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Pik3ca Mutation Metastatic Breast Cancer

Frequency And Location Of Pik3ca Mutations

PIQRAY® (alpelisib) Mechanism of Action | PIK3CA Mutation in Metastatic Breast Cancer

As shown in Fig. 1, PIK3CA mutations were found in 31.2% of the BC patients, among them 66.1% were mutations in exon 20 , 32.6% were mutations in exon 9 , and 4 mutation in both exons 9 and 20. H1047R was the most common mutation type, accounting for 17.7% of the total samples and 56.5% of the total mutated samples. E545K, E542K, E545D and H1047L mutation accounted for 5.2%, 4.9%, 0.1% and 3.0% of the total

Conditions And Cancers Associated With Pik3ca Mutations

With genetic testing now available to look for a predisposition to cancer, talking about gene mutations that drive the growth of cancer can be very confusing. This is easier to understand by breaking these mutations down into two categories:

  • Germline mutations:Germline mutations are genetic changes that are present from the time of conception and are found in every cell in the body. These mutations may raise the risk of cancer but are not usually targeted in the treatment of cancer. BRCA mutations are an example of germline mutations. Most germline mutations occur in tumor suppressor genes, genes that code for proteins that function to repair damaged DNA or eliminate cells that can’t be repaired so that they can’t develop into cancer cells.
  • Somatic mutations: Mutations such as PIK3CA mutations are considered somatic mutations and are acquired in the process of a cell becoming a cancer cell. They are found only in the tissue or organ affected by cancer and not other cells of the body. They are not considered hereditary and cannot be passed from a mother or father to a child. When drugs are available that target these mutations, the mutations are referred to as “targetable” mutations or genetic alterations.

In addition to playing a role in many breast cancers, PIK3CA mutations have been noted in a dozen other cancers, particularly uterine cancer, bladder cancer, colon cancer, and head and neck cancers.

Sample Collection And Processing

For cfDNA samples, 20 ml of blood were collected using two 10 ml K2EDTA blood collection tubes and processed within four hours of collection. Plasmas were obtained through double centrifugation at 1600g for 15 min and 4500g for 10 min, and were stored at 80 °C prior to cfDNA extraction. Frozen tumor tissue samples were stored in a freezer at 150 °C.

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Effect Of Pik3ca Mutations On Breast Cancer Treatments

PIK3CA mutations have been linked to both a better and a poorer response to breast cancer treatments depending on the receptor status and type of treatment used.

HER2 Positive Breast Cancers

A 2014 study found that HER2 positive breast cancers with a PIK3CA mutation were less likely to achieve a complete pathological response when treated with a combination of neoadjuvant chemotherapy plus HER2 targeted therapies. The chemotherapy was a combination of a taxane such as Taxol and an anthracycline such as Adriamycin .

This was true even in people who were treated with two HER2 targeted therapy drugs, both Herceptin and Tykerb . That said, disease-free and overall survival were similar in both those with and without the mutation.

Several subsequent studies have found similar results, especially in people who had both HER2 positive and estrogen receptor-positive tumors.

Metastatic Estrogen Receptor-Positive Breast Cancer

A 2019 study found that people with metastatic ER+ breast cancer who had tumors with a PIK3CA mutation in the H1047R domain were more sensitive to the drug Afinitor . Afinitor is a drug that is classified as an mTOR inhibitor.

Treatment specifically targeting the mutation is now available.

Molecular Biology Techniques To Detect Pik3ca Mutations

Figure 2 from Mutation distributions and clinical correlations of ...

Direct Sequencing

Direct or Sanger sequencing is the gold standard for the mutational assessment of different biomarkers due to its reliability, availability, reagent affordability, and relatively low costs. Despite these advantages, low sensitivity remains its main limitation . Arsenic and colleagues compared the results obtained by Sanger sequencing and next-generation sequencing for PIK3CA hotspot mutations in exons 9 and 20 in 184 breast cancer samples, reporting a concordance rate of 98.4% . The three mutated tumors identified by NGS and missed by Sanger sequencing displayed a low allelic frequency. In another study, Sanger sequencing showed a lower performance rate in the detection of PIK3CA-mutated cases compared to multiplex PCR-mass spectroscopy and locked nucleic acid -PCR .

Real-Time PCR

Next-Generation Sequencing

Analysis of Liquid Biopsy Samples

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Pik3ca Mutation In Metastatic Breast Cancer

Metastatic breast cancer , also known as stage 4 or advanced breast cancer, means that the cancer has traveled from the breast tissue, or metastasized, to other parts of the body, like the liver, lungs, or brain.

