Living Longer: Advanced Breast Cancer (ABC) – HER2 over-expressed (I)

Introduction

HER2 over-expression constitutes around 20% of all breast cancer.

Two different methods are being used to test for HER2 over-expression, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH)

  • Immunohistochemistry (IHC);
    • identifies HER2 expression on the cell surface, with a grading system of 0 to 3+ positive.
    • tumors are classed as HER2-positive if they have a staining intensity of 3+.
  • Fluorescent in situ hybridisation (FISH)
    • HER2 gene signals to chromosome 17 signals; HER2/CEP17 > 2.2 as a positive result for HER2 gene amplification
her_meta_moa_top.jpg
HER2 receptors over-expression

Those with HER2 over-expression have (OP Kallioniemi, 1991):

  • High histological and nuclear grade (higher grade tumor)
  • Lack of estrogen and progesterone receptors (more often ER/PR negative)
  • Two fold risk of death as compared with those without over-expression.
  • Metastasised/ spread 3 times more often to the lungs, liver and brain and 3 times less often to the bone, which carry better prognosis.
livingproof.jpg
Living Proof (2018), one of my favourite movie! A movie made about the development of trastuzumab (Herceptin) by Dr Dennis Slamon and all the women who made it possible.

Prognosis for patients with HER2 over-expression was extremely poor but improved significantly since the discovery of HER2-targeted therapy, trastuzumab.

  • Trastuzumab was approved by FDA for medical use in 1998 (30 years old!!!)
  • Trastuzumab is a recombinant, humanised monoclonal antibody directed against extracellular domain of HER2 @ subdomain IV.

In early breast cancer, when used in adjuvant setting, it reduces risk of death by at least 30% (see image below).

In advanced breast cancer, HER2-directed targeted therapy doubled the average/ median overall survival (see image below).

Screen Shot 2018-07-17 at 11.37.09 PM.png
Reduces risk of death by 30% in adjuvant setting for early breast cancer. Doubling survival in metastatic/ advanced breast cancer.

HER2-targeting agents are making huge impact in advanced/ metastatic/ stage 4 breast cancer treatment and some had even proven effective (increasing survival, reducing recurrence, etc.) in adjuvant and neoadjuvant settings.

Newer generation of HER2-targeting agents available now are lapatinib (2010), pertuzumab (2012) and T-DM1 (2013).

All these agents can be used as single agent or can be combined with either chemotherapy and hormonal therapy to yield better results.

In advanced setting, the aim is to control the disease but in adjuvant and neoadjuvant setting, the aim is to cure.

By virtue of being ‘promoted’ to be used in adjuvant/ neoadjuvant setting, HER2-targeting agents gained the ‘recognition’ that it’s very effective and an important component in curing cancer.

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Timeline of HER2-targeted therapies. (Shanu Modi, ASCO 2015)

First line HER2-directed treatment for advanced breast cancer (ABC)

Here are the summaries of multiple clinical trials conducted on HER2 over-expressed breast cancer cohorts, plus the results (numbers!) that matters:

Progression free survival (PFS): the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse.

Overall survival (OS): the length of time from either the date of diagnosis or the start of treatment for a disease, that patients diagnosed with the disease are still alive, including all other treatments subsequently after failure of the initial study treatment.

Singe agent

  • Trastuzumab (T) alone, phase 2 trial (MA Cobleigh, ‎1999)
    • Duration of response:  9.1 months
    • Average/ median OS: 13 months

Combination trastuzumab with chemotherapy:

