Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘TNBC’

Crowds of People at ASCO 2016

The ASCO Wall 2016

There has been much frustration on many fronts at the number of trials that do not see a relationship between PD-L1 expression and response. Some do, but many don’t. This has lead to quite a few investigators suggesting that the IHC assay may not be as useful as originally hoped, for predicting response to checkpoint blockade or selecting patients for therapy.

While we often do see a trend for more responders with higher levels of expression, the main issue is that PD-L1-negative patients can also see some responses, albeit at a lower rate.

There are many factors that can affect the measurement:

  • Fresh vs. archival tissue
  • Heterogeneity within the tumour
  • Tumour cells (TC) vs. immune cells (IC)
  • Different antibodies used for each assay
  • The dynamic nature of the tumour microenvironment – does timing of the biopsy matter?
  • Human error – a pathologist has to eyeball the IHC readouts and decide the level of staining intensity

And so on. These are just a few examples of the factors that can potentially affect the results, making it quite a challenging test to undertake. There is also time – does the level of expression vary temporally depending on which prior therapies are administered?

It would be easy to be disheartened by this, but fear not!

There were some impressive new data presented at ASCO that were not only intriguing, but also show us a way forward on how a multi-factorial approach could be used in different tumour types. By this I mean we might end up with different tests used in conjunction for several different cancers in order to a) predict responders and non-responders and b) better select patients for appropriate regimens or clinical trials.

It’s not going to be as easy as one size (or test) fits all.  Sometimes a more more sophisticated approach will be needed.  New data at ASCO gave us hints on what’s to come in this direction.

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At the European Cancer Conference (ECC 2015) held in Vienna recently, a number of promising targets emerged along with new drugs in development in several different tumour types.  Not all of them were from big Pharma – some were from up and coming young biotechs that will be worth watching out for.

Austria SchnappsIn this first part of our ‘New Drugs on the Horizon’ mini series, we chose four interesting and largely positive studies to highlight and discuss in-depth.

In the past, there were many negative trials to pick over and ponder why they didn’t quite pan out.  After all, it’s relatively easy to be an armchair critic and hindsight is a wonderful thing.

Picking only four from the many promising choices of trials presented this year available turned out to be quite hard given there were many that caught our attention – a bit like choosing only one of four out of the many schnaps to sample locally!

Today’s review looks at four very different drugs and approaches in early development from Pfizer, Stemcentrx and Ignyta – they include encouraging early data on both small molecule tyrosine kinase inhibitors (TKIs), as well as antibody drug conjugates (ADCs).

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SABCS BannerSan Antonio – The San Antonio Breast Cancer Symposium (Twitter #SABCS14) is underway, and one of the key questions everyone is asking is do checkpoint inhibitors work in Triple Negative Breast Cancer (TNBC)?

TNBC is defined as the absence of estrogen receptor (ER), progesterone receptor (PR) and HER2 protein expression. This means that treatments aimed at these targets such as aromatase inhibitors and Herceptin are unlikely to work in TNBC.

TNBC represents approximately 15% of breast cancer patients in the U.S, and to put this number into perspective, around 200,000 women have the disease, with 40,000 deaths each year. Globally, there are an estimated 1 million cases of breast cancer, of which 170,000 are triple-negative (ER-/PR-/HER2-).

The only currently available treatment for TNBC is chemotherapy, but sadly patients often do not live long, and rapidly progress. Progression-free survival (PFS) is estimated to be around 4 months in TNBC. This means there is a real unmet medical need for effective new treatments.

Checkpoint inhibition of the programmed-death 1 receptor (PD-1) such as pembrolizumab (Merck) and the ligand (PD-L1) e.g. MPDL3280A (Genentech/Roche) can increase the effectiveness of a body’s T cells to fight cancer. Are checkpoint inhibitors the future in TNBC and will they offer hope to patients?

Some early preliminary clinical data is being presented this week at SABCS. Subscribers can login below or you can purchase access to read more about what this data signals about the potential of checkpoint inhibition in TNBC.

“You may say I’m a dreamer

But I’m not the only one.”

