Systemic Therapy De-Escalation in Early-Stage Triple-Negative Breast Cancer: Dawn of a New Era?

Abstract

Early-stage triple negative breast cancer (TNBC) has been traditionally treated with surgery, radiation, and chemotherapy. The current standard of care systemic treatment of early-stage II and III TNBC involves the use of anthracycline-cyclophosphamide and carboplatin-paclitaxel with pembrolizumab in the neoadjuvant setting followed by adjuvant pembrolizumab per KEYNOTE-522. It is increasingly clear that not all patients with early-stage TNBC need this intensive treatment, thus paving the way for exploring opportunities for regimen de-escalation in selected subgroups. For T1a tumors (≤5 mm), chemotherapy is not used, and for tumors 6–10 mm (T1b) in size with negative lymph nodes, retrospective studies have failed to show a significant benefit with chemotherapy. In low-risk patients, anthracycline-free chemotherapy may be as effective as conventional therapy, as shown in some studies where replacing anthracyclines with carboplatin has shown non-inferior results for pathological complete response (pCR), which may form the backbone of future combination therapies. Recent advances in our understanding of TNBC heterogeneity, mutations, and surrogate markers of response such as pCR have enabled the development of multiple treatment options in the (neo)adjuvant setting in order to de-escalate treatment. These de-escalation studies based on tumor mutational status, such as using Poly ADP-ribose polymerase inhibitors (PARPi) in patients with BRCA mutations, and new immunotherapies such as PD1 blockade, have shown a promising impact on pCR. In addition, the investigational use of (bio)markers, such as high levels of tumor-infiltrating lymphocytes (TILs), low levels of tumor-associated macrophages (TAMs), and complete remission on imaging, also look promising. In this review, we cover the current standard of care systemic treatment of early TNBC and review the opportunities for treatment de-escalation based on clinical risk factors, biomarkers, mutational status, and molecular subtype.

Racial and Ethnic Disparity in Preoperative Chemosensitivity and Survival in Patients With Early-Stage Breast Cancer

“…With the widespread use of chemotherapy and immunotherapy as NACT in TNBC, the survival of patients has increased; however, NACT causes serious adverse effects . Therefore, rather than giving toxic chemotherapy and immunotherapy to all patients, identifying ways to de-escalate therapeutic options without affecting the efficacy by identifying the predictive biomarkers is essential . Based on our study results, race and ethnicity may be considered an important predictive marker when considering neoadjuvant therapeutic options for patients.…”

“…8 Therefore, rather than giving toxic chemotherapy and immunotherapy to all patients, identifying ways to de-escalate therapeutic options without affecting the efficacy by identifying the predictive biomarkers is essential. 26 Based on our study results, race and ethnicity may be considered an important predictive marker when considering neoadjuvant therapeutic options for patients. This is especially important in light of studies showing higher pCR to neoadjuvant chemoimmunotherapy in Black compared with White patients.…”

PIK3CAcopy-number gain and inhibitors of the PI3K/AKT/mTOR pathway in triple-negative breast cancer

“…Activating mutations of PIK3CA represent the second most common alteration in TNBC after the TP53 mutation, with a prevalence of ∼10%–15%, and they are especially found in the LAR and mesenchymal-related subtypes, the latter including metaplastic cancers as the one presented in case 2, characterized by aggressive behavior and chemo-refractoriness ( Lehmann et al 2011 ; Bianchini et al 2016 ; Basho et al 2017 ; Piscuoglio et al 2017 ; Zhang et al 2017 ; Bareche et al 2018 ; Pascual and Turner 2019 ; Martínez-Sáez et al 2020 ; Fuso et al 2022 ). PIK3CA alterations are mainly represented by activating mutations affecting “hotspot” regions encoding the PI3K catalytic subunit α, but several other mechanisms of oncogenic activation of the PI3K/AKT/mTOR pathway have been described in TNBC, such as amplification of PIK3CA or other upstream regulators, loss of function of the pathway down-regulators phosphatase and tensin homolog ( PTEN ) or inositol polyphosphate-4-phosphatase ( INPP4B ), activating mutations of AKT1 or MTOR , or overexpression or phosphorylation of the mTOR protein, globally occurring in 25%–70% of TNBCs ( López-Knowles et al 2010 ; Koboldt et al 2012 ; Costa et al 2018 ; Goncalves et al 2018 ; Fuso et al 2022 ; Gupta et al 2022 ; Zagami and Carey 2022 ). There are scant reports regarding the prevalence of PIK3CA copy-number alterations (CNAs), mainly referring to all BC subtypes as a whole and suggesting a prevalence of 6%–20%, whereas a search on the GENIE database (GENIE Cohort v11.0) yielded a prevalence of 14% across all BC subtypes ( López-Knowles et al 2010 ; Koboldt et al 2012 ; Firoozinia et al 2014 ; Thorpe et al 2014 ; AACR Project GENIE Consortium 2017 ; Gerratana et al 2022 ; Migliaccio et al 2022 ).…”

The molecular landscape of breast mucoepidermoid carcinoma

“… 67 , 68 , 69 Similarly, the de‐escalation of adjuvant medical treatment, including chemotherapy, immunotherapy, targeted therapies, and radiotherapy requires a multidisciplinary approach. 70 , 71 , 72 Hence, the paucity of comprehensive molecular information on large cohorts of patients prevents any specific recommendation and thus, our results should be validated and discussed in the context of multi‐institutional studies and dedicated cancer registries.…”