December 1, 2023

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Why breast cancer classification and treatment may be about to change?


Why breast cancer classification and treatment may be about to change?

On June 5, 2022, AstraZeneca and Daiichi Sankyo announced at the ASCO conference ( the annual meeting of the American Society of Clinical Oncology), the most concerned antibody peptides for breast cancer and even the entire cancer treatment.

Results of the Phase III DESTINY-Breast04 clinical trial of Trastuzumab Deruxtecan in HER2-low breast cancer.


The results show that Trastuzumab Deruxtecan, which also targets HER2, is significantly more effective than the existing standard therapy (chemotherapy) in this population that has been ineffective against HER2-targeted therapy in the past [1].

This result will inevitably change the current classification and treatment standards of breast cancer, which can be said to be a subversive progress.


The current classification and treatment of breast cancer is based on the expression of HER2 and hormone receptor (HR) on tumor cells. For example, the new cases of breast cancer in the United States from 2015 to 2019 are classified according to the expression of HER2/HR:



Why breast cancer classification and treatment may be about to change?


HR-positive (HR+) patients can be treated with hormone blockade, such as Tamoxifen. As long as it is HER2-positive (HER2+), it can be treated with drugs targeting HER2, the most famous being Herceptin ( Trastuzumab ).

If neither HR nor HER2 is positive, it is a so-called triple-negative breast cancer, and there are few suitable targeted therapies.


In recent years, there have been many breakthroughs in breast cancer treatment. For example, in HR+/HER2- patients, the emergence of CDK4/6 inhibitors has added an extremely effective treatment option.

Triple-negative breast cancer, if there is a BRCA1 mutation, PARP inhibitors can be used.

But a big pity is that although HER2-targeted drugs are excellent, the population that can benefit from them has been relatively limited – HER2-positive patients are only a few.


In fact, the standard of HER2 positivity is very strict. It does not mean that tumor cells express HER2, but express a large amount of HER2. The standard HER2 expression identification uses a combination of protein expression and gene expression.

Only protein expression (identified by IHC) is scored 3 (scoring system 0-3), or 2 points and gene expression is positive (identified by ISH technology) , is HER2 positive, otherwise it will be negative – including many cases with HER2 expression, but not so high.


Some people may be curious, why is it so harsh, relax the standards, and let more patients use HER2-targeted drugs? It’s really not good, because I tried it and it didn’t work. This futility is not just a problem in breast cancer.

When you hear HER2, everyone’s first reaction is breast cancer. In fact, HER2 is also expressed in other tumors.

Why haven’t you heard much about it? Because HER2-targeted drugs have been tried before, they are useless except in rare cases.

The reason for this result is probably because the HER2 expression of other tumors is much lower than that of breast cancer.


Because of this kind of regret, since the introduction of Trastuzumab ( Herceptin ), many pharmaceutical companies have been tinkering with a better HER2-targeted drug.

Some are making a better HER2 monoclonal antibody, while others are adding a cytotoxic drug (such as a chemotherapy drug) to the HER2 antibody.

HER2 expression is not high enough” is a stumbling block.


However, before the emergence of Trastuzumab Deruxtecan, the success was more to solve the drug resistance of Trastuzumab in breast cancer – such as Trastuzumab emtansine, an antibody-linked drug developed on the basis of Trastuzumab, after HER2-positive patients were resistant to Trastuzumab, this Medicines can also work.

This kind of progress is still positive for patients, but after all, it has not benefited more patients who cannot use HER2-targeted drugs.


Until Trastuzumab Der uxtecan came along, and suddenly HER2 positivity was not enough.

As can be seen from the name, as an antibody-linked drug, the antibody part of Trastuzumab Der uxtecan targeting HER2 is still Herceptin ( Trastuzumab ), which was launched in 1998 , but it is loaded with the cytotoxic drug Der uxtecan through a cleavable link. 


On Trastuzumab Der uxtecan, each Trastuzumab molecule is linked to 8 Der uxtecans , compared to Trastuzumab emtansine, which is linked to an average of 3.5 cytotoxic drug emtans ine per Trastuzumab.


In late 2019, the FDA first approved the use of Trastuzumab Der uxtecan in patients with HER2-positive breast cancer resistant to prior HER2-targeted therapy.

