Introduction

Breast cancer (BCa) is a complex disease often necessitating multimodal care. It is a disease which is developed by the accumulation of genetic and epigenetic alterations. These alterations are activated oncogenes and silenced tumor suppressors in mammalian ductal or lobular tissues [1]. Furthermore, the altered phosphatidylinositol-3-kinase (PI3K) signaling pathway is frequently involved in the regulation of cellular processes required for breast carcinogenesis. Interestingly, phosphatidylinositol-4,5-bisphosphate 3-kinase-catalytic subunit alpha (PIK3CA) mutations in exons 9 (helical domain) and 20 (kinase domain) lead to amino acid changes and result in increased PI3K activity. Increased PI3K activity can cause cell proliferation and progression in cancer cells [2]. PIK3CA mutation can be an emerging tumor marker and it might affect or alter BCa treatment modalities. Further studies about this gene would be helpful to design new treatment strategies.

Breast cancer

Among cancers affecting women, BCa is the most deadliest [3]. Recently, the mortality rate of BCa has declined in the USA and Europe, by means of improved detection and treatment [4]. Statistical data predict more than 231,840 women in the USA will be diagnosed with invasive BCa in 2015. Also, 1/12 women in the West has developed BCa at some point in their life [5]. Therefore, better tools are needed for diagnosis and monitoring. Recent strategies for early diagnosis of BCa are not sufficient despite the increased prognosis rate of the disease.

It has been known that the most important indicators for identifying patients with BCa are mammography, histopathology, and blood tests [6]. Mammography detects about 80–90 % of the BCa in women without symptoms. Another important diagnostic method is magnetic resonance imaging (MRI) which is not recommended as a routine screening tool for BCa due to false positive results. Positron emission tomography (PET) scans are more powerful in identifying aggressive tumors [7]. PET scans utilize radioactive tracers to detect BCa. These tracers better define cancer regions than an MRI or CT scan [www.nlm.nih.gov]. Clinical breast examination (changes or differences in breast shape, rashes, visible lumps or swelling, nipple discharge, etc.) can also help early diagnosis. Series of tumor markers as CA15-3, CA 27–29, and CEA are suggested by some clinicians. CA 15–3 and CA 27–29 are used routinely for monitoring. And they are elevated more than 70 % of metastatic BCa patients, whereas blood CEA level is only increased 55 % [8]. Detecting BRCA1 and BRCA2 gene mutations and family history are also significant for diagnosis. There are other candidate genes such as TP53, PIK3CA, or PTEN which can be used for screening.

The prognosis of BCa and response to the treatment are affected by series of factors such as histological grade, type and size of tumor, lymph node metastasis, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (Her-2/neu) status, and hormone levels. These factors allow researchers to classified BCa types as “clinical” (age, tumor, and node), “histopathological” (grade, ER, and HER2, ductal, lobular, invasive) and “molecular” (normal like, luminal, basal, HER2). This classification is vital for diagnosis due to the outcomes are various. Treatment approaches may be developed based on this classification. Thus, specific and predictive biomarkers can be chosen for suitable treatment for BCa [9].

Most women with BCa suffer from the surgery which is generally combined with the other treatments (radiation therapy, chemotherapy, hormone therapy, and targeted therapy) [7]. Particularly, breast conserving surgery or lumpectomy are performed to eliminate the cancer cells but not breast itself. Lumpectomy is always followed by about 5 to 7 weeks of radiation therapy. Radiation destroys cancer cells remaining in the breast, chest wall, or underarm area. Thus, the size of tumor can be reduced. Additionally, chemotherapeutic drugs such as cyclophosphamide, 5-fluorouracil, methotrexate doxorubicin, and paclitaxel postpone the further growth and spread of the tumor. Tamoxifen is used for to ER+ patients as hormone therapy [7]. Alternatively, targeted therapy is an option for BCa treatment. It targets specific genes, proteins, or the tissues which are involved in cancer growth. This type of treatment blocks the growth and spread of cancer cells while limits damages on healthy cells [10].

Typically, any mutation in DNA and induction of the cell proliferation are basic triggers to initiate molecular abnormalities in cancer [11, 12]. Especially, a mutation which occurs on the critical genes plays an important role for regulating cell growth, death, differentiation, and replication. Depending on the location of the gene, this mutation can be beneficial, harmful, or nonsense and it can effect the prognosis of cancer. However, development of a tumor is a multistep process, only a single mutation does not give a rise to cancer; most of the time, several mutations are required (e.g., colorectal cancer). Thus, transformed cells should be proliferating before they become fully malignant [13]. Proliferation of cancer cells exerts its tumor-forming effects by promoting the expansion of a cell population [14]. The genetic profile of BCa, 5–10 % of all cases in women, is linked to hereditary mutations in autosomal dominant genes.

