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Old 12-17-2014, 02:32 AM   #1
Lani
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Lightbulb Is THIS the reason adding herceptin to chemo only improves OS by 40%?

I had assumed that de novo resistance to herceptin (initial p95 truncated receptors, presence of complex mucin which prevented herceptin from approaching the receptor, inadequate immune system response capability etc) and acquired resistance to herceptin (selecting out the clones with more her3+, with other driving or downstream active pathways, etc) were the reasons that OS was only improved 40%, but perhaps , as was proposed at SABCS, herceptin works mainly not by blocking the her2 receptor or preventing formation of dimers of her2 and other her2,her3,egfr or her4 receptors, but rather because of ADCC. Here it appears that tumor-associated hyaluronan (the same substance temporarily degraded to allow subcutaneous herceptin to gain access to the body) in 60% of cases her2 ihc 3+ early breast cancers may not provide access of the NK immune cells to the tumor by "gumming up the matrix" thus preventing ADCC from taking place.

This article presents the intriguing possibility of combining anti-hyaluronan monoclonal antibodies with antiher2 antibodies to provide effective treatment in that other 60% of tumors where herceptin can't get to "where the money is"

Hopefully the new mAbs don't cost an arm and a leg. They will need to be targeted as hyaluronan has a lot of different important functions in a lot of different normal tissues. Seems quite "doable" though.

Mol Cancer Ther. 2014 Dec 15. pii: molcanther.0580.2014. [Epub ahead of print]
Tumor-associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy.
Singha NC1, Nekoroski T1, Zhao C1, Symons R1, Jiang P1, Frost GI2, Huang Z1, Shepard HM3.
Author information
Abstract
Despite tremendous progress in cancer immunotherapy for solid tumors, clinical success of monoclonal antibody (MAb) therapy is often limited by poorly understood mechanisms associated with the tumor microenvironment (TME). Accumulation of hyaluronan (HA), a major component of the TME, occurs in many solid tumor types, and is associated with poor prognosis and treatment resistance in multiple malignancies. In this study, we describe that a physical barrier associated with high levels of HA (HAhigh) in the TME restricts antibody and immune cell access to tumors, suggesting a novel mechanism of in vivo resistance to MAb therapy. We determined that ~60% of HER23+ primary breast tumors and ~40% of EGFR+ head and neck squamous cell carcinomas are HAhigh, and hypothesized that HAhigh tumors may be refractory to MAb therapy. We found that the pericellular matrix produced by HAhigh tumor cells inhibited both natural killer (NK) immune cell access to tumor cells and antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Depletion of HA by PEGPH20, a pegylated recombinant human PH20 hyaluronidase, resulted in increased NK cell access to HAhigh tumor cells, and greatly enhanced trastuzumab- or cetuximab-dependent ADCC in vitro. Furthermore, PEGPH20 treatment enhanced trastuzumab and NK cell access to HAhigh tumors, resulting in enhanced trastuzumab- and NK cell-mediated tumor growth inhibition in vivo. These results suggest that HAhigh matrix in vivo may form a barrier inhibiting access of both MAb and NK cells, and that PEGPH20 treatment in combination with anti-cancer MAbs may be an effective adjunctive therapy for HAhigh tumors.
Copyright © 2014, American Association for Cancer Research.
PMID: 25512619 [P
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Old 12-17-2014, 10:57 AM   #2
linn65
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Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?

I don't understand this?? Can you break it down ??
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IDC breast cancer
7/2012 diagnosed with multiple solid lesions
7/20/12 biopsy done. ER+ 30 PR -, HER+++,k167 80% Grade 2
9/2012 biopsy on lymph node - showed malignant

9/2012 Pre-adjunctive TCH chemo.

12/6/12 MRI after Pre-adj.
Results: Modest Decrease in size of left breast malignancy As well as the associated satellite lesions and auxiliary Adenopathy compared to prior study. Doctors hoped for better but good response it didn't grow.

12/18/2012 left masectomy with axillary nodes
Size 3.2 CM, Nottingham score 9/9
Grade 3, no evidence of in situ carcinoma
Areas of angiolymphatic are identified
Carcinoma is 0.5 cm from inked deep
Margin of excision
Attached axillary lymph nodes: metastatic
Carcinoma in 6 of 8 nodes.
Size of largest node 1.5 cm
Extracapsular
ER + 73%, PR+2%, HER2+

2/27/13 6 weeks of IMRT radiation finished

2/2013 Started on Tamoxifan 5 years.