Survival rates are lower in advanced breast cancer, but the right treatment can improve both length and quality of life.

According to a 2018 study involving more than 10,000 people, genetic mutations like those found in PIK3CA arent as common in early stage breast cancers.

But when PIK3CA mutations do occur in these cases, their presence is often associated with better clinical outcomes.

However, testing for a PIK3CA mutation isnt typically done in people with early stage breast cancer. Clinical guidelines recommend testing for PIK3CA mutations after a person has metastases from breast cancer.

Blocking Drivers Of Tumor Growth

Its important to remember, Shagisultanova says, that HER2 and PI3K are necessary for cell development and growth the sort of growth that takes place in normal tissue. However, when it becomes abnormally activated, all systems of checks and balances get unbalanced, and thats when cancer starts.

HER2 is a protein present in about 20% of breast cancers. HER2-positive breast cancers tend to be more aggressive than other breast cancers, though treatments designed to specifically target HER2 have been shown to be very effective. Many of those treatments involve blocking HER2 growth signals.

Since we discovered HER2 inhibitors, life expectancy for patients with HER2-positive breast cancer has improved tremendously, because were able to block one of the main drivers of this cancer, Shagisultanova says. If we just use chemotherapy and dont block HER2, cancer cells divide faster than we can kill them, even with a powerful chemotherapy. But once we block HER2 growth signals, the combination of that HER2 blocker and chemotherapy can kill tumor cells and cure patients with early stage HER2-positive breast cancer or prolong the life of patients with metastatic HER2-positive tumors.

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Breakthroughs And Clinical Trials

Alpelisibs approval was based on the results of a clinical trial called the SOLAR-1 study.

The trial included 572 female and male participants with HR-positive and HER2-negative breast cancer who already tried treatment with an aromatase inhibitor, like anastrozole , letrozole , and exemestane .

The study found that alpelisib significantly improved the amount of time people lived without their breast cancer getting worse. This is called progression-free survival.

The median progression-free survival was 11 months for people who received alpelisib plus fulvestrant. It was 5.7 months for people who received a placebo plus fulvestrant. This effect was stronger in people with a mutation in the PIK3CA gene.

Additional clinical trials are underway to assess new combinations of treatments involving alpelisib. These trials will also look at the role of similar gene mutations to better select people for this therapy.

There are also several other PIK3CA inhibitors under investigation in clinical trials in people with advanced breast cancer and a mutation in the PIK3CA gene, including taselisib and pictilisib.

Targeting The Pi3k Pathway In Hr+/her2 Advanced Breast Cancer

Dr. Jhaveri on Results of Taselisib in PIK3CA-Mutated Metastatic Solid Tumors

In the past decade, several translational research studies and clinical trials aimed to define the efficacy of targeting the PI3K pathway in breast cancer. However, the development of PI3K inhibitors has been historically troubled by toxicity, suboptimal activity, and the lack of reliable diagnostic strategies for an accurate selection of candidate patients . In the BOLERO-2 landmark study, the combination of ET with the mTOR inhibitor, everolimus, has been evaluated in postmenopausal women with ET-refractory HR+/HER2 MBC . In phase III clinical trial, 724 patients who have progressed after ET with aromatase inhibitors were randomized to receive either exemestane plus everolimus or placebo plus exemestane. The study met its primary endpoint by showing a significant progression-free survival benefit for the everolimus arm , with an assessment from a local investigator. The blinded independent central review revealed a median PFS of 10.6 months in the experimental arm against a median PFS of 4.1 months in the control arm . The OS was similar in both groups . Given the substantial benefits observed, everolimus is now approved for use in HR+/HER2 MBC upon progression after AI therapy however, no predictive biomarkers are available to date.

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Association Between Pi3kca Mutational Status And Pcr

A total of 52/55 patients underwent surgery the 3 remaining patients were refractory to neoadjuvant chemotherapy. Pathological assessment in the operated patients showed 13 pCRs, 38 partial responses and 1 non-responder.

There was no difference in the pathological response rate according to PI3KCA tumour mutation status, with pCRs of 21.4% and 24.4% in the patients with and without mutations, respectively. Among the 14 patients with PIK3CA tumour mutations at diagnosis, 3/14 achieved a pCR after neoadjuvant chemotherapy, and 2/14 were non-responders .2). Seven tumours had enough tissue to analyse PIK3CA mutation status after neoadjuvant chemotherapy. We found the same PIK3CA mutations as those described at diagnosis in 5 patients , with a lower rate of VAF. Of note, plasma samples were available after neoadjuvant treatment in 5/14 patients with mutations , with only one circulating mutation found . These results are detailed in Table Table22.