There are many pathways responsible for BCa including hormone signaling pathway (ESR1, PGR, and AR), PI3K/AKT/MTOR pathway (AKT1, PIK3CA, and PTEN), receptor tyrosine kinase/growth factor signaling pathway (ERBB2/HER2), and cell cycle control/DNA damage pathway (CCND1, CDK4, CDK6, RB1, and TP53). Specifically, estrogen signaling and the estrogen receptor (ER) are important in BCa. A great number of the BCa depends on the increased estrogen secretion. Most BCa are constructed on the estrogen signaling for growth promotion. Some studies reported that ER signaling affords metastasis. This finding is important for therapeutic targets to block ER-driven metastasis [15]. The other important factors are EGFRs and their signals through the RAS → PI3K → PKB pathway [16]. When RAS is hyperactive, it may enhance BCa. RAS genes, which play an important role in human cancers, have been detected in BCa. Incidence of K-RAS oncogene activation is 0–10 %. As we implied previously, the PI3K pathway has critical roles for the regulation of cell survival and proliferation in BCa [16].

PI3K signaling pathway and PIK3CA gene mutations in different types of cancer

Phosphoinositide-3-kinase (PI3K) was studied and declared by Lewis Cantley and his colleagues [17] and later, its tumorigenic role was identified [18]. PI3K activation is critical for cell survival, proliferation, differentiation, and migration. PI3Ks are the family of lipid kinases that have been compromised in signal transduction through the tyrosine kinases and G-protein coupled receptors (EGF, IGF, FGF, or PDGF). These receptors are most frequently implicated in cancers [19, 20]. Also, signaling proteins that are phosphorylated signal through class IA PI3K, which includes p85 (α and β) regulatory subunits (Fig. 1). These isoforms are encoded by genes respectively PIK3R1, PIK3R2, and PIK3R3. p110 (α, β, and δ) is catalytic subunits. These isoforms are encoded by genes respectively PIK3CA, PIK3CB, and PIK3CD. PI3K is the most common mutation pathway and PI3K p110α (PIK3CA) and p110ß (PIKCB) catalytic subunit encode genes in BCa. The PIK3CA gene is situated on the long (q) arm of chromosome 3. IK3CA subunits are composed of several modular domains: a RAS binding domain, an NH2-terminal domain, the catalytic lipid kinase domain, and the helical domain interacting with the regulatory subunit. The PIK3CA gene provides instructions for making the p110 alpha (p110α) protein, which is one of the subunit of an enzyme called phosphatidylinositol 3-kinase (PI3K). The p110α protein is called as the catalytic subunit, it activates PI3K, while the helical subunit (produced by a different gene) regulates the enzyme activity. PIK3CA is mutated or amplified in a wide spectrum of tumors [21–23].

Fig. 1
figure 1

PI3K signal pathway through receptor tyrosine kinases and G protein

Full size image

In the PI3K pathway, p85 interacts directly or via adaptor proteins with RTKs. This interaction activates PI3K. RTKs activate RAS which activates subsequently ERK, MAPK, AKT, and mTOR pathways. Thus, inhibitory effect of p85 onto p110 is cancelled on the cell membrane. Immediately, PI3K acts as a kinase. PI3K catalyzes the conversion of PIP2 to PIP3. PIP3 activates PDK and S6 (Fig. 1). AKT signaling results in increased cell growth, proliferation, and motility. Also, it has an anti-apoptotic role. PI3K is antagonized by PTEN. Because, PTEN catalyzes the alteration of PIP3 to PIP2 [24, 25] (Fig. 1).

Another way through the activation of PI3K: G-protein-coupled receptors (GPCRs) signal through class 1B PI3K, which includes p101 regulatory and p110γ catalytic subunits [26] (Fig. 1). Hyperactive p85 removes inhibitory effects on p110. When p110 is activated, it catalyzes the phosphorylation of PIP2 to PIP3. Then, it induces Akt sub-pathway. Subsequently, phosphorylation of Akt allows to reactivation of several target proteins in the cell. Moreover, class 1B PI3K includes seven transmembrane domain receptors (serpentine receptor), chemokine receptors, and signal through heterotrimeric G proteins, Gα and Gβγ. They are important to induce cell migration. Also, GPCR ligation dissociates the Gβγ dimer, allows its binding to p101 regulatory subunits and subsequent activation of associated p110γ catalytic subunits [27].

