Precision oncology is revolutionizing the way we treat cancer by tailoring therapies to the genetic makeup of individual tumors. As our understanding of cancer’s molecular biology continues to expand, therapies are becoming more targeted, effective, and individualized. This shift toward personalized medicine is gradually becoming the standard of care, offering hope for better outcomes in patients with advanced cancers.
Molecular Tumor Boards (MTBs), are multidisciplinary teams of experts that play a pivotal role in the application of precision oncology and the translation of research findings into clinical practice. The Molecular Tumor Board routinely reviews cases of individuals with advanced cancer and interprets the genomic data obtained through next-generation sequencing (NGS) to ultimately explore molecularly-informed treatment recommendations. These MTBs however, are most commonly available in tertiary cancer centers, making access to them still limited. That is why our team at the Johns Hopkins Molecular Tumor Board (JH MTB) recently published a case report (DOI) in The Journal of Clinical Oncology (JCO), to open up an educational discussion on the genomically informed treatment paradigm. This case report leverages a discussion held at our Molecular Tumor Board that highlights the important role of the MTB in the management of metastatic breast cancer, and it details the journey of a patient whose tumor developed resistance to targeted therapy, identified using NGS, and interpreted by the JH MTB.
We discussed the case of a young woman diagnosed with early stage hormone receptor–positive, HER2-negative breast cancer, who as per standard of care, received neoadjuvant chemotherapy followed by bilateral mastectomy. Germline testing identified a heterozygous pathogenic loss-of-function PALB2 frameshift mutation which is known to be associated with an increased lifetime risk of breast, pancreatic, and ovarian cancer. The patient’s cancer recurred four years after the initial diagnosis and as biopsy of a metastatic site showed hormone receptor–positive breast cancer, she received letrozole monotherapy. Following further disease progression 15 months later she received the PARP inhibitor olaparib as part of a clinical trial given the presence of the PALB2 germline mutation.
PALB2 is one of the genes involved in DNA repair, specifically in homologous recombination (HR). Loss of function of PALB2 leads to the inability to properly repair DNA, specifically double-strand breaks, which can result in genetic instability and contribute to cancer progression. This is referred to as homologous recombination deficiency (HRD), and, as in this case, it can be driven by loss-of-function mutations in one of the genes of the HR pathway. Cancers with DNA repair deficiency rely on alternate DNA repair mechanisms and this creates an opportunity for therapies that block these alternate DNA repair pathways such as PARP inhibitors (PARPi) to block DNA repair in cancer cells ultimately leading to tumor cell death.
However, some tumors can develop resistance to PARPi through acquired mutations that restore homologous recombination, like in this case. At the time of disease progression on olaparib, a liquid biopsy detected the germline PALB2 mutation, together with a plethora of new PALB2 mutations that all restored the PALB2 reading frame, practically negating the effect of the germline loss-of-function mutation. The JH MTB reasoned that these reversion mutations all restored homologous recombination that allowed the metastatic clones to escape synthetic lethality through PARPi therapy. A large number of different PALB2 reversion mutations were detected in the bloodstream, which represents the reservoir where circulating DNA from any metastatic site is shed. As such, the JH MTB team hypothesized that different PALB2 reversion mutations were acquired and selected for in various metastatic sites and potentially at different timepoints during PARPi therapy. This essentially means that these reversion mutations, although all driven by a shared selective pressure of PARPi therapy, emerged separately at different metastatic sites and at different times during tumor evolution.
The emergence of polyclonal reversion mutations in PALB2, following PARP inhibition, suggest convergence evolution in this tumor, through independent genomic events, in response to the shared selective pressure of target therapy, ultimately restoring homologous recombination and DNA repair, and leading to a clinically refractory phenotype. Such reversion mutations have been observed in ovarian, breast, pancreatic, and prostate cancer with a prevalence of approximately 26% and the cancer clones harbouring these reversion mutations gain a fitness advantage, followed by positive selection that clinically manifests as therapy resistance. As seen in this case, different subclones can develop genomically distinct but phenotypically similar resistance when subjected to a shared selective pressure.
This case highlights the importance of elucidating the underlying mechanism of resistance and uncovering the molecular biology driving the refractory phenotype. By leveraging advanced genomic techniques like next-generation sequencing and the multi-disciplinary expertise of Molecular Tumor Boards, we can uncover the intricate mechanisms behind treatment resistance, such as the polyclonal reversion mutations observed in this patient. Our findings also illustrate the importance of real-time monitoring to adapt treatment approaches. As personalized therapies continue to evolve, the integration of genomic profiling into clinical decision-making remains essential for identifying the most effective treatment options and overcoming resistance. This case additionally highlights the advantage of liquid biopsy to both allow for minimally invasive real-time serial monitoring for arising resistance variants and to enable comprehensive assessment of the genomic landscape across metastatic sites in heterogeneous tumors. The collaborative, multidisciplinary MTB review process exemplified by this case is a powerful model for translating molecular insights into actionable treatment strategies, ultimately improving outcomes for patients with advanced cancer. Lastly, we emphasise the need for broadening access to MTBs, ensuring that genomically informed care is available to a wider range of patients.