Among the 14 patients harbouring somatic PIK3CA mutations, compared to 3/8 without circulating mutations, 0/6 patients with circulating PIK3CA mutations at diagnosis had pCR . Thus, there is no predictive value of circulating PIK3CA mutations for pCR.

Biochemistry Of The Pi3k Signaling Pathway

Three PI3K classes have been discovered, of which class IA PI3K, a heterodimer comprising a p85 regulatory subunit and a p110 catalytic subunit,5 is clearly implicated in human cancers.6 The genes PIK3CA, PIK3CB, and PIK3CD encode three homologous class IA catalytic isoforms: p110, p110, and p110, respectively.7 In usual state, the PI3K p85 regulatory subunit interacts with p110 and inhibits its kinase activity, upon the receptor tyrosine kinase activation the p110 is relieved,8,9 then phosphorylates phosphatidylinositol -bisphosphate to generate phosphatidylinositol -trisphosphate at the plasma membrane. The second messenger PIP3 enables phosphorylation of the serine/threonine kinase AKT and of 3-phosphoinositide-dependent protein kinase-1 . Moreover, PDK-1 also activates AKT, which phosphorylates many downstream kinases, including the mammalian target of rapamycin complex.13,14 This phosphorylation cascade regulates cell survival and metabolism .15 On the other hand, the tumor suppressor phosphatase and tensin homolog dephosphorylates PIP3, counteracting PI3K signaling.16

Figure 1 Signaling by the phosphatidylinositol-3-kinase /AKT/mammalian target of rapamycin pathway.

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In Silico Design And Verifications Of The Pik3ca Assays

All primers and hydrolysis probes were designed using the software Primer3Plus with the sequences of the PIK3CA gene for the studied mutations they were then analyzed for gene specificity using Primer-BLAST. UNAfold and OligoAnalyzer webtools provided by Integrated DNA Technologies were used for secondary structures, self-dimer and hetero-dimer predictions. OligoAnalyzer was also used to adjust the melting temperature of the hydrolysis probes via locked nucleic acids substitutions in order to reach sufficient Tm compared to the associated primer pairs, while also improving the specificity of detection. To further improve the specificity of H1047L and H1047R detections, a non-fluorescent blocker was designed with the corresponding wild-type sequence and a 3-Phosphate modification. All oligonucleotides were synthesized by Eurogentec.

Pik3ca Mutations May Be A Favorable Predictive Factor For Response To Hormonal Therapy

Figure 2 from Mutation distributions and clinical correlations of ...

The last potential explanation for why PIK3CA mutations are associated with an increase in survival rate of some patients is that, although these mutations may enhance tumorigenicity, the same mutations may improve the response to treatments. In this hypothesis, PIK3CA mutations may increase hormonal therapy sensitivity and would not be a prognostic factor but rather a predictive factor for response. Our study found that PIK3CA mutations were significantly higher in ER-positive tumors than in ER-negative tumors . We speculate that this positive association between PIK3CA mutations and ER-positive tumors is due to cross-talk between the PI3K and ER pathways. Indeed, it has been shown that AKT phosphorylates the Ser167 residue of ER and increases its transcriptional activity, resulting in the preferential growth of ER-positive cells in the presence of PIK3CA mutations. Additionally, it is possible that negative feedback secondary to PI3K activation yields insensitivity to growth factor receptor stimulation, delaying the development of hormonal therapy resistance. Given that almost all ER-positive breast cancer patients are treated with tamoxifen or aromatase inhibitors, the generally favorable prognosis observed in PIK3CA-mutated tumors may simply be the consequence of a specific sensitivity of these tumors to hormonal therapy.

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Role Of Pik3ca Mutations In Breast Cancer

In discussing PIK3CA mutations in breast cancer it’s important to note that this mutation can coexist with other genetic alterations .

