Good question!

Based on a recent review I completed of trastuzumab resistance (a shorter version of which is posted here at:

https://www.researchgate.net/post/What_is_Herceptin_resistant_cancer10

and in an abbreviated version of my full review, that condensed version being available as one of my publications here on ResearchGate, the best evidence to date suggests that approximately 20% - 30% of all HER2 overexpressing breast tumors express the p95HER2 truncated form of the HER2 receptor lacking the ECD (extracellular domain) but retaining kinase activity, using quality methodological studies and trials, including the EGF20009 and EGF100151 trials [1], the Barcelona "P95HER2 Coexpressive" Study from José Baselga and colleagues [2], the Joaquín Arribas' (Barcelona) p95HER2 review [3] and the same team's p95HER2 antibody study [4], and the early OHSU review from Tracy Christianson and colleagues [5].

What's clinically relevant here is the residue of trastuzumab-resistant tumors other than those whose resistance is p95HER2-induced: with 20 - 30% of HER2-positive tumors expressing the truncated p95HER2 receptor, that leaves some 30 - 50% of trastuzumab-resistance unaccounted for by receptor truncation, since that we know that 50 - 70% of HER2-positive patients are trastuzumab-resistant, and as my own review has shown, these are induced and secondary to the other resistance mechanisms I detailed in my Trastuzumab Resistance Framework (TRF). Still, as the inducive factors I present make clear, truncated (p95HER2) receptor arguably remains the largest single contributor to trastuzumab resistance.

1. Sperinde J, Jin X, Banerjee J, et al. Quantitation of p95HER2 in Paraffin Sections by Using a p95-Specific Antibody and Correlation with Outcome in a Cohort of Trastuzumab-Treated Breast Cancer Patients. Clin Cancer Res August 15, 2010 16; 4226.

2. Scaltriti M, Chandarlapaty S, Prudkin L, et al. Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor. Clin Cancer Res 2010 May 1; 16(9):2688-95.

3. Arribas J, Baselga J, Pedersen K, Parra-Palau JL. p95HER2 and breast cancer. Cancer Res 2011 Mar 1; 71(5):1515-9.

4. Parra-Palau JL, Pedersen K, Peg V, et al. A Major Role of p95/611-CTF, a Carboxy-Terminal Fragment of HER2, in the Down-modulation of the Estrogen Receptor in HER2-Positive Breast Cancers. Cancer Res November 1, 2010 70; 8537.

5. Christianson TA, Doherty JK, Lin YJ, et al. NH2-terminally truncated HER-2/neu protein: relationship with shedding of the extracellular domain and with prognostic factors in breast cancer. Cancer Res 1998 Nov 15; 58(22):5123-9.

Thank you very much.. Will look for the suggested papers...

Burcak:

I neglected to give the online links to the full-text version of the articles, so the below might help, and I have also cited the relevant text on the p95HER expression levels, which may help in your research into this issue:

1. http://clincancerres.aacrjournals.org/content/16/16/4226.long

Note: total populations = 184, of which 21 + 22 = 43 exceeded the p95 threshold (p95 > 2.8), = 23%, from the Kaplan-Meier Statistical Summary, at: http://clincancerres.aacrjournals.org/content/16/16/4226/T1.expansion.html

2. http://clincancerres.aacrjournals.org/content/16/9/2688.long

"The percentage of p95HER2-positive patients was 20.5% in the EGF20009 study and 28.5% in the EGF100151 study" [results, abstract]. And "we observed that the presence of p95HER2 occurs in ∼25% of HER2-amplified breast tumors" [discussion]

3. http://cancerres.aacrjournals.org/content/71/5/1515.long

"the number of ER-positive tumors in the 100- to 115-kDa p95HER2-positive subgroup was very low (∼30%)"

4. http://cancerres.aacrjournals.org/content/70/21/8537.long

"Approximately 30% of HER2-positive patients express a variety of receptor fragments of 90 to 115 kDa, collectively known as p95HER2 of carboxy-terminal fragments"

5. http://cancerres.aacrjournals.org/content/58/22/5123.full.pdf

"Western analysis of 161 breast cancer samples revealed that 22.4% were p95 positive"

There are of course dozens of other studies impinging on this question, but for the sake of expediency, I have restricted attention to these primary sources. The second reference and the associated EGF20009 study and EGF100151 studies cited therein, and the fifth reference on NH2 / p95 truncation are now considered the most authoritative.