Posted on Oct 09, 2024
We gathered four experts to discuss how breast cancer treatment has advanced, whether current diagnostics are up to the task, and how we can move forward in the molecular era for the benefit of breast cancer patients.
Our four experts are: ● Prof John Bartlett – retired professor of molecular biology from the University of Edinburgh. ● Dr Liz O’Riordan – retired consultant breast surgeon who has had breast cancer three times. ● Prof Emad Rakha – professor in breast pathology from the University of Nottingham, and honorary breast consultant at Nottingham University Hospital. ● Prof Abeer Shaaban – specialist breast pathologist working at the University of Birmingham and Queen Elizabeth Hospital Birmingham.
Treatment has changed, but diagnostics have not
Prof Bartlett started the discussion with an overview of how treatments for breast cancer have changed since the introduction of endocrine therapy in the 1970s, and trastuzumab in the 1990s. Treatments continue to advance, such as checkpoint inhibitors, CDK4/6 inhibitors, and new antibody-drug conjugates for HER2-positive breast cancers.
The molecular age started properly with the first use of Oncotype DX in the late-2000s as a predictive test for chemotherapy. Beyond that, our knowledge of breast cancer – particularly at the molecular level – has advanced significantly in even the last 10 years.
However, although breast cancer treatment has undergone a transformation since the 70s, “in diagnostic pathology not a lot has changed since then, in terms of what is used,” Prof Bartlett argued. “The questions have changed, but the actual technologies have not.”
Immunohistochemistry (IHC) has remained the main test used for biomarkers of many breast cancer treatments. The only exceptions for now are FISH for HER2 amplification, and a limited array of molecular tests such as Oncotype DX.
Pressures on pathology, and needs of patients
Prof Shaaban set out the many challenges facing her and her colleagues working in a major pathology reference centre. “We get at least 10% increase in our workload in pathology labs every year. However, our staffing numbers are still the same, sometimes decreasing,” Prof Shaaban said. “With the COVID pandemic, things have gotten worse, and we have a backlog of tumours that need to be sectioned and stained and tested.”
Dr Liz O’Riordan said that at the time of diagnosis, patients want answers quickly, so that they can start treatment as soon as possible. “Anything we can do to make sure they get their results within a week – so we can say it's definitely ER-positive, HER2-negative, or whatever – will really, really help.”
Can IHC face the challenges of today?
IHC is the established test for many biomarkers. But one of the concerns that Profs Bartlett and Rakha expressed is the ‘dynamic range’ of IHC, which is much smaller than the range of protein expression levels of ER or HER2.
This has become even more important with new treatments targeting patients with low levels of these markers, such as the DESTINY-Breast trials showing that Enhertu is effective treatment against HER2-low and -ultralow tumours. Pathologists face real challenges using IHC-based tests to diagnose low levels of HER2 protein expression.
“Our current techniques and assays were not really designed to look at these very low levels,” Prof Shaaban explained, “they were originally designed to select the high expression levels”.
The upshot is that even expert pathologists struggle to agree on whether a tumour is HER2-low. Prof Shaaban pointed to her recent study looking at the agreement between 16 expert pathologists on scoring HER2-high and -low tumours. “We found that we were concordant except for the very low levels,” Prof Shaaban summarises. “We found that it was difficult using the eyeballing even for expert pathologists, even when we tried a second round of scoring. So we were basically 50/50, whether calling them zero or 1+.”
This lack of concordance using IHC to identify HER2-low and -ultralow patients is concerning for Prof Rakha. “So now the test may be irrelevant, because how can you differentiate between what’s called ultra-low and what is negative? You are making the test a bit difficult, [as it is about] which patient should be excluded now, not which patient should be included.”
How do we move forward?
Prof Bartlett pointed out that “the ASCO CAP guidelines for HER2 have always stated that for a novel technology to be introduced for HER2 testing, it needs to show at least 95% concordance to FISH results”. Prof Shaaban showed data from her team’s research that MammaTyper® had excellent concordance with protein expression, including 95% for HER2 and 94.7% for ER – which suggests MammaTyper® could meet that 95% ASCO-CAP threshold.
However, “we have to also recognise that there are prejudices to overcome,” said Prof Bartlett. “[The ASCO CAP guidelines] precluded the use of any test except for immunohistochemistry for determining ER and PR, irrespective of the evidence base. […] And I think that’s bad science.”
While none of the experts believes that IHC will be disappearing from pathology labs any time soon, Profs Shaaban and Bartlett think using MammaTyper® alongside IHC could improve the accuracy of diagnosis.
But Prof Rakha argued that it is not enough for a test to be ‘as good’ as IHC in the technical validity, the focus should instead be on improving predicting response to treatment. Despite how well established IHC testing for HER2 and ER testing is, at best only 70% of patients who are positive for either of these markers actually respond to treatment, he says.
Again, MammaTyper® may provide an answer. In a recent study, Prof Rakha and his team looked at a cohort of breast tumours which had all been designated HER2-positive by IHC, and reanalysed them using MammaTyper®. 13% of cases reanalysed were found by MammaTyper® to be either HER2-low or HER2-negative. Crucially, MammaTyper® was more able than IHC to predict which patients would have better disease-free survival and distant metastasis-free survival in response to Herceptin therapy.
“These are people’s lives that we are dealing with”
From the patients’ perspective, Dr O’Riordan warned that we must be careful before bringing in new tests that determine treatment, as the potential consequences of inaccuracy could be catastrophic.
“We need to remember these are women and men with lives at stake – you could incorrectly diagnose someone as HER2-negative when they’re HER2-positive, you give them a drug that could kill them, or they get brain metastases six months later. These are people’s lives that we are dealing with.
“Patients have blind trust in doctors, that we are using the best evidence-based technology and tests to diagnose,” Dr O’Riordan continued. “We need to make sure that if we're bringing [a new test] in, it is just as good if not better as what we are already using.”
Prof Shaaban agreed the stakes are high: “We cannot afford in the diagnostic setting to get one patient wrong, one tumour wrong,” she says. “We have to have this degree of certainty that we are providing the best test and getting it in the right time as well.”
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