Hereditary Cancers as a Key to Targeted Treatment: Which Drugs for Which Syndrome?

Hereditary cancer syndromes increase susceptibility to certain cancers because of genetic mutations. However, hereditary cancer syndromes do more than identify disease risk: they also indicate which targeted drugs may be effective. Treatments targeting specific genetic mutations offer patients more effective and personalized treatment options.

A notable study addressing this timely topic was published in March 2023 in Genes under the title "Personalized Systemic Therapies in Hereditary Cancer Syndromes". 

Study Summary:

• In women carrying a BRCA1 mutation, the risk of breast cancer is 55-72% and that of ovarian cancer is 39-44%. In BRCA-mutated cancers, PARP inhibitors can extend survival by up to 7-19 months.
• In Lynch syndrome, the risk of colon cancer is 30-73% and that of endometrial cancer is 30-51%. Pembrolizumab provides a response rate above 50% in patients with MSI-H Lynch syndrome.
• In VHL syndrome, belzutifan treatment offers a 50% tumor shrinkage rate.
• In RET-mutated medullary thyroid cancer, selpercatinib has a response rate of 69%.

Personalized treatments make more effective care and longer survival possible for patients with hereditary cancers!

The Importance of Personalized Treatment in Hereditary Cancers

The rise of personalized medicine in cancer treatment represents a major revolution, particularly for hereditary cancer syndromes. These syndromes are conditions in which inherited mutations in specific genes create a predisposition to cancer. Developing targeted systemic treatments for tumors arising from these genetic changes has improved patients' survival rates and substantially enhanced treatment responses.

In this article, we examine the latest and most effective personalized systemic treatments used in hereditary cancer syndromes and highlight their importance in light of scientific evidence.

1. BRCA- and PALB2-Associated Cancers: PARP Inhibitors

Inherited mutations in BRCA1, BRCA2 and PALB2 increase susceptibility to several cancers, including breast, ovarian, pancreatic and prostate cancer. Because these genes play a critical role in DNA repair, people with these mutations have impaired homologous recombination repair (HRR). This is where PARP inhibitors come into play.

• Olaparib, talazoparib, rucaparib and niraparib have received FDA and EMA approval for patients with BRCA mutations and have shown effectiveness particularly in breast and ovarian cancers.

• Olaparib (Lynparza) has been shown to extend median survival by up to 7 months in metastatic breast cancer and to provide a substantial progression-free survival (PFS) benefit of 19 months in platinum-sensitive ovarian cancer.

As these treatments become standard for patients carrying BRCA mutations, HRR gene panels are being expanded to include ATM, CHEK2 and other DNA repair genes, while new indications are being investigated for patients carrying mutations in these genes.

2. Lynch Syndrome and Immune Checkpoint Treatment

Lynch syndrome results from mutations in the DNA mismatch repair (MMR) system and increases the risk of colorectal, endometrial and other gastrointestinal cancers. These patients' tumors have high microsatellite instability (MSI-H) and an immunogenic tumor microenvironment.

• Immunotherapies such as pembrolizumab and nivolumab that target PD-1 have received FDA approval, particularly for advanced MSI-H Lynch syndrome-associated cancers.

• Studies have shown that pembrolizumab increases the tumor response rate to above 50% in patients with Lynch syndrome and produces a complete response (CR) in some patients.

Recent studies have shown that locally advanced rectal cancers associated with Lynch syndrome can be eliminated using immunotherapy alone, without surgery or radiotherapy. This opens the door to an "organ-preserving" strategy that does not require surgery.

3. Von Hippel-Lindau (VHL) Syndrome and HIF-2α Inhibitors

Von Hippel-Lindau syndrome increases the risk of tumors such as renal cell carcinoma (RCC), pheochromocytoma and hemangioblastoma in people with a VHL gene mutation. Hypoxia-related tumor growth is a fundamental mechanism in this syndrome. HIF-2α inhibitors target this hypoxia signaling pathway and are effective in VHL-associated cancers.

• The FDA-approved drug belzutifan has achieved an objective response rate above 50% by shrinking tumors in patients with VHL syndrome-associated RCC.

• Clinical research suggests that these next-generation agents could become standard treatment options for metastatic RCC in the future.

4. RET-Mutated Cancers and Selective RET Inhibitors

RET mutations can cause multiple endocrine neoplasia type 2 (MEN2), leading to medullary thyroid cancer and pheochromocytoma. Selective RET inhibitors offer effective treatment options for these cancers.

• Selpercatinib and pralsetinib have received FDA and EMA approval, particularly for patients with advanced RET-mutated medullary thyroid cancer.

• Clinical trials have achieved objective response rates of up to 69% and substantial improvements in survival.

Conclusion: Genetic Testing and the Future of Personalized Medicine

Hereditary cancer syndromes are now being identified earlier as genetic testing becomes part of routine clinical practice, and they are managed more effectively with personalized targeted systemic therapies. As genomic analyses become accessible to more patients, they open the way to new and more successful approaches to cancer treatment.

In the future, treatment plans are expected to become even more precise through multi-omics analyses that go beyond gene mutations to examine tumor molecular biology in greater depth. This could provide more patients with more effective treatment options and fewer side effects.