In the relevant clinical trials, the subjects were all drug-resistant people after receiving multiple lines of therapy (at least two or more HER2-targeted therapies), and in such a population, Trastuzumab Der uxtecan is still very Good efficacy, the overall response rate reached 60.3% [3].


Later, in earlier HER2-positive patients, Trastuzumab Der uxtecan also showed better efficacy than Trastuzumab emtansine and became the standard therapy after Trastuzumab resistance.


The latest data show that the efficacy of Trastuzumab Der uxtecan is not limited to HER2 positive.

The HER2 protein expression is only 1 or 2 but the gene expression is negative. These patients with low HER2 expression can also benefit.


In the DESTINY-Breast04 trial in a population with low HER2 expression , tumor progression-free survival was 5 months in the chemotherapy arm and nearly 10 months in the Trastuzumab Der uxtecan arm.

Overall survival was 16.8 months in the chemotherapy arm and nearly two years in the Trastuzumab Der uxtecan arm [1].


In other words, patients treated with Trastuzumab Der uxtecan had a significantly lower risk of disease progression (half the risk) and significantly longer survival.


The HER2 low-expression population in DESTINY-Breast04 includes two current breast cancer classifications: HR-positive HER2-negative and triple-negative.

90% of the subjects have received at least two lines of therapy, and 70% of HR-positive patients also use over CDK4/6 inhibitors.

It can be said that this is a group of patients who have experienced drug resistance after multiple treatments and have no choice.


In this context, the results for Trastuzumab Der uxtecan were surprisingly good.

Undoubtedly, with this breakthrough, people with low HER2 expression in breast cancer patients will no longer be classified as HER2 negative, and Trastuzumab Der uxtecan is about to become the new standard of care for these patients.


And how big is this crowd? 80% of breast cancer patients are HER2 negative, but more than 60% of them have HER2 expression.

That is to say, Trastuzumab Der uxtecan has increased the applicable population of HER2-targeted drugs from the original 14% of the HER2-positive population to more than half of breast cancer patients.


Therefore, Trastuzumab Der uxtecan is about to bring about a major change in the classification and treatment of breast cancer.


And Trastuzumab Der uxtecan is only in its infancy. In this trial of HER2-low breast cancer, there was no difference in patient benefit with a protein expression score of 1 or 2.

From another perspective, in this group with a low overall HER2 expression level, people with relatively lower expression levels also benefited well, not worse than those with higher expression levels.


What about those who did not enter the trial and had a HER2 protein expression score of 0?

The expression of HER2 in it should also be a bit uneven, right? Are there many people who also benefit from Trastuzumab Der uxtecan?

The original 0-3 points IHC identification of HER2 expression is obviously not enough.

Finding the lower limit of HER2 expression applicable to Trastuzumab Der uxtecan is likely to lead to new methods of HER2 expression identification.


There are other tumors, and now HER2-targeted drugs are only suitable for HER2-positive people in gastric and esophageal cancers, in addition to breast cancer.

The success of Trastuzumab Der uxtecan in breast cancer is redefining the concept of HER2 positivity.

Perhaps in the near future, Trastuzumab Der uxtecan will also redefine which tumors can be targeted with HER2.


Of course, the success of Trastuzumab Der uxtecan has also overwhelmed other competitors. For example, the antibody-linked drug Sacituzumab govitecan targeting TROP2 is now suitable for triple-negative breast cancer and urothelial cancer.

But Gilead, which bought Sacituzumab govitecan at a huge cost, is also working hard to expand its scope of application.

A key target is the HR-positive HER2-negative breast cancer population.


It’s a pity that the results of the Phase III clinical trial also announced at ASCO were painless – Sacituzumab govitecan , relative to chemotherapy, delayed the time of tumor progression, but the degree of delay was not high.

In the trial, tumor progression-free survival in the chemotherapy arm was 4 months, and sacituzumab govitecan increased by only 1.5 months.

This inconsistent result may not be able to “convince the public”. Now that HR-positive HER2-negative has to be re-defined, it is even more difficult to say what the future holds.


But such headaches are exactly the boon for patients, because every successful new drug raises the bar for the next success, and the better it is, the higher the bar will be raised.







Why breast cancer classification and treatment may be about to change?

(source:internet, reference only)

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