8/2013 will take last Herceptin, 17 treatments total every 3 weeks.

BRCA1 & BRAC2 - Negative

August 28, 2013 DIEP flap on the left breast.
February 2014 Nip & Tuck
March 14, 2014 nipple reconstruction and removed port.
August 14, 2014 lump in lymph nodes under arm and above clavicle. Stage IV
August 28, 2014 herceptin And projeta starting and port put back in.

3/18/15 stopped arimidex.
3/18/15 progression....Tdm1
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Old 12-17-2014, 03:52 PM   #3
tricia keegan
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Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?

Sadly me neither, thank you Lani.
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Dx July '05 IDC 1.9cm Triple positive 3/9 nodes positive
A/C X 4 ..Taxol/Herceptin x 12 wks then herceptin 1 yr
Rads x 36 ..oophorectomy August '06
Currently taking Arimidex..
June 2011 osteopenia/ zometa x1 yearly- stopped Zometa 2015 as Dexa show normal bone density.
Stopped Arimidex July 2014- Restarted Arimidex 2015 for a further two years on the advice of my Onc.
2014 Normal Dexa scan
2018 Mammo all clear, still NED!
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Old 12-18-2014, 12:45 AM   #4
Lani
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Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?

hyaluronan is like glue in the space between cells and surrounds her2+ breast cancer cells in about 60% of her2+ tumors

translation of the rest:

Despite tremendous progress in cancer immunotherapy for solid tumors, clinical success of monoclonal antibody (MAb) therapy is often limited by poorly understood mechanisms associated with the tumor microenvironment (TME)--this is the area outside the tumor but adjacent to the tumor which serves as a home for the tumor, who we will compare to a fugitive mass murderer. The tumor(fugitive mass murderer) asks the microenvironment--mom, dad, grandma grandpa for food, warmth, blankets, drink and entertainment.

Mom, dad, grandpa and grandma besides sheltering and feeding the mass murderer/tumor also like the company of the tumor (mass murderer) and pass on wisdom, information on the location of the FBI/police, binoculars to look for lurking police/FBI outdoors, disguises and hope and other things that help it cope.
Accumulation of hyaluronan (HA), a major component of the TME, occurs in many solid tumor types, and is associated with poor prognosis and treatment resistance in multiple malignancies.( It is a sticky, glue-like stuff leet's say it is a hedge-high moat or wall of supersticky cotton candy). In this study, we describe that a physical barrier associated with high levels of HA (HAhigh) in the TME restricts antibody and immune cell ( police and FBI who come to take away the fugitive mass murderer) access to tumors, suggesting a novel mechanism of in vivo resistance to MAb therapy.

We determined that ~60% of HER23+ primary breast tumors and ~40% of EGFR+ head and neck squamous cell carcinomas (those responsible for cancers of the mouth and other areas of the head and neck) are HAhigh, and hypothesized that HAhigh tumors may be refractory to MAb--monoclonal antibody) therapy.(monoclonal antibodies are smart-bombs, such as herceptin--if herceptin cannot get to the cancer cell because of the cotton candy moat it cannot stick to its her2 receptor or invite in killing immune cells like NK cells.) We found that the pericellular matrix(cottoncandy moat or hedge) produced by HAhigh tumor cells inhibited both natural killer (NK) immune cell access to tumor cells and antibody-dependent cell-mediated cytotoxicity (ADCC)--the process by which those killer cells kill the her2+ cells) in vitro.

Depletion of HA(cotton candy) by PEGPH20, a pegylated recombinant human PH20 hyaluronidase(enzyme that eats hyaluronon or cotton candy), resulted in increased NK cell access to HAhigh tumor cells, and greatly enhanced trastuzumab- or cetuximab-dependent ADCC in vitro. Furthermore, PEGPH20 treatment enhanced trastuzumab and NK cell access to HAhigh tumors, resulting in enhanced trastuzumab- and NK cell-mediated tumor growth inhibition in vivo. These results suggest that HAhigh matrix in vivo may form a barrier inhibiting access of both
MAb(herceptin) and NK cells(the cells attracted to come kill the her2+ breast cancer cells after being summoned by the herceptin"hey, guess what I found, a lovely her2+ breast cancer cell to kill and eat!" or alternatively, an FBI agent who is happy to have had
in informant call in but is frustrated because he cannot see thee location and whether the serial murderer is unarmed because the sticky cotton candy hedge obscures the murderer so the FBI agent cannot swoop in and "take him out!")
, and that PEGPH20 treatment in combination with anti-cancer MAbs may be an effective adjunctive therapy for HAhigh tumors (both, acting together, serve to 1) act as an informant as to where the murderer is and 2) takes down the cotton candy hedge/moat so the FBI can come in for the kill)

I continue to believe you could utilize my chocolate, cherry and whipped cream system to fathom the information without my help. It might take a bit of practice, though.
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Old 12-18-2014, 11:04 AM   #5
lkc Gumby
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Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?

