/Xeloda -not working:(
12/11 Begin MM302 Phase I trial - bust:(
03/12 3rd times the charm? AKT trial
5/12 Scan shows reduction! 7/12 More reduction!!!!
8/12 Whoops...progression...trying for Perjeta/Herceptin (plus some more nasty chemo!)
9/12 Start Perjeta/Herceptin, chemo on hold due to infection/wound in leg, added on cycle 2 &3
11/12 Poops! progression in liver, Stop Perjeta/Taxo/Herc
11/12 Navelbine/Herce[ptin - try for a 3 cycles, no go.
2/13 Gemzar/Carbo/Herceptin - no go.
3/13 TACE procedure
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