How is HER2/neu-negative metastatic breast cancer treated?

Updated: Apr 23, 2020
  • Author: Joseph A Sparano, MD; Chief Editor: John V Kiluk, MD, FACS  more...
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For patients with HER2/neu-negative disease, options include the following: [1]

  • Single-agent cytotoxic therapy
  • Single-agent cytotoxic therapy plus  bevacizumab
  • Olaparib
  • Combination cytotoxic therapy
  • Endocrine-based therapy

Bevacizumab seems to be effective only when used in combination with chemotherapy and as first-line therapy and is most effective when used with weekly paclitaxel. [46, 47, 48] It is not effective when used beyond second-line therapy with capecitabine. [49]

Olaparib inhibits poly (ADP-ribose) polymerase (PARP) enzymes. It is the first PARP inhibitor approved for breast cancer, based on the first phase 3 randomized trial to show superior PFS with PARP inhibitors than with single-agent chemotherapy in patients with HER2-negative metastatic breast cancer who have a BRCA mutation. [50]  The regimen is as follows:

  • Olaparib: 300 mg (two 150-mg tablets) PO BID
  • Use tablets for breast cancer indication; do not substitute olaparib capsules for olaparib tablets on a mg-to-mg basis due to differences in the dosing and bioavailability of each formulation

In postmenopausal women with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer, initial endocrine-based therapy for metastatic disease may include the following [51] :

  • P albociclib (Ibrance) 125 mg PO once daily with food for 21 days followed by 7 days off therapy to comprise a complete cycle of 28 days,  plus
  • Letrozole 2.5 mg/day PO continuously throughout the 28-day cycle

Ribociclib was approved for hormone receptor (HR)–positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women in combination with ribociclib as initial endocrine-based therapy or following disease progression on endocrine therapy [52]

  • Ribociclib (Kisqali), 600 mg/day PO for days 1-21 of a 28-day cycle,  plus
  • Fulvestrant (Faslodex) 500 mg IM on days 1, 15, 29, and once monthly thereafter 

Palbociclib and abemaciclib are also approved for HR-positive, HER2-negative advanced breast cancer in combination with fulvestrant in women (regardless of menopausal status) who have disease progression following endocrine therapy. [53, 54, 55, 56] The regimens are as follows:

  • Palbociclib, 125 mg PO once daily with food for 21 days followed by 7 days off therapy,  plus
  • Fulvestrant 500 mg IM on days 1, 15, 29, and once monthly thereafter  or 
  • Abemaciclib (Verzenio) 150 mg PO BID with or without food,  plus
  • Fulvestrant: 500 mg IM on Days 1, 15, and 29, and then once monthly thereafter  

Another option in postmenopausal women with HR+/HER- advanced or metastatic breast cancer is the following [57] :

  • Ribociclib (Kisqali), 600 mg/day PO for days 1-21 of a 28-day cycle,  plus
  • Letrozole 2.5 mg/day PO continuously throughout the cycle

The US Food and Drug Administration (FDA) has approved everolimus (Afinitor) 10 mg/day in combination with exemestane 25 mg/day for postmenopausal women with advanced HR-positive, HER2-negative breast cancer. The drug combination is intended to be used in women with recurrent or progressive breast cancer after failure of treatment with either letrozole (Femara) or anastrozole (Arimidex). [58]

Alpelisib plus fulvestrant is indicated for treatment of men and postmenopausal women with HR+/HER2-, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen. [59]  The regimen is as follows:

  • Alpelisib 300 mg PO daily  plus fulvestrant 500 mg IM on Days 1, 15, 29, and once monthly thereafter

Atezolizumab in combination with nab-paclitaxel is approved for patients with unresectable locally advanced or metastatic triple-negative (ER-, PR-, and HER2-negative) breast cancer whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells of any intensity covering ≥11% of the tumor area), as defined by an FDA-approved test. [60]  The regimen is as follows: 

  • Nab-paclitaxel 100 mg/m 2 IV on days 1, 8, and 15,  plus
  • Atezolizumab 840 mg IV on days 1 and 15 of a 28-day cycle

Sacituzumab govitecan is indicated for metastatic triple-negative breast cancer in patients who have received at least two prior therapies for metastatic disease. [61]  The regimen is as follows: 

  • Sacituzumab govitecan10 mg/kg IV on Days 1 and 8 of every 21-day cycle
  • Continue until disease progression or unacceptable toxicity

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