A few of the ways in which PIK3CA mutations are thought to play a role in breast cancer include:

  • Development of breast cancer: PIK3CA mutations appear to play an important role in oncogenesis, or the process of cancer developing in the first place. This is supported by the fact that there appears to be a high frequency of PIK3CA mutations in stage 0 breast cancer or DCIS .
  • Evading cell death: PIK3CA mutations are thought to be associated with breast cancer cell’s ability to evade programmed cell death .
  • Ability to spread: PIK3CA mutations may enhance the ability of cancer cells to break free and migrate to other regions .
  • Treatment resistance: PIK3CA mutations may be associated with resistance to hormonal treatments for breast cancer , resistance to targeted therapies , and resistance to some chemotherapy drugs.

Association Between Pcr And Survival Data

Among the 13 patients with pCR after neoadjuvant treatment, only 2 experienced tumoral relapse during follow-up, compared to 20 relapses among the 42 patients with partial or refractory histological response . A significant difference was found in OS according to the response to neoadjuvant treatment Fig. 5, and in DFS , Fig. 6.

The online version contains supplementary material available at 10.1038/s41598-021-02643-y.

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Cu Cancer Center Researchers Are Developing New Treatments For Patients With Her2

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PIK3CA is a gene that makes an enzyme called PI3K, which is involved in many important cell functions. When PIK3CA mutates, however, it can make the PI3K enzyme become overactive and cause cancer cells to grow.

Researchers have known for a long time that PIK3CA is one of the most commonly mutated genes in breast cancer, and recently published research shows that PIK3CA mutations also drive therapeutic resistance in HER2-positive breast cancer.

A lot of growth signals into breast cancer cells are mediated through receptors that go through the cell membrane one part of the receptor is outside the cell and one is inside, explains researcher Elena Shagisultanova, MD, PhD, a University of Colorado Cancer Center member and assistant professor of medical oncology in the CU School of Medicine. The HER2 receptor has two parts the part outside of the cell interacts with growth factors, and the inner part sends growth signal to the ‘command center,’ the cell nucleus. PI3K is immediately below the cell membrane, and its connected to the HER2 receptor. So, even if were blocking HER2, PI3K can still send growth signals to the nucleus, and the tumor cell will grow.

Pik3ca Mutations And Breast Cancer Patient Survival: A Blurred Picture

PIK3CA Mutations in HER2-Positive Breast Cancer

To address the clinical impact of PIK3CA mutations on breast cancer, we performed a search on PubMed using the following keywords: breast, cancer, pik3ca, and mutation . We identified 12 studies from the 119 abstracts evaluated. Clinical characteristics of the studies are summarized in Table 1. The 12 studies reported the outcomes of 2587 breast cancer patients. The discrepancies in observed clinical outcomes are likely due to variations in patient population and tumor characteristics. In fact, the effects of PIK3CA mutations are likely dependent on the subtype of breast cancer and the location where the mutation in PIK3CA occurs. Indeed, estrogen receptor -positive and HER2-positive breast tumors are two molecularly distinct diseases that differ in both biological and clinical behaviors. Moreover, previous studies suggest that mutations in the HD and the KD have different biological and clinical consequences.

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Pi3k/akt/mtor Pathway Signaling In Breast Cancer

Phosphatidylinositol-3 kinases are heterodimeric lipid kinases characterized by regulatory and catalytic subunits, with the former subunit inhibiting the latter in quiescent cells . PI3Ks are involved in several cellular processes, such as protein synthesis, cell proliferation and survival, glucose homeostasis, and DNA repair . The interaction of the catalytic subunit with the phosphotyrosine residues of activated growth factor receptors or adaptor proteins is critical to elicit PI3K activation . As a consequence, the membrane lipid phosphatidylinositol-4,5-bisphosphate is converted to phosphatidylinositol-3,4,5-trisphosphate . PIP3 directly activates Akt and other proteins harboring the PIP3-binding pleckstrin-homology domains . Upon complete activation, Akt induces multiple downstream cytosolic and nuclear effectors. This mechanism, considered as the core of cell survival and cell cycle progression, is turned off by several phosphatases that dephosphorylate mTORC1 and PIP3 .

Determination Of The Limits Of Blank And The Theoretical Limits Of Detection

Following the instructions provided by Stilla Technologies, we determined the limits of blank and the theoretical limits of detection for the PIK3CA assays by testing 30 replicates of WT-only samples with theoretical concentrations of at least 10,000 copies/PCR, and calculating the means of the numbers of false positive droplets of each detection. The corrected means were then calculated using the following equation:

, where is the mean, the standard deviation of false positive events and N the number of experiments performed. The LOB95% were determined by fitting the corr on Normal Law approximation and Chernoffs inequality, and the LOD95% were calculated using a similar approach as in Milbury et al. .

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