The HER2 protein is the new opportunity for less frequent cancers and orphans of therapies

In cancer, as in life, there are classes. Not only from patients with more or less chance of living, but more or less famous tumors, which have more research resources. Yes, it sounds cruel, but that's how it is.. “Breast cancer has a very important social component. The figure of women has made more efforts. In addition, she participates more in the trials, deals with and worries about the disease,” says Miguel Martín, president of Geicam (Spanish Breast Cancer Research Group) and head of Medical Oncology at the Gregorio Marañón University Hospital.

But these tumors have served as a lever of change. Research in breast cancer has opened the door to other tumors, less frequent, but more aggressive and with fewer therapeutic options.. In this case, a marker associated with breast cancer (lung and colorectal) has also been observed in other tumors, specifically HER2. It is a protein that participates in the normal development of cells.

And if HER2 is found in more tumors than breast tumors, can we treat them all in the same way? The response found by researchers has been positive.. With the same drug? Yeah. At the Congress of the American Society of Medical Oncology (ASCO) they have presented the results of a study, the Destiny-Pantumor02 study, which shows how the use of a conjugated antibody, trastuzumab-deruxtecan, can be used transversally in various types than tumors that share HER2 overexpression, such as gynecological (endometrium, cervix and ovary), genitourinary (bladder), biliary tract and pancreas, among others.

If we put the figures on the table, we realize the magnitude of the problem. Even more so when we remember those numbers are lives. The forecasts of new diagnoses for this year of the Spanish Society of Medical Oncology (SEOM) in breast cancer point to 35,001 cases. If we add the cases of tumors in the study, all together they reach 46,703 (biliary, 2,648; cervix, 2,326; uterus, 7,171; bladder, 21,694; ovary, 3,584; and pancreas, 9,280).

Some types of cancer cells in these tumors produce a number of abnormal amounts of this protein.. This is thought to cause malignant cells to multiply rapidly, allowing them to travel and colonize other parts of the body.. For this reason, “measuring the amount of this protein in some types of cancer cells is useful for planning treatment,” explains Antonio González Martín, director of the Cancer Center Clínica Universidad de Navarra and one of the Spanish participants in the international study.

Together with him, Aranzazu Manzano, clinical coordinator of the Experimental Cancer Therapies Unit of the San Carlos Clinical Hospital in Madrid, points out that not everything that is presented at ASCO is a turning point, “but with this study we are going to change clinical practice, because we are going to provide a therapeutic solution to an infrequent subgroup of patients”.

Five other Spanish centers have had lead patients in the trial: Hospital 12 de Octubre and Hospital La Paz in Madrid, Hospital and Cancer Research Institute Vall d'Hebron in Barcelona, Hospital General Universitario de Valencia and Hospital Universitario Reina Sofía in Córdoba.

What does this new opportunity for less frequent tumors consist of?

Bradley Alexander McGregor, assigned as an ASCO Expert and specialist oncologist at the Dana-Farber Cancer Institute in Boston, explains to this medium the role of this protein. “HER2-targeted therapies have long been established as playing a critical role in breast cancer (as well as gastric cancer), but there are others that express HER2 in which no therapy has been approved, so they represent a unmet need”.

The essay has been presented under the late-breaking modality, a way for works that arrive at ASCO at the last minute. Specifically, the results of the interim analysis of the phase II Destiny-PanTumor02 trial have highlighted the efficacy and safety of the drug in heavily pretreated patients with multiple HER2-expressing advanced solid tumors, such as those of the bile duct, bladder, cervix , endometrial, ovarian, pancreatic and other rare cancers.

González points out that “it is an interesting point that the number of lines of previous treatments to which patients with gynecological tumors had been subjected has been ignored.. There might even be some that had gone through about eight so far.”. As early as March, this therapeutic approach achieved the objective response rate in this phase II trial and demonstrated durable responses in multiple types of HER2-expressing tumors.

The data showing the efficacy of the conjugated antibody, trastuzumab-deruxtecan, are the following response rate percentages: in endometrial cancer 57.5%; in the case of the cervix, 50%; ovary 45%; urothelial, 39%; bile ducts, 22%; and, pancreas, 4%. Most study participants tolerated treatment, however 11.6% discontinued due to adverse events. The most common side effects were nausea, fatigue, and cytopenia (low blood cell levels).

The director of the Cancer Center of the Clínica Universidad de Navarra insists that “the response rates are significant. It has also been seen that they are durable over time [11.8 months the work points out]”. And this leads us to consider that beyond the proof of concept it can be reproduced in the early stages of tumors, “here they will be better, because the patients will not have gone through so many previous options and their body will be less damaged (by the tumor and the toxicities of the treatments)”, predicts González.

A HER2 screening to find patients who are candidates for therapy

The three experts coincide in pointing out that HER2 is already an old acquaintance for tumor diagnostic services, “since it has been widely used in breast, colon and lung cancer to determine whether cancer cells have HER2 receptors or of hormones on its surface”, stresses the oncologist at the Madrid center.

“HER2 expression can be easily identified by immunohistochemistry (IHC). Drug conjugates and antibodies are like guided missiles that can aim at a target and deliver high doses of chemotherapy directly to the cancer,” explains McGregor, adding that “in this study, we see that regardless of the cancer studied, as long as the tumor expresses the right target (HER2), T-Dxd [technical name of trastuzumab-deruxtecan] can shrink the tumor and minimize side effects.”

Trastuzumab-deruxtecan is called an antibody conjugate because it has a dual function. On the one hand, trastuzumab (a monoclonal antibody) targets the HER2 protein, expressed on the surface of certain tumor cells.. After sticking to it, it acts like a space rocket: it releases its cargo, deruxtecan (a chemotherapy drug), which crosses the membrane, damages the DNA and causes cell death by apoptosis.

Manzano stresses that now the fundamental step is to find HER2 in tumors, “in my clinical practice I already do it”. It would be setting up a kind of screening for HER2 overexpression, “because in pathology departments it is already done with other tumors and it is neither complicated nor does it involve additional cost.”

For this reason, the novelty lies in looking for those small groups, which are no more than 4-7% of the tumors in each location, in order to offer a real option to patients who, in many cases, do not have more options.. “We already knew about his work in breast cancer, he presented last year in plenary here too [at ASCO]. But now we have successfully tested it in other less common cancers,” explains Manzano.

More results in more ‘known’ cancers: colorectal and breast

On the other hand, a presentation at the congress of the primary results of the phase II trial DESTINY-CRC02 demonstrated the safety and efficacy of the drug in patients with HER2-positive advanced colorectal cancer with progression after baseline treatment. This trial was initiated on the basis of positive data for this treatment in the Phase II trial DESTINY-CRC01.

Another communication thus reported the pooled analyses of the drug’s efficacy and safety in the DESTINY-Breast01, 02 and 03 trials in breast cancer patients aged 65 years and older compared with patients younger than 65 years.