Aggresive breast cancer types

Her2 positive breast cancer

Despite great advances in the threatment of breast cancer over the past 20 years, breast cancer treatment remains an enormous challenge, with more than 400,000 women dying from breast cancer globally each year. About 20 percent of breast cancers are HER2-positive. HER2-positive breast cancer has the tendency to be more aggressive and metastasize more often than other cancers. However, drugs like trastuzumab, pertuzumab and lapatinib target HER2 directly. But patients show after some time recurrence of the cancer. This aggressiveness and metastatic proclivity are mainly driven by subpopulations of cells within the tumor with high self-renewal capacity.1 A recent study demonstrated that Her2 and Myc cooperate to promote the formation of these aggressive subpopulations in breast cancer tissue.2 The number of copies of HER2 and MYC are frequently increased together in breast cancer and are associated with aggressive clinical behavior of the tumor and poor outcome. In HER2 positive breast cancer patients receiving adjuvant chemotherapy, MYC amplification is associated with a poor outcome.

Drug Candidates in Clinical Studies


MM-302 plus trastuzuma

Development status: phase 2, by Merimack Pharmaceuticals

MOA: HER2-targetedantibody-drug conjugarted liposomal doxorubicin

Indication: HER2-positive,locally advanced/ metastatic breast cancer (MBC)


It is planned to enroll 250 anthracycline-naïve patients with locally advanced/metastatic HER2-positive breast cancer in Phase 2.
In Phase 1, MM-302 appears to be well tolerated both as a monotherapy and in combination with trastuzumab. That trial included 69 patients with HER2-positive metastatic breast cancer. 12% percent of patients responded to treatment with at least 30 mg/m
2 of MM-302 alone or in combination with trastuzumab. The most common grade 3/4 adverse event was neutropenia, which occurred in eight patients. Adverse events occurring in more than 20% of patients included constipation, cough, decreased appetite, diarrhea, dyspnea, fatigue, nausea, neutropenia, stomatitis, and vomiting.

BKM120

Development status: phase 3 ongoing, by Novartis

MOA: PI3K inhibitor

Indication: HR+, HER2-, AITreated, Locally Advanced or MBC cancer 


Phase 3 trial will recruit about 1,060 women. Half the women taking part have fulvestrant and BKM120. The other half have fulvestrant and a dummy drug (placebo). In Phase 1 there were 31 Patients enrolled. The maximum tolerated dose was defined as buparlisib 100 mg daily plus fulvestrant. Buparlisib plus fulvestrant is clinically active with manageable AEs in patients with metastatic ER(+)breast cancer. Weekend breaks in buparlisib dosing reduced toxicity. Patients with PgR negative and TP53 mutation did poorly, suggesting buparlisib plus fulvestrant may not be adequately effective against tumors with these poor prognostic molecular features.

Abemaciclib (LY2835219)

Development status: phase 3, by Eli Lilly

MOA: cycleinhibitor 

Indication: breast cancer (metastatic disease), HR+

 

Abemaciclib is an investigational, oral cell cycle inhibitor, designed to block the growth of cancer cells by specifically inhibiting cyclin-dependent kinases, CDK 4 and CDK 6. In many cancers, uncontrolled cell growth arises from a loss of cell cycle regulation due to increased signaling from CDK 4 and CDK 6. Abemaciclib inhibits both CDK 4 and CDK 6, and was shown in cell-free enzymatic assays to be most active against Cyclin D 1 and CDK 4. Phase 2 enrolled 132 patients who were given 200 mg of abemaciclib orally every 12 hours until disease progression. Patients enrolled in the study were heavily pretreated, having experienced progressive disease on or after prior endocrine therapy, and had received prior chemotherapy with one or two chemotherapy regimens for metastatic disease. 
At the final analysis of response (minimum of 12 months follow-up), patients treated with abemaciclib achieved an ORR of 19.7 percent, with a median time to response of 3.7 months and a median DoR of 8.6 months. Of the 13 patients who remained on treatment at the time of this analysis, nine were responders and four had stable disease (SD).
The safety and toxicity profile of twice daily, continuously dosed abemaciclib was consistent with previous Phase 1 experience. The most common grade 3 non-laboratory treatment emergent adverse events (AEs) were diarrhea and fatigue
.