Until now, a lot of intracellular pathways were identified and PI3K pathway is the most important one BCa in which this pathway is activated [23, 28]. Samuels et al. [23] and Philp et al. [29] reported that in breast, ovarian, and colon cancers, phosphorylated AKT (pAKT) levels are increased whereas PI3K signals are reduced. Moreover, it is suggested that PIK3CA contains p11α mutations in approximately 15 % among all tumor types [21]. Interestingly, over the 80 % of the mutations have been detected in exon 9 (E545) of the phosphatidylinositol kinase homology domain, and in exon 20 (H1047) adjacent site of the edge of the catalytic domain (Fig. 2). Other important mutation regions are exon 1, 4, and 5. On the contrary of general mechanism which is known as through the growth factor activation, PIK3CA mutations in exon 9 and 20 promote constitute PI3K signaling through distinct mechanisms.

Fig. 2
figure 2

Location of the most common PIK3CA mutations

Full size image

A lot of point mutations of PIK3CA gene are seen in hepatocellular, colon, brain, and BCa [17, 30–33]. As reported by the COSMIC database, distribution of PIK3CA somatic mutation in breast, endometrium, urinary tract, colon, and upper digestive tract are respectively 27, 23, 15, 17, and 7 % [34]. But, PIK3CA mutations have been observed less frequent in some cases such as head (<10 %), melanoma, prostate, pancreas, and lung cancer [35]. In a study belong to Garcia-Dios et al. [36], 172 PIK3CA mutations are detected among all tumors (16.2 %) in patients with primary endometrial carcinoma. Sun et al. [37] announced that 13 % PIK3CA amplification and 3 % PIK3CA mutation have been detected in 40 % of prostatic carcinomas. Liu et al. [38] proclaimed that PIK3CA mutations were appointed in 25 % (2 of 8) of ARMS exemplars. Tong et al. [39] have detected 22/120 mutations relevant to PIK3CA in BCa thereby using specific appliance known as high-throughput mass-spectrometry based cancer gene mutation profiling platform (Table 1).

Table 1 Frequency of mutations in PIK3CA gene in breast cancer
Full size table

Importance of PIK3CA gene mutations in breast cancer

A mutation occurred in PI3K pathway can be considered as an important target in BCa therapy. PI3K pathway plays a critical role in myriad of cellular actions that are necessary in both normal and cancer cell, for instance cell division, motility, growth, and survival [40]. In many cancer types, somatic mutations in PI3K pathway are recurrent. Oncogenic mutations in the PI3K pathway generally are evaluated in accordance to two different functions: activate mutation of the gene encoding PI3K (PIK3CA) or AKT (AKT1), and extinguish or reduce expression of PTEN. In BCa management, PI3K is a new way for clinicians. Samuels et al. [23] and Levine et al. [41] reported that the frequency of PIK3CA mutations in BCa are in range from 8 to 40 %. Other studies reported that activated mutations in PIK3CA were proximately 30 % of BCa and more frequent in ER (+) BCa [24, 42]. Especially, within exons 9 and 20, there would be found 80 % of PIK3CA mutations. These two exons are known as ‘hot spots’ and encode the helical and kinase domains. Helical domain is encoded sooner than kinase domain. As a result of E542K and E545K (exon 9) mutations reported by Miled et al. [43]. The inhibitory interaction between p110α and p85 may be blocked and this affect provides a gain-of-function. According to Gonzalez-Angulo et al. [44] and Stemke-Hale et al. [45], PIK3CA and AKT mutations are more frequent in HER2+ BCa. PI3K has been interacted with ER directly or indirectly. In either case ER phosphorylation is induced [46, 47]. According to Generali et al. [48], estrogen deprivation downregulates PI3K activity. PIK3CA is generally mutated in ER-positive BCa. Campbell et al. [49] at least 41.3 % of BCa is ER-positive. The researchers concluded that the presence of any PI3KCA mutation is an independent factor for survival, and effects are negatory. According to Maruyama et al. [50] PI3KCA mutation status was a significant and independent prognostic factor. These differences from the conventional prognostic factors are more predictive for a better prognosis [50].