John Lennon, Imagine

As part of our ongoing series on the AACR Previews, today I want to take a closer look at some interesting scientific and clinical data in triple negative breast cancer (TNBC).  One reason for this is that we need to remember that the disease, as currently defined, is essentially what’s left after taking out the ER+, HER2+ and inflammatory breast cancer subsets. In other words, it’s a very heterogeneous catch-all population, making clinical trials rather challenging at best. It also means that the chances of success in general all-comer trials is rather low.

It is my hope that as we learn more about the biology of this disease, we may see further subsets be defined by molecular peculiarities, much in the same way that gastrointestinal stromal tumours (GIST) were defined by KIT expression and CD117. Once we have more homogenous subsets, it will be easier to conduct trials just looking at those specific patients, thereby improving the chances of clinical success with therapeutic intervention.

There’s been a lot of work focused on this area over the last few years, so it seems a good point to find out where the progress has got to.

Without much further ado, what can we learn about the biology of TNBC from AACR this year and which potential new targets might emerge?

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Following on from yesterday’s update on how proteomics and genomics can help us make better decisions in breast cancer at the Miami Breast Cancer Conference (#MBCC14) organised by PER, today also looks at the complexity of genomics, but from a different lens – can genomics impact the way we actually treat patients?

Interestingly, last week there was a rumour (unconfirmed) that Dr Debu Tripathy (UCLA) was heading to MD Anderson to head up the breast cancer division following Gabriel Hortobaygi’s retirement. That move was confirmed yesterday, with a tweet from Dr Naoto Ueno, who is part of the group:

His talk on the increasing role of genomics in breast cancer on Friday was engaging, thoughtful and well delivered.

It also made me (and several others) stop and think.

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On Friday, I headed uptown to attend the Miami Breast Cancer Conference (#MBCC14) held at the Fontainebleau Hotel and organised by the Physicians Education Resource (PER).  It was fun to grab a local Deco Bike and furiously cycle over 45 blocks in under half an hour – most probably the only attendee who arrived on two wheels that day!

MBCC14: Dr Lance Liotta

MBCC14: Dr Lance Liotta

Now, I haven’t attended this event since it was at the Loews Hotel in midtown, which was rather low key and fairly small.  Certainly there wasn’t a big exhibition area then, as far I can recall.  Fast forward a decade on and the event is MUCH bigger, with an excellent Academic panel and an interesting mix of didactic talks and case studies.  The stage setting is also much more impressive, as you can see in the photo right.

To give you some basic background, the audience polls at the beginning of the first day were really useful to put things into context:

  1. The majority of attendees (88%) were physicians (mix of Community medical oncologists, radiation oncologists and surgical oncologists)
  2. 49% of respondents treated 1–5 patients with breast cancer per week
  3. 25% of respondents treated 6–10 patients with breast cancer per week

Being a scientist, and having missed the San Antonio Breast Cancer Symposium (SABCS) due to an overlap with the American Society of Hematology (ASH) meeting in December, I was particularly keen to catch up on the new developments in genomics and molecular profiling, with early morning talks from Drs Lance Liotta (George Mason Univ) and Debu Tripathy (USC).  There were also updates on neoadjuvant treatment for breast cancer by Drs Kathy Albain (Loyola) and Hal Burstein (Dana Farber).  Neoadjuvant therapy prior to surgery is an area that is seeing many new trials and potential therapies emerge.

In today’s post, the attention is on the important topic molecular profiling. This is something I believe we will see much more of going forward.  Two separate articles will follow on personalised treatment in advanced breast cancer (including TNBC) and also on neoadjuvant developments.

Genomics can sometimes be a bit of a dry topic, at least to some people, as anyone who has sat through slide after slide of those fuzzy green-red assays in systems biology sessions at AACR will attest. This time, much to my pleasant surprise, it was different…

What I heard blew my mind and changed the way I think about some aspects of breast cancer.

Now I’m not joking or trying to hype progress here, but sometimes you experience an epiphany when you least expect it.

