Thread by @prat_aleix

📢 I am very happy to announce that the HER2DX genomic test for patients with early-stage HER2+ breast cancer is officially available at @RevealGenomics!

See thread below where I explain story + details behind HER2DX 👇

@OncoAlert @_SEOM @myESMO @ASEICAnews @_SOLTI @GEICAM #COI

HER2DX is the consequence of >10 years of research in HER2+ breast cancer (by many researchers, not only me/us!)

In 2012, I was a postdoc at Charles M. Perou Lab (bit.ly/3Ku9nn0) @UNC_Lineberger

Yes, I had more hair👱, and I "pipetted"🧪🧑‍🔬

In the TCGA Nature 2012 study (go.nature.com/3Aqswlg)...we observed that gene expression identifies various subtypes of HER2+ breast cancer...

and tumors that are both HER2+ and genomically HER2-enriched (HER2-E) have the highest expression of HER2 protein + phospho-protein 🎆

In 2013, our colleagues @TheTBCRC @mfrimawi reported TBCRC006 trial at @JCO_ASCO, showing that dual HER2 blockade is highly effective in a subset of pts

In an editorial, Baselga and I pointed out potential biological explanations driving this observation: bit.ly/3fWtpso

Back in Barcelona @VHIO, I continued studying the heterogeneity within HER2+ breast cancer --> clinical meaning?

In 2014, we showed @JNCI_Now (bit.ly/3rLMCSS) that HER2 "does not mean much" from a biological perspective once subtype is considered!

In addition, a Luminal A HER2+ is practically the same as a Luminal HER2-neg. Same for the other subtypes. The only difference is the amplification of the 17q12-21 amplicon, where HER2 is, in HER2+ tumors.

bit.ly/3rLMCSS @JNCI_Now

but was this heterogeneity clinically meaningful?

In 2014, we (Baselga, Gianni and @BianchiniGP) analyzed the genomic data of the NOAH phase III trial

HER2-E tumors respond more to anti-HER2-based chemotherapy than other subtypes

@CCR_AACR (bit.ly/3Aq7AL3)

Note: this previous paper was rejected from @CCR_AACR, I fought back with a constructive letter, and when back to review and was accepted!

never give up! although it usually does not work!

At that point, it was time to demonstrate prospectively that HER2-E are HER2 addicted! and we did!

@JavierCortesMD, Toni Llombart, and I designed the @_SOLTI PAMELA trial and presented the results @SABCSSanAntonio and @TheLancetOncol 2017

bit.ly/3qPGsSB

Over the yrs, many neoadj studies confirmed that HER2-E identifies pts highly responsive to anti-HER2 therapy with/out chemo

We published a meta-analysis to show it! bit.ly/3rPr6wW @FrancescoSche20

Note: HR status is useless to predict pCR in the presence of subtype

In summary, HER2+ tumors can be divided into HER2-E and non-HER2-E subtypes (LumA, LumB and Basal-like)

HER2-E tumors are the most HER2 addicted

Importantly, these entities cannot be recapitulated by hormone receptor status

Within HER2+/HR+, a substantial proportion of tumors will be HER2-E

Within HER2+/HR-, a substantial proportion are non-HER2-E

However, subtype information by itself does not explain the whole story. More is needed!!!

For example, the levels of ERBB2 mRNA provide additional information for predicting response to anti-HER2 therapy, as shown in @JNCI_Now (bit.ly/3FZwPVD) in 2020

By the way, ERBB2 mRNA levels might be a good way to identify patients with HER2+ disease who don´t benefit from ADCs against HER2

Why? it is a more sensitive way to measure HER2

With T-DM1 is quite clear:
bit.ly/3u8eSlR
bit.ly/3fSvPIk
bit.ly/3Au1mtF

In addition, TILs and immune gene signatures provide additional info for predicting response to antiHER2-based therapies BEYOND subtype

This was of the first times we saw it, thanks to a collaboration with @vitti10 @UniPadova reported @Annals_Oncology

bit.ly/3FSH0LF

Many others observed that the immune infiltration provides independent clinical information beyond tumor cell features

Here a summary of what I said, presented @myESMO

Note: HR status by IHC becomes irrelevant when you have genomic tumor cell data, immune data, and tumor burden

Gene expression data also revealed that in HER2+/HR+ disease:

More endocrine sensitivity (measured by gene expression) --> less HER2 addiction --> less chemotherapy sensitivity

@CCR_AACR bit.ly/3AuK9jL @TomasPascualMD

Thus, the main drivers of HER2+ disease are: HER2 amplicon expression, immune infiltration, proliferation and luminal differentiation

What was next then? combine all these variables? and for what purpose? what is the clinically relevant question?

With an amazing collaborator Dr. Conte and his team @UniPadova, we analyzed immune+tumor+clinical data of 435pts from ShortHER (an academic trial!!)

We combined features->developed a prognostic risk score

bit.ly/3nTkOee @TheLancetOncol

1st version HER2DX was born!

Several reasons made us develop a 2nd version of HER2DX before moving forward to the clinic:

1. TILs measured as % are not reproducible 🔬

In the previous study:
2. we measured a short gene list and didn´t include immune genes
3. we did not build a predictor of pCR response

After extensive work, we published recently at The Lancet @EBioMedicine the development and validation of the HER2DX 27-gene assay, which provides 2 scores (0-100):

1.Prognostic
2.Probability to achieve a pCR

bit.ly/3rPDD3s

Another tweet will go over the publication!

To deliver HER2DX + other tests, Patricia Villagrasa and I created @RevealGenomics in 2020 with @AnaVivancosVHIO, Joel Parker and Chuck Perou

🙏thanks to our business angel L.P.! and all the Reveal team

bit.ly/3IuHtp8 #COI

@hospitalclinic @idibaps @UniBarcelona @VHIO

I also want to thank @hospitalclinic "Centro de Diagnóstico Biomédico (CDB)" led by Dr. Aurea Mira @AureaMira1 for believing in this project and being a great partner!

bit.ly/3fTwWaG

I want to thank all pts+families, whose altruism has allowed discoveries, many of which are reflected in this tool

I also want to thank all lab members, collaborators, institutions, and funders

And our friends and especially our families for your unconditional support🙏