PIK3CA mutation is detected in the range of 20–25 %, depending on the BCa subtype (HER2 tumors and triple-negative BCa (>30 %). But, it may be less frequent [42] in other subtypes. As well Kalinsky et al. [51] pointed in their study, in case of PIK3CA mutations have been detected, clinical outcomes and clinicopathologic founds are better, including survival benefits. In case of three subtypes of BCa were compared each other, gene-level mutation frequencies of PIK3CA were found significantly common in ER (+) (40 %) BCa [45–52]. But, its prognostic significance has not been explained yet. According to the Cancer Genome Atlas Network report [53], in TN BCa, even though PIK3CA mutation is seen at a low rate, the PI3K pathway activity inferred from gene expression or protein array signatures is actually the highest. Wright et al. [54] stated that Ras combined with PIK3CA (H1047R), an oncogenic mutant related to ERα (+)/luminal BCa in humans, induced metastatic luminal B-like tumors. Stachler et al. [55] presented that BCa had the highest rate of PIK3CA mutations (34 %), which correlated with estrogen receptor + status (P = 0.0002). Pogue-Geile et al. [56] reported that 741 (47.0 %) of 1578 tumors were classified as HER2-enriched (HER2E) subtype. Also, 166 (24.7 %) of 671 tumors had PIK3CA mutations. Lehmann et al. [57] displayed that activating PIK3CA mutations were enriched in AR + TNBC. Sakr et al. [58] indicated that molecular aberrations affecting the PI3K pathway may play a role in the progression from high-grade DCIS to IBC in a subset of cases (e.g., a subgroup of ER-positive/HER2-negative lesions). Arsenic et al. [59] show that the rate of PIK3CA mutations was increased in HR (+)/HER2 (−) tumors (18.6 %). In their study, the lowest rate of mutations was observed in HR (+)/HER2 (+) tumors (5.3 %). Christgen et al. [60] refer that PIK3CA mutations were positively selected for during ILBC progression to local recurrence but not distant metastasis, which might have clinical implications for PI3K inhibitor-based therapy.

In 2014, we determined an association between PIK3CA gene mutations and clinicopathologic differences in 101 Turkish BCa patients [61]. We studied PIK3CA gene mutation in exon 9 and exon 20 regions using high resolution melting (HRM) (Table 1). According to our results, PIK3CA exon 9 mutations, Q546R, E542Q, E545K, E542K, and 545D, were detected in 10 tumor samples. On the other hand, 21 mutations on exon 20 hotspot region were identified. Interestingly, one of the tumor samples had two different mutations on exon 20. The following mutations were defined using by Sanger sequencing: H1047L, H1047R, T1025T, and G1049R. Furthermore, we detected the mutation in one sample with both exon 9 (E542Q) and exon 20 (H1047R) mutations. Additionally, we should have emphasized that any correlations between PIK3CA, clinicopathological parameters (ER, HER2, stage and age, etc.) and survival analysis were detected in BCa.

Therapeutic and prognostic potential of pik3ca gene mutations in breast cancer

The biological markers are predictive and prognostic role in cancer. These biomarkers have to be confirmed by clinical and therapeutic applications. Therefore, in many molecular studies, a lot of inhibitors and antibodies have been developed for BCa treatment. These target molecules may be a gene or protein. Moreover, in some studies, these molecules have been detected considerably effective with in clinical settings (e.g., ALK or EGFR inhibitors for lung cancer).

In literature, there are lots of studies about PIK3CA-PI3K relation with cancer treatment. These studies indicate that alterations of PI3K signal pathway are important to treat cancer. There are different approaches for PI3K treatment such as trastuzumab, lapatinib, pertuzumab, anti-PI3K drugs, etc. There are lots of inhibitors for PI3K in biomedical industry. The most important kinase inhibitors for cancer therapies are perifosine (for colorectal cancer), idelalisib (for CML), PX-866 (for solid tumor), BAY 80–6946 (for PI3Kα and δ), INK1117 (for PI3Kα), and IPI-145 (for hematologic cancers) (Fig. 3 and Table 2). Other important kinase therapies use imanitib (Gleevec), trastzumab (Herceptin), and gefitinib (Iressa) [62–65], pertuzumab, lapatinib and endocrine therapies. On the other hand, there are important anti-PI3K pathway drugs. Imatinib was the first member of tyrosine kinase inhibitors [66]. Although targeted kinases like imatinib can destroy cancer cells but a resistance is developed frequently. Another study reported that p110α isoform-selective inhibitors look promising in heavily pretreated PIK3CA mutant BCa [67].

