**4.3. PARPi**

outcomes for patients with TNBC. The specific adjuvant regimens that may be effective for TNBC are still being determined. Many large randomized trials have established the benefit

The evidence consistently shows that 10–20% of patients with TNBC who would not experience pCR following treatment with a current third-generation taxane and anthracycline will achieve pCR when a platinum drug is added to the regimen. However, because of the substantial added toxicity and predicted modest overall survival benefit across patient subgroups, carboplatin and cisplatin have not been routinely incorporated into neoadjuvant treatment [29]. The principles of local treatment in breast cancer, i.e., surgery and radiotherapy, are the same for the TNBC and all other types of breast cancer. Over the last several years, the percentage of patients operated on for breast cancer has increased; this trend has also been observed in

In patients with the TNBC, radiation therapy is given as in other types of breast cancer, i.e., after mastectomy or breast-conserving surgery. However, this approach to radiation therapy remains controversial because more and more patients have TNBCs, which has a fast local growth. The general rule that breast-conserving surgery followed by radiation therapy in

tions. Also the general consensus that post-mastectomy radiation therapy is not indicated for patients with node-negative tumors less than 5 cm in diameter should not be oversimplified

Although chemotherapy can be effective in patients with TNBCs, molecular studies could still improve treatment outcomes by giving new treatment targets. The molecular heterogeneity of TNBCs means that patients with TNBCs need personalized treatment because currently 60–70% of patients with TNBC do not respond fully to chemotherapy. Genomic analyses of the TNBC revealed large-scale transcriptional, mutational, and copy number heterogeneity, without any frequently recurrent mutations, other than *TP53*. Consistent with this molecular heterogeneity, most targeted agents, so far, have a very low activity in unselected TNBC, but important "basket" trials are ongoing. Therefore, there are promising opportunities for studying targeted therapy in appropriately selected patients with residual disease after neoadjuvant chemotherapy. Several ongoing phase I/II studies are investigating phosphatidylinositol-3-kinase (PI3K) inhibitors in advanced TNBC, and early-phase studies are also assessing Janus kinase 2 and cyclin-dependent kinase inhibitors in hormone-negative breast cancer [29].

At least some important discoveries made in recent years seem to be worth emphasizing in this textbook. The molecular pathways and receptors mentioned below might become new

Blockage of angiogenesis has been one of the ways to treat patients with breast cancer. In patients with the TNBC, bevacizumab, among the drugs that interfere with angiogenesis, has

) is the equivalent of mastectomy, in this case, has many limita-

of adjuvant anthracyclines and taxanes in breast cancer [28].

patients with TNBC.

84 Breast Cancer and Surgery

early stage cancers (T1-2 N<sup>0</sup>

in patients with triple-negative tumors [28].

treatment targets for patients with the TNBC.

**4.1. Anti-angiogenic factors**

**4. Targeted therapy in TNBC**

Poly-ADP-ribose polymerases (PARPs) are enzymes that are essential for cell survival. Cell damage activates PARPs, which, in turn, induces cell repair systems that maintain genome stability and regulation of transcription. Preclinical studies showed that PARPs are inhibited in cancer cells with pre-existing DNA repair defects, e.g. with the *BRCA1* mutations. The FDA has recently approved monotherapy with olaparib, a PARPi, as a first-in-class drug to treat germline *BRCA* mutation-associated advanced refractory breast cancer. Several ongoing studies are assessing the activity of PARPi alone or in combination with chemotherapy for germline BRCA-associated metastatic and early-stage breast cancers. Because a substantial proportion of TNBCs are thought to harbor DNA repair defects, it might be possible to extend the observation of PARPi sensitivity of germline BRCA-associated tumors to *BRCA* wild-type TNBCs that harbor a BRCAness phenotype. Accordingly, PARPi are being explored in the general population of patients with the TNBC [33].

## **4.4. PI3K/AKT/mTOR pathway inhibitors**

The high frequency (about 50%) of PI3K pathway alterations in the TNBC makes this pathway a promising target for therapeutics, and inhibitors of PI3K, AKT, and/or mTOR are in clinical development. PI3K blockade promotes HR deficiency by downregulating BRCA1/2 and thus sensitizing BRCA-proficient tumors to PARP inhibition [34].