Love this Lani!!
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Dxed Stage IIIC May 05, 12 pos nodes
er/pr -neg,Her -pos
LVI
Right partial mast & partial axillary dissection-June14,2005
Right modified mast-no clear margins- June 30, 2005
DD AC x4
Taxotere X4 with Herceptin
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Left prophylactive mast( atypia & hyperplasia found ),
put on Tamoxifen x 1 yr; D/ced due to endometrial thickening
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Old 12-18-2014, 02:00 PM   #6
linn65
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Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?

That is a great analogy! Do pathologists always know what your tumor is made of?? Like all I know about mine is her2+++ and ER+ 55 on the last biopsy.
__________________
myleftlump.wordpress.com - started blogging my
IDC breast cancer
7/2012 diagnosed with multiple solid lesions
7/20/12 biopsy done. ER+ 30 PR -, HER+++,k167 80% Grade 2
9/2012 biopsy on lymph node - showed malignant

9/2012 Pre-adjunctive TCH chemo.

12/6/12 MRI after Pre-adj.
Results: Modest Decrease in size of left breast malignancy As well as the associated satellite lesions and auxiliary Adenopathy compared to prior study. Doctors hoped for better but good response it didn't grow.

12/18/2012 left masectomy with axillary nodes
Size 3.2 CM, Nottingham score 9/9
Grade 3, no evidence of in situ carcinoma
Areas of angiolymphatic are identified
Carcinoma is 0.5 cm from inked deep
Margin of excision
Attached axillary lymph nodes: metastatic
Carcinoma in 6 of 8 nodes.
Size of largest node 1.5 cm
Extracapsular
ER + 73%, PR+2%, HER2+

2/27/13 6 weeks of IMRT radiation finished

2/2013 Started on Tamoxifan 5 years.

8/2013 will take last Herceptin, 17 treatments total every 3 weeks.

BRCA1 & BRAC2 - Negative

August 28, 2013 DIEP flap on the left breast.
February 2014 Nip & Tuck
March 14, 2014 nipple reconstruction and removed port.
August 14, 2014 lump in lymph nodes under arm and above clavicle. Stage IV
August 28, 2014 herceptin And projeta starting and port put back in.

3/18/15 stopped arimidex.
3/18/15 progression....Tdm1
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Old 12-18-2014, 03:03 PM   #7
rhondalea
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Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?

That was hilarious, Lani.

I know it's more work for you (and I'm grateful), and I'm also well aware that it's possible to understand study results with a little help from Dr. Google, but I wouldn't have missed that for anything.
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2/6/09 Core needle biopsy: negative; Mammos through 2010: no change
3/30/11 Pea-sized lump in left breast at site of prior biopsy; mammo negative, sonogram not so much
4/14/11 Core needle biopsy: negative for cancer
5/18/11 Excisional biopsy 1.2 cm tumor, LVI, positive margin; ER+60%,PR+20%,HER2/CEP17 5
6/15/11 BMX: Left DCIS & LH; Right ADH; SNB: 2/3 nodes: 1.4 cm and 1 mm; ALND L1&2: 0/10; Stage IIa, Grade 3
7/14/11 CT/Bone scans NED; MUGA 66%
7/19/11 Biweekly dd AC w/Neulasta; done 8/30/11
9/13/11 Transfusion (Hemoglobin 8.6); MUGA 64%
9/20/11 Start Taxol + Herceptin; Taxol done 12/6/2011; continue Herceptin until 9/4/2012
12/27/11 Radiation - 6 weeks; 2/27/2012 - DONE! Yayyyy!
2/29/12 Start Tamoxifen 20 mg/day; continue until 2/28/17
5/16/12 Start five-years Metformin trial
6/19/12 MUGA 61%
8/21/12 Brain MRI NED (head still hurts, brain still fogged)
9/4/12 Herceptin done!
9/6/12 Port out!
7/11/13 Aricept 5mg for cognitive impairment; increased to 10mg as of 8/23/13; back to 5mg 12/2013
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Old 12-19-2014, 11:22 AM   #8
Lani
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Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?

linn65--they only look for what is requested by the doctor ordering the pathology examination with report and only with the means requested

eg, if IHC (immunohistochemistry) is requested and only ER PR and her2 are checked of, those are the only stains utilized and those the only items reported

if FISH is ordered(or ordered only if her2 2 and above) for her2, that is reported

As regards "cotton candy" it has only now been reported to be potentially so important. If these findings are corroborated by others we may see the test for "cotton candy" added to the list to be checked off for tests the pathologist should run and maybe it will become standard of care to add a monoclonal antibody to "cotton candy" to herceptin to the treatment of those whose her2+ tumors that have enough of it
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Old 12-19-2014, 04:04 PM   #9
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Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?