Fig. 3
figure 3

A schematic shows key PI3K pathway of breast cancer tumorigenesis and their targeted inhibitors

Full size image
Table 2 A summary of PI3K pathway inhibitors in clinical development
Full size table

Combined therapy approaches which use PI3K-targeting pathway are also important treatment strategies. According to the findings of Roulin et al. [68], treatment of 786–0 and Caki-1 cells with NVP-BEZ235 or sorafenib resulted in diminished tumor cell proliferation and improved tumor cell apoptosis in vitro. The combination of NVP-BEZ235 and sorafenib was more effective than each compound alone. Hu et al. [69] indicate that when doxorubicin (DOX) was combined with BKM120, strong synergistic anti-proliferative effect was observed. BKM120 activity induced the blockage of PI3K/AKT signaling and NF-κB expression, which in turn led to activate caspase-3/7 and caspase-9 and changed the expression of several apoptosis-related gene expression. According to the Blackwell et al. [70] pilaralisib or voxtalisib, in combination with letrozole, was associated with an acceptable safety profile and limited efficacy in endocrine therapy-resistant HR+, HER2-negative metastatic BCa. Ayub et al. [71] used small-molecule kinase inhibitors, namely, NVP-AEW541, NVP-BKM120, KU0063794, and PD0325901 to target IGF-1R, PI3K, mTORC, and MEK, respectively. Mainly, combination treatments of PD0325901 with NVP-AEW541, NVP-BKM120 or KU0063794 and NVP-AEW541 with KU0063794 revealed a significant synergistic growth inhibition. Park et al. [72] showed that the combination of GSK2126458 and AZD6244 blocks both the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways simultaneously and is an effective strategy for the treatment of CRPCs. Using the mTOR inhibitors rapamycin, everolimus and PF-04691502 (a dual PI3K/mTOR inhibitor) and in combination with tamoxifen, significant reduction in mammosphere formation was observed [73]. Sweetlove et al. [74] expressed that ZSTK474 and BEZ235 also inhibited cell proliferation in all cell lines and enhanced the antitumor activity of selumetinib and vemurafenib in the majority of lines by either interacting synergistically or additively to increase potency or by inducing cytotoxicity by significantly increasing the magnitude of cell growth inhibition. Gedaly et al. [75] established that the combination of PKI-587 and sorafenib has the advantage over mono drug therapy on inhibition of HCC cell proliferation by blocking both PI3K/AKT/mTOR and Ras/Raf/MAPK signaling pathways.

PIK3CA driver mutations might be resistant to chemotherapeutic agents. Therefore, this review suggests the presence of different molecular features for breast tumors that should be considered when defining the therapeutic decisions. In the absence of PIK3CA mutations, we can estimate that clinical/preclinical efficacy for the treatment. In the present review, predictive or prognostic importance of PIK3CA for BCa will be explained and also briefly discussed.

In the researches exist so far, there is a resistance to hormonal therapy which caused by PI3K mutations. In a specific study, hyperactivation of some receptors (GFR or IGFR) induced the PI3K pathway. This hyperactivation also led to a discernible resistance to anti-estrogen therapy [76]. The mechanism of this resistance has been defined as a straight effect of estrogen receptor (ER) transcription. In some studies, PI3K mutations were shown as a downstream mediator which causes a resistance development to mTOR inhibitors. Deng et al. [77] revealed that the treatment with combination of PI3K/AKT/mTOR inhibitors and endocrine therapy has resulted with poorer outcome if there is a PIK3CA mutation in ER positive breast carcinomas. Correlatively, De La Rochefordiere et al. [78] proved that among the cervical cancer patients with mutation in PIK3CA pathway show poor response following standard radio chemotherapy +/− Cetuximab. In a trial of lapatinib monotherapy in HER2+ metastatic BCa, three PIK3CA-mutant patients were detected, and one durable PR and two stable disease responses were observed [79]. However, we have not found any specific study about resistance to antiestrogen therapy in Turkish women with BCa population.

Although it is known that PIK3CA driver mutations might be resistant to chemotherapeutic agents, the mechanism of this resistance is not clear yet. Black et al. [80] reported that oncogenic PIK3CA mutations are common in HER2/neu-amplified USC and may constitute a major mechanism of resistance to trastuzumab treatment. Boch et al. [81] suggested that the effects on the transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Moreover, fulvestrant markedly sensitized ER-positive tumors to PI3Kα inhibition, resulting in major tumor regressions in vivo. There was a correlation of the EGFR expression with sensitivity to EGFR and resistance to active agents of PI3K [82].

