04/18/2025
Here is the thing...
The following will be important information for anyone monitoring for molecular recurrence, i.e. through Signatera, or considering doing so soon. It could also apply to anyone newly diagnosed with breast cancer who has the inclination to think knowledge is power...
We need to differentiate between direct and indirect evidence of therapy effectiveness.
Let me explain myself. In the metastatic setting we are collecting loads of evidence on up-and-coming targeted therapies for cancer. Why? For two reasons: 1. It is a cancer setting in which there are visible lesions that can be measured for determining response to treatment. 2. Standard of care has been tried in this population and failed, so other options are considered.
From this, these next points follow and are also true: We do not often **test** targeted therapies in the early setting because 1. Standard of care works, so why try something different, 2. Curative treatment in this setting which includes surgery, means there is no visible lesion to monitor.
Here is what is NOT true. Lack of evidence directly collected in the early breast cancer setting means we don't know anything about how these treatments work. WE DO KNOW HOW THEY WORK. Some targeted therapies work in ways that require a tumor microenvironment (and lesion) to form, i.e. to have tumor infiltrating lymphocytes, for vascularization to exist etc. Examples of these are immunotherapy and VEGF inhibitors.
MANY targeted therapies work at the molecular level, targeting mutations and their impact on individual cell functioning - there is no working rationale for thinking that these therapies do not work on molecular level disease - NONE. To be clear - the fact that these therapies have shown they work in the metastatic setting through very well characterized mechanisms CAN BE USED to reasonably deduct that they will work for molecular level disease without the existence of any visible lesion, i.e. it is indirect evidence of this.
Why is this important?
It is important for cancer patients to know when current treatments are truly optimal, and when they are the product of constraints and inefficiencies in the system being used to evolve care.
Here is what is new and where Signatera comes in... 1. We can now SEE effectiveness of treatment by measuring impact on molecular level disease without the need for visible lesions to happen in order to be able to tell. We did not have this level of specificity and sensitivity in a test before. 2. More and more patients in the early setting are wishing and hoping for options that will allow for de-escalation of treatment and/or for treatment alternatives with better toxicity profiles in order to maintain a better quality of life.
The good news is off-label use of treatments by oncologists are on the rise. Good oncologists consider all the information they can about your own specific case to make decisions, and that includes your preferences, your toxicities and indirect evidence on therapy effectiveness. Why? Because most good oncologists know that standard of care is there as baseline ground evidence, but that most of the time it alone cannot constitute optimal care for each individual patient. The discretion for decision-making remains with the oncologist and patient for this very reason.
But what do oncologist and patients need for this discretionary decision-making? They need MORE INFORMATION. Without personalized information about your tumor, the justification for even trying many of these targeted options is non-existent.
I have compiled a list of the major subtypes of breast cancer and what their first line standard of care treatment is upon clinical recurrence/ metastasis. The first thing you may notice is how limiting/homogeneous standard of care can be particularly in TNBC which is such a heterogeneous disease, but which is also true for all subtypes. This is true despite the availability of a whole slew of targeted options currently being investigated with very sound mechanisms of action and many with comparable effectiveness and better or comparable toxicity profiles. In the second table I have compiled the list of these therapies, the biomarkers that can lead to reasonable consideration for the therapy, and whether or not the mechanism of action APPLIES TO MOLECULAR DISEASE. You can also see the toxicity profile of some of these options and how they compare to chemotherapy.
This is one of MANY reasons I think patients need to be as informed as they can be about their own personal tumor profile as they embark on their patient trajectory or even after curative treatment as you are monitoring for molecular recurrence. And for this reason, I am conducting tumor profiling direct to patients who are getting Signatera testing, or planning to soon, AND putting together a pipeline for TNBC expression profiling.
Here is a sample of a tumor profiling report I have put together for a real patient (I am sharing with her permission).
https://storage.cloud.google.com/cethisharing/files/Danielle.html
I have likewise profiled 13 patients in what we are calling CEtHI's "Legacy Cohort", many of whom have chimed in before in this FB group. I am currently putting together an additional group of 10 to 12 patients I am calling "The Foundational Cohort" for a second round of tumor profiling. Below are links to the opportunity to join this initiative, and the TNBC subtypes profiling one, as well as a video which explains what we are doing and gives an overview of the report.
Tumor profiling: https://health-collaboration-hub.mn.co/plans/1515286?bundle_token=8a8b5a312e7107074ee14a00f2f7bd77&utm_source=manual
TNBC subtyping pipeline: https://health-collaboration-hub.mn.co/plans/1512811?bundle_token=ee28f68fffc72f86f24977e034f4789a&utm_source=manual
As you see, these initiatives are distinct from the longitudinal MRD Signatera study we are also conducting at CEtHI. Many of you have asked me about the tumor profiling and how it is different from the survey - the longitudinal study... hopefully, this clears this up! I know this tumor profiling will not be for everyone here, but I wanted to make the information accessible to those for whom it may be...
And even if these initiatives are not for you right now, I did also want to provide the tables and the whole argument contained in this post as a PSA regarding the importance of patient empowerment and access to personalized information.
Thanks for your attention!
(Feel free to DM me or hit BOOK MEETING on this page, if you want to dig into any of this further - it is free, and I enjoy getting to know people and discussing their case to see if I can be of support in any way.)