  • Trastuzumab plus chemotherapy (anthracycline, or paclitaxel if previously treated with antracycline before during adjuvant setting) vs. chemotherapy alone ( DJ Slamon, ‎2001)
    • PFS: 7.4 vs 4.6 months
    • Average/ median OS: 25.1 vs 20.3 months
    • Why then, those without trastuzumab can still live 20+ months? Because there is crossover in the clinical trial, meaning those who failed in the chemotherapy only arm will be allowed crossover to the other treatment arm with trastuzumab but will still be analysed in the original group.
  • Trastuzumab + paclitaxel + carboplatin vs T + paclitaxel (N Robert, ‎2006)
    • PFS: 10.7 vs 7.1 months
    • Average/ median OS: 35.7 vs 32.2 months
    • No significant different in 3 agents (T+P+C) vs 2 agents (T+P)
  • Study BCIRG 007; T + docetaxel vs T + docetaxel + carboplatin (V Valero, ‎2011)
    • PFS: 11.1 vs 10.4 months
    • Average/ median OS: 37.1 vs 37.4 months
    • Not significant different in both regime. Additional of extra chemotherapy carboplatin only incur more side effects but without added benefit.
  • HERNATA study; T + docetaxel vs T + vinorelbine (M Andersson, 2011)
    • PFS: 12.4 vs 15.3 months
    • Average/ median OS: 35.7 vs 38.8 months
    • Both combination with docetaxel and vinorelbine are similar
  • BOLERO-1 study; T + paclitaxel (P) + eveolimus (E) vs T + P
    • PFS: 15 vs 14.5 months
    • Average/ median OS: 48.6 vs 50 months
    • No significant different between two treatment arms but PFS and OS were significantly longer in hormone receptor negative sub-group population.

Combination trastuzumab with hormonal therapy:

  • TAnDEM study; T + anastrozole vs anastrozole alone (B Kaufman, ‎2009)
    • PFS: 4.8 vs 2.4 months
    • Average/ median OS: 28.5 vs 23.9 months
    • No significant different in overall survival seen here.
    • The long duration of survival after progression at 4.8 months was likely due to subsequent treatments, not the initial treatment only.
  • eLEcTRA study; T + letrozole vs letrozole alone (J Huober, ‎2012)
    • PFS: 14.1 vs 3.3 months
    • Average/ median OS was not reported
    • The very short PFS with letrozole and anastrozole (above) showed that hormonal therapy have almost no effect for HER2 over-expressed breast cancer.

Combination with newer generations HER2-directed treatment (lapatinib, T-DM1, pertuzumab)

EGF30008 study; lapatinib + letrozole vs letrozole alone (S Johnston, ‎2009)

  • PFS: 8.2 vs 3.0 months
  • Average/ median OS: 33.3 vs 32.3 months
  • No different in survival in both arms. Longer survival likely due to subsequent treatments.
  • Hormonal therapy alone in HER2 over-expressed, failed!

CLEOPATRA trial; pertuzumab (P) + trastuzumab (T) + docetaxel (D) vs T + D (J Baselga, ‎2012)

  • PFS: 18.7 vs 12.4 months
  • Average/ median OS: 56.5 vs 40.8 months
  • With dual HER2-targeted treatment, almost 50% of patients able to live 5 years and above.
  • Although after 19 months, half of the patients progressed in P+T+D treatment, subsequent treatments able to prolong survival another 2 years. (The importance of subsequent treatments, don’t give up!)
  • Do you know if you purchase pertuzumab, you get trastuzumab free now in Malaysia?!

PERTAIN study; pertuzumab (P) + trastuzumab (T) + aromatase inhibitor (AI) vs T + AI, (G Arpino, ‎2017)

  • PFS: 18.9 vs 15.8 months
  • Average/ median OS not reported yet
  • Dual HER2-targeting agents (pertuzumab, trastuzumab), plus with a hormonal therapy (AI: letrozole, anastrozole, exemestane) might be effective for patients who unable to tolerate chemotherapy (as per CLEOPATRA trial).
  • It can also be used when there is no visceral crisis (severe organ dysfunction/ rapid progression of disease) that needed the chemotherapy component for fast response.

MARIANNE study; Trastuzumab (T) + taxane (chemotherapy) vs T-DM1 vs T-DM1 + pertuzumab (P), (EA Perez, ‎2017)

  • PFS: 13.7 vs 14.1 vs 15.2 months (not significant different)
  • Average/ median OS: 50.9 vs 53.7 vs 51.8 months

Finally

The average/ median overall survival for HER2 over-expressed breast cancer subtype is now at par, if not already better than hormone receptor positive (ER/PR positive) breast cancer.

  • Average/ median overall survival for HER2 over-expressed breast cancer now ranges from 25.1 – 56.5 months.

The gold standard first-line treatment for advanced breast cancer with HER2 over-expressed is dual blockage with HER2-targeting agents plus chemotherapy, which offers best results so far.

Subsequent treatments after progression from initial HER2-targeted treatment are also important to achieve maximal survival (I will write more about subsequent lines of treatment soon).

Similarly, close monitoring and management of side effects are equally important to maintain good quality of life.

Till then, stay strong and don’t give up.

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