A tumor’s ‘signature’ reveals the key to treatment in precision oncology

A potential response to cancer is written — on a microscopic level — in its very tumor cells. For decades, treatment and prognosis of the disease has been largely determined by the organ, the anatomical location in which the cancerous mass is located. But now, science has placed a spotlight on something more ambitious: learning the tumor’s signature, or rather, the molecular alterations that characterize its malignant cells. The latest meeting of the American Society of Clinical Oncology (ASCO), which took place last weekend in Chicago, has given further impetus to precision oncology and highlighted how cancer biology, those microscopic genetic characteristics that define it, are playing an increasingly important role in determining therapeutic approach, and even predicting prognosis.

One paradigmatic example of this conceptual revolution has been a celebrated Daraxonrasib study, on a pancreatic cancer treatment that has managed to double survival rates in metastatic stages (the new drug achieves a median survival of 13 months, compared to six months with conventional chemotherapy). This treatment has achieved something scientists once thought impossible: targeting the mutated KRAS gene, which is responsible for the aggressive growth of pancreatic cancer and other tumors. This research, presented during one of the conference’s plenary sessions, drew a long ovation and brought the audience to its feet, due to the treatment’s promise in treating the devastating cancer.

“Oncology is becoming biologically fragmented within each tumor. We no longer speak of a single type of cancer [linked to a specific organ]: the subdivision of different diseases within a tumor based on molecular alterations has been confirmed,” notes Aleix Prat, director of the Clinic Barcelona Comprehensive Cancer Center. There are an increasing number of biomarkers and more genetic alterations being identified that allow us to assign specific “labels” to tumors.

For example, within breast cancers, there are some that grow in response to hormones (luminal), others with a mutation in the HER2 gene (called HER2+), and a third group — the most aggressive — known as triple-negative (they express neither estrogen nor progesterone receptors, nor do they have excess HER2). Subdivisions have also been created for lung cancer, depending on whether or not they have certain molecular alterations (for example, in the ALK or EGFR gene).

The presence of key mutations can determine treatment if there are pharmaceuticals that target them, and ultimately, prognosis. “We are moving away from an approach to oncology that involves intensifying treatments and adding drugs empirically, toward a more targeted selection of patients based on tumor biology,” notes Prat. The most impactful research presented at the world’s leading conference on clinical cancer research reflects this shift: biomarkers, genetic mutations and molecular subtypes have taken center stage in defining therapeutic strategies.

Such is the case with the LIBRETTO-432 clinical trial, which evaluates a targeted therapy as an early-stage adjuvant treatment for non-small cell lung cancer with alterations in the RET gene. This accounts for just 2% of patients with non-small cell lung cancer, but this molecular alteration can determine the prognosis of their disease. The drug, called Selpercatinib, is a RET kinase inhibitor (it blocks the abnormal activity caused by this molecular alteration) and, according to the study, reduces the risk of relapse and death by 83%.

“This study shows that precision medicine through targeted therapies is beginning to play a role in curative settings and is extending survival rates,” says Ernest Nadal, scientific director of the Catalan Institute of Oncology. The doctor emphasizes that today, “a good molecular diagnosis” is essential for making the best treatment decisions. “This study is an example of how, by applying precision medicine, we improve curability outcomes.”

Another study in patients with high-risk localized prostate cancer who underwent radical prostatectomy showed that adding apalutamide to androgen deprivation therapy increases relapse-free survival time. Apalutamide is another targeted therapy directed against a specific molecular target: an androgen receptor.

Similarly, two other trials in prostate cancer patients with alterations in DNA repair genes have shown that the combination of two targeted therapies (Enzalutamide, another androgen inhibitor, and Talazoparib, a PARAP inhibitor) can improve anti-tumor response with advanced prostate cancer. According to Joaquín Mateo, a researcher at the Vall d’Hebron Institute of Oncology who participated in these studies, the results “highlight the importance of identifying patients whose tumors have these types of mutations.” He also emphasizes the importance of “providing healthcare systems with access to genomic testing for all patients with metastatic prostate cancer.”

Organ-agnostic tumors

There is no longer any doubt that identifying a cancer’s signature is a way to uncover its vulnerabilities. Prat also points out that there are biomarkers that are beginning to be “organ-agnostic”. In other words, these molecular alterations can be found in tumors from different organs. “HER2+ is no longer exclusive to breast cancer; it is also seen in gastric cancer. KRAS alterations are found in the pancreas and also in the lung. BRAF mutations are not exclusive to melanoma either,” the oncologist explains.

Prat argues that oncology is moving towards being “more organ-agnostic and more based in the tumor’s underlying biology,” but admits that strategies like basket trials, in which a small group of patients is grouped based on the molecular alterations in their tumor, rather than its location — “have not yet taken hold.” Regulatory authorities, particularly the European Medicines Agency, are reluctant to approve a drug without specific data for a particular tumor.

According to Nadal, “the organ where the tumor is located still plays a major role, but more and more treatable genetic alterations are being identified.” Javier Cortés, director of the International Breast Cancer Center at the Pangaea Oncology Group in Barcelona, agrees: “Agnostic treatment has not yet been implemented, but it is true that we must examine the tumor’s biology. In fact, sequencing the tumor is key. The treatment of a hormone-receptor-positive breast tumor in the metastatic phase depends on the tumor’s biology, because by blocking alterations, the patient improves,” he explains.

There are no molecular markers for all tumors, nor are all genetic alterations treatable. There is an important limit, Nadal admits. “The more complex the tumor is molecularly, the higher the patient’s risk of a poor outcome,” he says. “That makes sense because the greater the number of genetic alterations and aberrations, the more leeway the cancer has to evade treatment. When you sequence a tumor, you find many things. There are drivers [key mutations] that have an effect on the tumor, but very few alterations are actionable.”

New targets are still to be discovered, but the oncologist believes that the most common alterations have been identified. “There are some alterations that are currently targets and for which we have a drug, but there are others for which we don’t, and in those cases, the solution will have to come from a different angle,” he notes. For example, through trying to boost the immune system so it can better attack the tumor.

Hopes for liquid biopsy

A deep understanding of tumor biology has also paved the way in the field of diagnostics, Prat adds. “Translational oncology, based on understanding biology and using biological tools, is beginning to make its way into actual clinical practice with artificial intelligence, liquid biopsy, and biomarkers for diagnosis and treatment decisions.”

In this regard, the results of a British study assessing an early-detection test for various tumors are particularly telling. It involves a type of liquid biopsy — a test that uses a blood sample (similar to one taken for a routine blood test) to detect minute traces of cancer before it is visible.

The study’s goal was to advance tumor detection through earlier detection, and although the research did not achieve its objectives (significantly reducing the number of tumors detected in more advanced stages), it did show “encouraging” prospects for the early identification of certain tumors. The research suggests that annual screening via blood tests could change the timing of cancer detection.

Such findings are particularly relevant in situations lacking available early detection tests, such as in the case of ovarian or pancreatic cancer. According to its authors, the study “demonstrates that annual multi-cancer early detection testing is feasible at scale within a national health system and can increase the number of cancers detected through screening.”

The scientific community has been touting liquid biopsy for years as the tool of the future when it comes to early detection, but its actual role remains very limited. “It’s still erratic. It’s used as a monitoring tool within the context of studies,” notes Nadal.

Cortés, who just received the Giants of Cancer Care award for his career in breast cancer research, argues that the role of liquid biopsy lies in patient monitoring, to “try to diagnose metastases before they become visible.” “In the future, the most sensitive monitoring will be done through blood tests. And if something comes up, we treat it,” he says.

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