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Lance Liotta always gives well organised presentations and illustrates the key facts on proteomics (a tough subject for many to follow) with critical learning points.  At this year’s MBCC, he focused his talk on a vision for combining genomic mapping with proteomic analysis of the metastatic lesion.  Part of the challenge with using genomics is the sheer heterogeneity and complexity of every single patient’s tumour.  He also had a second talk in the afternoon that was equally interesting, but more about that in another post.

One of the main findings from the SideOut trial (run by TGen and George Mason, sponsored by the Side Out Foundation; reported at ASCO 2013 – download the poster here) a proof-of-concept study, which showed that molecular profiling often yielded a treatment recommendation that was different from the one recommended by the treating physician:

Source: L Liotta, MBCC

Source: L Liotta, MBCC

You can see that some of the regimens mentioned here are quite noticeably different – patient #103 is particularly fascinating, for example.

Here’s my quick summary of some of the main points from his first talk:

  1. Basic concept of SideOut I: map the signaling network of metastatic tumour cells to understand which growth or survival pathways are functionally in use in the tissue microenvironment.
  2. Combine this information with genomic analysis from biopsies to determine true drivers from passengers.
  3. Use a combination of genomics and proteomics to recommend appropriate therapies.
  4. The trial was largely successful at generating good responses to therapy and demonstrating PFS – 40% of patients exceeded the PFS ratio of 1.3 and three pats still continue on therapy for 199, 254 and 816 days.
  5. 60% of patient samples had activation of drug targets in only 3 major clusters i.e.
    1. pan-HER-AKT
    2. EGFR/Src/ERK/mTOR
    3. IGF/RAF/MEK/PLK1
  6. Improved treatment may therefore be facilitated by biomarker-led understanding of subgroup molecular targets, which may predict benefit from currently approved agents and newer targeted drugs.
  7. Subclones are selected out based on selective pressure i.e. survival in a secondary tissue or organ during metastasis or survival in the face of therapy (adaptive resistance).  This is something we need to learn more about as our knowledge of the biology of the disease improves.

Following the success of this trial, SIDEOUT II has now opened in 9 sites looking at metastatic breast cancer patients progressing after 1–3 lines of therapy. The study will investigate genome sequencing, protein pathway mapping and multiplexed IHC before using all of the information available to provide a molecular rationale for individualising therapy.

For the SideOut I study, Liotta gave a nice example of a typical patient case study, as shown below.  The idea was to illustrate how they investigators tackled this difficult case and used the genomic and proteomic data to make better clinical decisions.  Note the patient had TNBC, yet had different findings for HER2 status based on two different tests – this isn’t an uncommon finding with lab results, unfortunately:

Source: L Liotta, MBCC

Source: L Liotta, MBCC

After the proteomic and genomic analysis, this is what they ended up with. Note the recommended treatment regimen that resulted – not something you would normally consider with such a detailed work-up!

Source: L Liotta MBCC

Source: L Liotta MBCC

To put this in better context – consider the attendee poll on what tests the physicians would order based on the biopsy of a metastatic lesion suggested that 60% would run ER, PR and HER2 only, while less than a third would test for ER, PR, HER2 and genomic profiling.  Personally, I was really surprised that so few respondents would consider genomic sequencing in the metastatic setting given the sheer molecular complexity that exists.  Clearly, there is a molecular world beyond hitting ER, PR and HER2.

Ultimately, the proof of the pudding in any clinical trial is outcome – how well did the patients do when molecular profiling was used to guide therapy?  Remember that many of these patients had quite advanced disease and were considered difficult to treat.

The answer is quite well, as this waterfall plot demonstrates:

Sideout waterfall plot

 

We have to wonder how can we possibly expect to treat any patient successfully, if we don’t know what driver mutations and targets exist?  In this respect, lung cancer has truly come out of the shadows and leap-frogged breast cancer in terms of molecular profiling and targeted therapies, at least in Academia.

In the future, it may be possible to better define triple negative breast cancers (TNBC) by what the are, rather than what they’re not i.e. ER, PR, HER2 negative, which is a broad catch-all and a very heterogenous population indeed.

Meanwhile, tomorrow we will continue the personalized theme and cover another mind blowing talk that demonstrated how far we really have to go before we can possibly expect to see major shifts in outcome based on the underlying biology and matching appropriate targeted therapy.

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