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Reposted by Katie Houlahan

Noah F. Greenwald @noahgreenwald.bsky.social · Jan 29

I’m super excited to share what I’ve been working on for the last (many) years: a spatial + genomic + transcriptomic characterization of how the breast cancer microenvironment evolves through immunotherapy! (1/x) 🧪🧬 🖥️ #AcademicSky #MLSky #ImmunoSky www.biorxiv.org/content/10.1...

Temporal and spatial composition of the tumor microenvironment predicts response to immune checkpoint inhibition

Immune checkpoint inhibition (ICI) has fundamentally changed cancer treatment. However, only a minority of patients with metastatic triple negative breast cancer (TNBC) benefit from ICI, and the deter...

www.biorxiv.org

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Katie Houlahan @khoulahan.bsky.social · Jan 8

Again, thank you to the patients, their families, the patient advocates and all the amazing scientists involved!!

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Katie Houlahan @khoulahan.bsky.social · Jan 8

This approach moves us closer towards the goal of tailoring treatments for aggressive ER+ subgroups based on underlying vulnerabilities beyond what is possible within the traditional hormone receptor-centric framework.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

In summary, our study puts forward a genomic map that represents breast cancer subtypes along a continuum.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

Interestingly, while 43.6% of TNBC tumours were HRD-like, 13.2% of ER+ high-risk tumours were also predicted to be HRD-like (with BRCA2-like signatures), suggesting some ER+ tumours may benefit from PARP inhibitors.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

More, ER+ and ER- tumours with HRD-like profiles (defined through WGS) had higher TNBC-archetype scores than their non-HRD-like counterparts.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

These ER+ high-risk tumours may similarly benefit from agents directed at their amplified oncogenic drivers and/or shared vulnerabilities.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

For instance, 43.2% of ER+ cases are dominated by mutational processes indistinguishable from those of HER2+ tumours. Rather than amplifying ERBB2/HER2, these ER+ high-risk tumours harbour focal amplifications of other oncogenes.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

What are the benefits of viewing this genomic heterogeneity along a continuum? We believe the mutational processes captured by these archetypes point to distinct therapeutic vulnerabilities, which may not neatly map onto receptor status.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

These data suggest that ecDNA may form early as a means to protect against further ER-induced genomic instability.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

When do these archetypes emerge? We found evidence that they are established early during tumorigenesis. The generation of focal amplifications in ER+ high-risk + HER2+ archetype through ecDNAs can be traced back to preinvasive ecDNAs and decades prior to diagnosis.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

These patterns mirror our prior observation that germline-mediated immunoediting contributes to immune depletion in the ER+ high-risk and HER2+ subgroups [Houlahan et al. 2024 science.org/doi/10.1126/...

Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity

Tumors with the same diagnosis can have different molecular profiles and response to treatment. It remains unclear when and why these differences arise. Somatic genomic aberrations occur within the co...

science.org

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Katie Houlahan @khoulahan.bsky.social · Jan 8

The other two archetypes were associated with distinct tumour microenvironment (TME): ER+ high-risk/HER2+ with a depleted TME vs. ER+ typical-risk with a fibrotic one.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

Interestingly, beyond the genome, these genomic archetypes capture tumour extrinsic differences. We found evidence for genomic immune escape owing to structural variants in TNBC, which also have elevated genome-wide instability and immune infiltrates.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

Our analyses indicate that ER-induced R-loops serve as a substrate for APOBEC editing, promoting double-stranded breaks at ER binding sites which serve as the origins of translocations that form chromosome bridges during mitosis, resulting in the genesis of ecDNA.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

Next, we investigated the mechanistic processes at play in the genesis of these focal oncogene amplifications that define aggressive, high-risk of recurrence ER+ disease.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

The TNBC-enriched archetype was enriched for genomic instability, HRD and APOBEC-editing SNVs. In contrast, the ER+ high-risk + HER2+-enriched archetype was enriched for complex rearrangement and amplifications at key focal IC-specific oncogenes, and frequently localized to ecDNA

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Katie Houlahan @khoulahan.bsky.social · Jan 8

These archetypes are correlated with distinct mutational patterns.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

Through deconstruction of mutational, copy number, and rearrangement signatures we found that breast tumours fall along a continuum constrained by three genomic archetypes: 1) ER+ high-risk + HER2+-enriched; 2) TNBC-enriched; and 3) ER+ typical-risk-enriched.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

In this new study, we established a meta-cohort of 1,828 tumours spanning pre-invasive, primary and metastatic disease. Using whole genome sequencing, we captured a wide range of mutations, including copy number alterations (CNAs) and structural variants (SVs).

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Katie Houlahan @khoulahan.bsky.social · Jan 8

These integrative clusters (IC) show distinct prognosis and relapse trajectories stratifying the ER+ breast cancer patients into two: the ER+ high-risk and ER+ typical-risk of relapse subgroups.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

The lab has defined 11 integrative breast cancer subtypes based on their genomic and transcriptional profiles [Curtis et al. 2012 nature.com/articles/nat..., Rueda et al. 2019 nature.com/articles/s41... ].

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Katie Houlahan @khoulahan.bsky.social · Jan 8

But what is their genetic underpinning, how do they evolve through disease progression, and could a deeper understanding of their heterogeneity through a genetic lens reveal potential therapeutic strategies?

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Katie Houlahan @khoulahan.bsky.social · Jan 8

The clinical approach to breast cancer is largely based on the expression of three receptors (ER, PR and HER2) which fundamentally shapes how we understand and treat the disease.

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Katie Houlahan @khoulahan.bsky.social · Jan 8

We show that complex rearrangements fuel the progression of ER+ high-risk and HER2+ tumours. A labour of love from @lisemangiante.bsky.social, @crissotomayor.bsky.social, @alvinahere.bsky.social and myself supervised by @cncurtis.bsky.social and Jennifer Caswell-Jin

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