Molecular Re-classification of Breast Cancer – Part 2

Q. What are the most promising therapeutic targets and agents currently under evaluation, and how might they change the breast cancer treatment paradigm?

Since the main classifications of breast cancer were established (based on the presence of oestrogen, progesterone and/or human-epidermal growth factor-2 [HER2] receptors), advances in technology have enabled far more detailed molecular analysis of tumours. This has led to the identification of new therapeutic strategies that have the potential to address key issues such as endocrine therapy resistance in hormone-receptor positive breast cancer and the treatment of triple negative breast cancer (TNBC). These new therapies can be broadly grouped into three categories: cyclin-dependent kinase (CDK) 4/6 inhibitors, phosphoinositide 3 kinase (PI3K) / mammalian target of rapamycin (mTOR) inhibitors, and DNA repair checkpoint inhibitors.

Cyclin-dependent kinase 4/6 inhibitors

Around 60–75% of all breast cancers are hormone-receptor positive (oestrogen and/or progesterone) and are therefore candidates for endocrine therapy.¹ However, resistance to endocrine therapy, either de novo or acquired, is a frequent occurrence.^1,2 Studies in models of hormone-receptor positive breast cancer have shown that endocrine resistance may be associated with persistent cyclin D1 expression and constitutive activation of CDK 4/6.^1,3 The inhibition of this pathway was therefore proposed as a therapeutic strategy to restore or increase endocrine sensitivity in hormone-receptor positive tumours.

There are three specific CDK 4/6 inhibitors currently in development for the treatment of breast cancer: palbociclib, ribociclib and abemaciclib.¹ Data from Phase III clinical studies have shown that adjuvant therapy with these agents can significantly improve progression-free survival compared with endocrine therapy alone in patients with hormone-receptor positive breast cancer (PALOMA-3 [NCT01942135], palbociclib + fulvestrant; MONALEESA-2 [NCT01958021], ribociclib + letrozole; MONARCH2 [NCT02107703], abemaciclib + fulvestrant).¹ It is hoped that these adjuvant therapies may help achieve true senescence in micro-metastatic breast cancer, with potential cures in patients who would previously receive long-term endocrine therapy or chemotherapy (e.g. intermediate- or high-risk patients¹). A key goal of future research is to determine specific patient subgroups who would benefit from endocrine + CDK 4/6 inhibitor therapy, and further results from ongoing Phase III studies are expected by 2019 (MONALEESA-3 [NCT02422615], ribociclib; MONARCH3 [NCT02246621], abemaciclib).¹

Phosphoinositide 3 kinase and mammalian target of rapamycin inhibitors

The PI3K/mTOR pathway is a survival pathway that is activated in many types of cancer.⁴ Hyperactivation of the PI3K/mTOR pathway is thought to be a common mechanism for endocrine resistance in hormone-receptor positive breast cancer, and therefore inhibition of the pathway was
proposed as a way to restore endocrine sensitivity in resistant cancers and potentially increase responsiveness in sensitive cancers.^1,4,5

Current PI3K/mTOR inhibitors in development include buparlisib (PI3K inhibitor) and everolimus (mTOR inhibitor).¹ Data from Phase III clinical trials has shown that adding these agents to endocrine therapy leads to significant improvements in progression-free survival in endocrine-resistant breast cancers (BELLE-2 study [NCT01610284], buparlisib + fulvestrant; BOLERO-2 study [NCT00863655], everolimus + exemestane).¹ It is also thought that selectively inhibiting PI3K-alpha could help reduce side-effects associated with PI3K-beta inhibition, and that certain patient subgroups (e.g. those with PI3K mutations, obesity or a poorer prognosis) could benefit substantially from this type of adjuvant therapy. As with CDK 4/6 inhibitor therapy, a key goal is identifying these subgroups and further Phase III clinical trial data are expected in 2018 and 2019 (SANDPIPER [NCT02340221] and SOLAR-1 [NCT02437318] studies).¹

DNA repair checkpoint inhibitors

Many cancers, including TNBC, exhibit defects in homologous recombination, either via a germline mutation (e.g. BRCA1 and BRCA2 mutations) or more commonly via somatic mutations. This leads to compensatory upregulation and/or reliance on other DNA repair pathways (e.g. non-homologous
end-joining, base excision repair), and could leave the tumour vulnerable to cytotoxic therapies (e.g. platinum agents, doxorubicin) and synthetic lethality (e.g. via polyadenosine 5’diphosphoribose polymerisation [PARP] inhibition).^6-8 Proof-of-concept for this approach has recently been
demonstrated for the PARP inhibitor olaparib, where positive results versus single-agent chemotherapy in over 300 patients with HER2-negative metastatic breast cancer and a germline BRCA mutation were reported (OlympiAD study [NCT02000622]).⁹ It is hoped that similar strategies will also provide positive results in other subtypes of TNBC that have a ‘BRCA-like’ tumour biology due to mutations in DNA-repair mechanisms.¹⁰

Looking to the future, the goal is to achieve personalised treatment by exploiting DNA repair pathway deficiencies unique to certain tumours. There is currently a large portfolio of DNA repair checkpoint inhibitors available, including ataxia telangiectasia mutated kinase (ATM) inhibitors, ATM-Rad3 related kinase (ATR) inhibitors, DNA dependent protein kinase (DNA-PK) inhibitors and PARP inhibitors.¹¹ The next step is therefore to understand which DNA repair pathways are deficient in which breast cancer subtypes and tailor treatment accordingly.

Support: This Insight article was supported by AstraZeneca.

Acknowledgements: Medical writing assistance was provided by Stuart Wakelin at Touch Medical Media.

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