Lani,
Bispecific MABs with anti-hyraluonic acid on the leg opposite the HER+ leg might work. I know they are doing this for T-Cell attractants to make the MAbs easier to pick up for recirculating white cells. I think I will ask someone to think about it. Someone that could actually try this concept pretty quickly.
Paul
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Old 12-20-2014, 03:14 PM   #10
Aussie Girl
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Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?

Interesting. They would need to attach the PEGPH20 enzyme to the Her2 antibody rather than an antibody, which might be easier - provided some of the her2 antibody could get to the receptor. An antibody to the cotton candy would probably affect to much normal tissue.

First up, it would be good to have a simple test to detect the HAhigh tumours in the first place. I don't think this would be too hard to do.

Aussie Girl
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Grade 3, ER/PR-, HER2+, Neg Sentinel nodes x 5
49mm field of DCIS
17 June '13: Screen detected impalpable mass, Mammogram neg, US.
25 June '13: Diagnosed after multiple biopsies and MRIs
28 June '13: Left lumpectomey
4 July '13: Left Mastectomy
12 August '13: Commenced TCH chemo
Mid December '13 : TCH finished. Herceptin continuing three weekly.
4 August 2014- Herceptin infusions finished.
END OF THERAPY - YAY!

Last edited by Aussie Girl; 12-20-2014 at 03:19 PM.. Reason: typo
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Old 01-27-2015, 09:47 PM   #11
Mtngrl
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Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?

This is cool.

Lani, your "translation" is priceless.
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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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Old 01-28-2015, 09:01 AM   #12
KathyT
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Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?

Lani,
Thanks for posting this and bringing to my awareness and for the breakdown or analogy of it all! I didn't have pCR of my tumor site(did of my lymph nodes) so I am thinking I have the HAhigh(cotton candy). Is there anything at this point that I could do? I don't even think they tested my tissue at the time of my mastectomy as to if it was her2+ or what?? They just said there was a 4 mm IDC area found in the tissue and I had neoadjuvent therapy so that's what scares me. I didn't have further chemo after mastectomy...
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January 17th 2014-mammo, ultrasound, biopsy
January 20th 2014- diagnosed, ER/PR+, Her2+++, Stage 2A
January 21st 2014-MRI, right breast only plus lymph nodes
January 23rd 2014- Pet scan-2 cm tumor, 3 lymph nodes
February 4th 2014-port insertion
February 12th 2014-first chemo treatment(TCHP x6 cycles)
May 28th 2014-LAST chemo treatment!!
July 10th 2014-double mastectomy
July 29th 2014-start radiation(30)
Sept. 11th 2014last radiation treatment!!!
November 12 2014-started Tamoxifen
January 20 2015-reconstruction begins, lat flap
February 4 2015-last Herceptin treatment!!
April 24, 2015- pet scan-NED!!
June 3 2015- exchange surgery, port removed!!
September 8 2015-hysterectomy/oophorectomy
September 15 2015-Revision of lat flap reconstruction
December 23 2015-nipple reconstruction
May 9th 2016-Mets to pituitary gland, liver and C7 vertebrae
May 10th-port put back in:(
May 17th- biopsy of mass on back
May 19th-started Herceptin/Perjeta
May 20th-5 treatments Cyberknife to pituitary gland tumor
June 9th-Started THP (will have 6 cycles)
August 17th-MRI of brain, significant reduction in tumor
😃, repeat MRI in 3 months. Received first Zometa
infusion.
June 24th 2019- Thoracic spine Mets, leptomeningeal Mets , 10 radiation treatments
Aug 1st- Ommaya Reservoir implanted
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Old 01-28-2015, 10:34 AM   #13
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Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?

Isn't 40% good?
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Dx Aug/05 at age 51
2cm. Stage 2A, Grade 3
ER+/PR-
Her2 +++

Sept 7/05 Mastectomy
4 FAC, 4 Taxol, no radiation
1 year of Herceptin
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