Maybe you are a breast cancer survivor? Breast cancer is surprisingly common. About 13% of women experience breast cancer some time in their life. The good news is that most cases of breast cancer are successfully treated. But even with the high cure rate, breast cancer kills almost as many women as lung cancer. About 10% of breast cancer treatments are unsuccessful, even with the state-of-the-art treatments now available.
How is it that we are not able “cure” every case of breast cancer? Well, consider that each patient presents their own unique set of circumstances. Some years ago, one of my relatives discovered something unusual in one of her breasts. It was not a lump, but a generalized swelling. After imaging and biopsies, it became clear that she had a rare form of breast cancer known as IBC (Inflammatory Breast Cancer). This disease spread through lymph vessels in the breast. Her prognosis was much worse than for more common forms of breast cancer, with IBC five year survival closer to 40% (versus 90% survival across non-metastatic invasive breast cancer). The point I want to make here is that there are several kinds of breast cancer. In the case of IBC, it can clearly be seen to be different from other breast cancers by how it looks and feels.
But there are also more subtle differences between cases of breast cancer. Some years ago, researchers started looking to see if cancer cases differ in how genes were behaving in tumour tissue. That is, the researchers looked at which genes were either “turned on” or “turned off” in the cancer tissue in comparison to the healthy tissue of an individual cancer patient. They did this with many hundreds of patients and then compared results between patients. They found that these breast cancer patients fell into about four subtypes based on similarities in gene expression.
Recognizing that breast cancer cases can be grouped into distinct “molecular” subtypes dictates how these cases are treated. One of the subtypes identified in gene expression studies is characterized by an over-abundance of HER2. What is HER2? Suffice it to say that it is something that is now routinely tested from breast cancer samples. In the past, patients with high HER2 had much worse prognosis compared to those with normal levels of HER2.
But HER2 is a cancer treatment success story. Savvy scientists at biotech pioneer Genentech saw HER2 as an opportunity. Using the tools of biotech, they came up with something that sticks to HER2. They called their product Herceptin, and it was approved for use in women with HER2 positive metastatic breast cancer in 1998. Trastuzumab (generic name for the active ingredient in Herceptin) is the start of a journey that led to better outcomes for patients with high HER2. It was one of the first “targeted” therapies in cancer treatment. That is, trastuzumab interacts directly with HER2, and HER2 is a cell component that can be described as a “driver” of cancer. The “job” of HER2 is to help tell a cell to grow and divide. Too much HER2 and cells grow out of control (they become cancer). Interfering with HER2, therefore, can slow or stop the growth of cancer cells. Herceptin and other drugs derived from trastuzumab have greatly improved prognoses for cases where HER2 is over-expressed.
However, the mainstay of cancer treatments are still the drugs from the previous century, i.e., chemotherapies like Adriamycin (doxorubicin), Taxol (paclitaxel) and Cytoxan (cyclophosphamide). In contrast to targeted therapies, these drugs reduce cancer growth by interfering with cell division in general. An analogy is that chemotherapies are like stopping all cars on the highway to stop one driver from speeding. Chemotherapies (also known as cytotoxins) have saved a lot of lives and continue to do so, but in some cases, they may not be effective, and this is where personalised medicine comes in.
The concept of targeting the nuts and bolts of cancer only became feasible in the light of understanding the workings of the cell. Knowledge of how cells work has grown by orders of magnitude in the last decades. Empowered by a host of advancements across all sciences, investigators in the field have seen possibilities for the development of therapies that combine elements. For example, it was recognized many decades ago that monoclonal antibodies (“mAbs” like trastuzumab) could be used to deliver a cytotoxic agent directly to cancer cells whilst avoiding non-cancer cells. The idea was that these would be like “silver bullets” especially effective against their target. Several examples of this approach have been realized and are now used as cancer therapies. These include mAbs coupled to radioactive isotopes (e.g. Pluvicto) as well as mAbs coupled to cytotoxins known as antibody drug conjugates (ADCs). There are several ADCs now approved for use in various cancers. These target components on the surface of cancer cells deliver a potent cytotoxic payload.
Enhertu is the most recent “weaponized” version of trastuzumab. Enhertu (trastuzumab deruxtecan) attaches to HER2 (just like Herceptin) but it also has several molecules of cytotoxic “chemo” attached. Enhertu is now the most famous ADC after clinical trials showed that it improved outcomes for a large number of participants, including patients with normal levels of HER2.
Breast cancer is not the only cancer that shows treatment relevant differences at the molecular level. Treatment of melanoma (a type of skin cancer) has also improved by recognizing variation in the cell component BRAF (using the drug vemurafenib). In fact, an early step on the path towards grouping cancer patients through molecular typing was in the recognition of chromosomal anomalies in certain types of leukaemia (the “Philadelphia chromosome” in CML) that resulted in one of the first “small molecule” targeted therapies (imatinib).
Examining cancer at the molecular level is a key aspect of what we like to call “personalised” cancer treatment. Although physicians have always considered their patients individually, therapies are usually limited and therefore applied in a “one-size-fits-all” approach. The tools that now exist allow cancer to be examined at the molecular level and have opened opportunities for treatment to be tailored more precisely to each individual case. Discussions of “personalised” a.k.a. “precision” medicine sometimes stray to “forward looking” concepts pushing to be “translated” from bench to bedside. But commercial products examining cancer genomes, although not routine, are now available (e.g. Foundation Medicine). There are also tests that look at expression level across several genes known to vary in certain cancers (e.g. Oncotype DX).
The reality in clinical practice is that the use of a companion diagnostic (a test used to assess whether the drug is likely to be effective in the particular patient) is normally required in the application of a targeted therapy. For example, in the USA the FDA has approved the use Guardant360 CDx to decide whether Enhertu might help certain lung cancer patients.
In summary, consider that there are now several targeted therapies that are usually used in conjunction with more “traditional” approaches including chemotherapy and radiation. Some drugs, like Enhertu, deliver toxic substances in a targeted way (e.g., ADCs) and have been shown to improve patient outcomes. A repertoire of companion diagnostics enables the use of targeted therapies in clinical practice today. There are also products that provide data across a broader panel of molecular markers, up to and including “whole” genome analyses. The fruits of cancer research are regularly being adopted into real life cancer treatment, with the effect of improving outcomes for patients.
Coremine Vitae can empower you with information on your cancer treatment. We can look at your treatment history and compare it to the most recent advances on the world stage, including treatments being developed in clinical trials. By looking at your treatment and testing history, we can uncover whether there are additional tests relevant to your case, as well as relevant and actionable therapeutic approaches and recruiting clinical trials. Our personalised report is designed to be discussed with your doctor, giving you specific questions to ask. We can also suggest leading experts and services from outside of your area or hospital system. Contact Coremine Vitae for more information.
