HER2-Positive Metastatic Breast Cancer

her2, metastatic, breast

HER2, or human epidermal growth factor 2, is a special protein (receptor) on the surface breast cancer cells, and it controls the growth of the cancer cells. The HER2 protein is present as a result of overexpression or amplification of the oncogene ERBB2. A tumor is considered HER2 positive by either the presence of HER2 protein presence and/or the overexpression of HER2 gene (the ERBB2). HER2 positive tumors are considered aggressive and have a tendency to recur, however, there are newer medications targeting HER2-positive cancer and led to significant improvement in outcome. 15% to 20% of all invasive breast cancer is reported to be HER2 positive. In this post, I will discuss the treatment of metastatic HER2 positive disease only, the nonmetastatic disease will be presented at a later date.

her2 testing must be done on biopsy material of metastatic site in all patients.

The above statement is applicable to patients presenting with metastatic disease at initial diagnosis or a recurrent and now metastatic disease which presented in the past as non-metastatic.

HER2 testing, given the predictive nature of HER2 positivity, as well as the availability of effective and specific targeted therapies that target HER2, the correct testing for HER2 is paramount. HER2 testing must be done by accredited lab and strict adherence to the 2013 ASCO/CAP guidelines. The diagram below illustrates the typical algorithm followed on biopsy material.


Once HER2 positivity is established, a HER2-directed therapy must be considered. For HER-negative there is no role for such therapy.

At the moment there are 4 approved HER2-directed therapies.

Decision making in treating metastatic HER2 positive disease, in making a treatment decision a number of factors come into consideration;

  • Was the patient treated in the past with HER2-directed therapy?
  • Is the tumor is also Estrogen receptor positive?
  • Overall patient functional status and other comorbidities


Overview of treatment options:

All patient with HER2-positive metastatic breast cancer (MBC) must receive HER2-directed therapy.

First line therapy, this is meant to be patients who never receive HER2-directed therapy or may have received Trastuzumab in the adjuvant or neoadjuvant setting, but more than 6 months lapsed till presenting with MBC. Such patient can be either,

A. Hormone positive disease:

I. majority of patients will need HER2-directed plus chemotherapy, preferred therapy would be in the following sequence,

  • Pertuzumab plus Trastuzumab plus taxane as evidenced by Cleopatra trial below. Other options
  • T-DM1 as evidenced by the MARIANNE trial below. Other options
  • Trastuzumab plus other cytotoxic therapy.

II. in other hormone-positive who have slowly progressing HER2-directed therapy plus endocrine therapy is reasonable,

  • Pertuzumab plus Trastuzumab plus AI as evidenced by the PERTAIN trial below.

B. Hormone negative disease:

Such patient will be treated as A. I above.

Second line therapy: this will include patients who have seen Trastuzumab in the adjuvant or neoadjuvant setting but presenting with MBC within 6 months of treatment. The recommended treatment of such patients would be,

  • T-DM1, as evidenced by EMILIA trial and the TH3RESA trial.
  • Trastuzumab plus lapatinib.
  • lapatinib plus capecetabine.
  • Trastuzumab plus other cytotoxic therapy not used before.
  • For the some of the hormone positive HER2-positive MBC, a second line therapy with Trastuzumab plus lapatinib plus AI as evidenced by ALTERNATIVE trial below.

Please note that T-DM1 efficacy as second-line therapy as evidenced by the EMILIA trial and TH3RESA trial did not include patients whos first line treatment included Pertuzumab, and given the wide spread use of Pertuzumab in recent years, a specifci trials are needed to find the appropriate second line therapy when Pertuzumab is used in the first line.

The table below displays, the most relevant trials listed above with links to citations.

CLEOPATRAAs first line for MBC
arm 1: Pertuzumab +Tras. +Doce.
arm 2: as above without Pertuzumab
The addition of Pertuzumab to Tras. + Doce. significantly improved PFS and OS vs. Tras + Doce. in first line metastatic disease.
MARIANNEAs first line for MBC
arm 1: Tras. + Doce.
arm 2: T-DM1 + placebo
arm 3: T-DM1 + pertuzumab
T-DM1 single agent, non inferior but not superior, better tolerance as first-line treatment for HER2 positive MBC
Phase II
SABC 2016
As first line for MBC
arm 1: Pertuzumab + Tras.+AI
arm 2: Tras. + AI
The addition of Pertuzumab to Tras. + AI improved PFS vs. Tras. + AI
TAnDEMAs first line for MBC
arm 1: Tras. + Anastrozole
arm 2: Anastrozole only.
The addition of Tras. to Anastrozole significantly improved PFS vs. Anastrozole alone
Phase III
As second line for MB
arm 1: T-DM1
arm 2: Physician choice.
T-DM1 improved PFS and OS vs. other therapies, (none of patients received Pertuzumab in prior therapies)
Phase III
As second line
arm 1: T-DM1
arm 2: Capcetabine + Lapatinib.
As second line HER2 directed therapy, T-DM1 improved PFS and OS vs. capecitabine + lapatinib, (none of patients received Pertuzumab in prior therapies)
ASCO 2017
As second line
arm 1:Trastuzumab +Lapitinib + AI
arm 2:Trastuzumab + AI
This trial was intended for patient who are deemed not candidate for chemotherapy, and received Tras. and chemotherapy in the past.
The Tras. + Lap. + AI showed significant PFS

As always refer to terms of use here