A much more important issue for the patients with BCa is whether a relationship exists between PIK3CA mutations and benefit with a specific type of therapy. Yet, PIK3CA mutations have been declared to confer resistance to endocrine therapy [83]. But, the data by Sabine et al. [84] showed opposite findings. Chemotherapy may reduce mutation frequency in patients with BCa. Recent studies explain that loss of PIK3CA mutations after neoadjuvant chemotherapy provides better prognosis for patients [85]. Yuan et al. [86] exhibited that phospho-PRAS40Thr246 expression was associated with activation of the PI3K pathway. Thus, these researchers have implied that there is an increased risk of tumor progression in patient with HER2+ metastatic BCa who have had trastuzumab therapy. Patients with PIK3CA/HER2+ BCa were treated with neoadjuvant therapy [87]. As a result of these neoadjuvant therapy trials, PIK3CA cannot be used as predictive biomarkers for adjuvant trastuzumab [88]. According to the Costa et al. [89] in HER2-amplified and PIK3CA mutant cancer, PIP3 rebound are prevented by the addition of the p110β inhibitor to BYL719. In this manner, a greater antitumor efficacy is induced. Pogue-Geile et al. [56] considered the benefit of adjuvant trastuzumab therapy in the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-31 trial, but the results showed that there were no evidence for differences between PIK3CA wild type and mutant type. In another study, PIK3CA-metastatic HER2-positive BCa, Pilaralisib in combination with trastuzumab with or without paclitaxel did not present any differences [90]. In 55 BCa patient, a resistance to Herceptin was found associated with PIK3CA mutations or low PTEN expression. Similarly, in cell culture models, PIK3CA mutations would debate resistance to Herceptin [91]. Junttila et al. [92] recorded that the resistance to trastuzumab is mediated by PIK3CA mutation, through the E545K and H1047R-HER2 overexpressing BCa cell lines were sensitive to GDC-0941, a pan-PI3K inhibitor. According to Liu et al. [93], PIK3CA mutant tumors lead to a resistance to PI3K inhibitors via overexpression of c-MET and MYC. Sabine et al. [94] reported in the TEAM adjuvant endocrine study, in 39.8 % of PIK3CA mutant and ER-positive post-menopausal BCa patient’s response to treatment was better.

There are also lots of studies about PIK3CA treatment for other cancer types. In a study, regular aspirin use after diagnosis influences survival in PIK3CA mutated colorectal cancer in contrast to patients with wild-type PIK3CA [95]. Inhibition of PI3K pathway by using aspirin can reduce cell proliferation then promote cell death. Any alteration of this pathway, straightforward for cancer treatment. Accordingly, plenty of PI3K inhibitors have been developed. For example, rapamycin analogs: temsirolimus and everolimus that inhibit mTORC1 are suggested that these inhibitors also can be used for the treatment of advanced renal cell carcinoma [96, 97]. Use of pertuzumab and trastuzumab resulted in an improvement in progression-free survival in both the PIK3CA-mutant and wild-type groups [87].

Briefly, several studies indicate that PIK3CA may be predictive value. But, there have been some studies which not affirm PIK3CA mutations might be significant for prediction of BCa [98, 99].

Conclusion

Profiling the patients with cancer molecularly, determination of mutations in arbiter to design accurate drug combination and to settle drug sensitivity. According to the type of cancer, pathogenesis of PIK3CA mutations may be variable. It is known that these mutations lead to resistance to HER-2 targeting agents and/or hormonal agents in BCa. PIK3CA mutations are detected nearly 25–40 % in patient with BCa which is mostly caused by PIK3CA mutation. We also have detected 31 % PIK3CA mutation in Turkish BCa patients (n = 101) [61]. These results show us PIK3CA mutations could have a major role in the diagnosis and treatment of BCa.

In this point of view, certain gene alterations or modifications may be screened routinely for BCa diagnosis. In this way, detection of PIK3CA mutations might lead to a better decision of sequential therapy for many cancer types. Moreover, survey and life quality of the patients may be improved. If cancer related genes and their molecular mechanisms could be clarified, these would be innovative for new treatment strategies. In this perspective, clinically significant alterations in the PIK3CA gene which were identified previously could have an important impact to provide a “targeted treatment decision” in patient with BCa.