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

What happen when first-line treatment fails?

In advanced or metastatic breast cancer, first-line treatment will fail after certain duration of time.

This is because cancer cells developed resistance to the treatment and not because the treatment is ineffective.

Life doesn’t end when first-line treatment fails.

We just continue fighting the cancer with other effective second-line and subsequent-lines treatments and the results can be seen from the improvement in average/ median overall survival.

Let’s go through HER2-targeted treatment after failure of first line HER2-targeting agents.

Second line setting

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1. EGF100151 trial: Lapatinib + capecitabine vs capecitabine alone (CE Geyer, 2006)

  • PFS: 8.4 vs  4.4 months in the combination and monotherapy group, respectively.
  • OS: 17.8 vs 15.2 months (Cameron D, 2010)
  • Treatment was well tolerated despite being a combination therapy.
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EGF100151 trial: Progression free survival (PFS)

2. EMILIA study: T-DM1 vs lapatinib + capecitabine (S Verma, ‎2012)

  • PFS: 9.6 vs 6.4 months, for T-DM1 and lapatinib plus capecitabine, respectively
  • OS: 30.9 vs 25.1 months
  • Suitable for patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane.
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EMILIA study: Average/ median overall survival was 30.9 (T-DM1) vs 25.1 months (lapatinib + capecitabine).

3. PHEREXA trial: Trastuzumab (H) + capecitabine (X) vs Pertuzumab (P) + TX (A Urruticoechea, 2017)

  • PFS: 9.0 v 11.1 months for HX and PHX combination respectively.
  • OS: 28.1 v 36.1 months
  • Magnitude of OS difference is in keeping with prior experience of pertuzumab in metastatic breast cancer
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PHEREXA trial: Average/ median overall survival was 28.1 (HX) vs 36.1 months (PHX combination)

4. GBG 26/BIG 3-05 study – transtuzumab use beyond progression: Advanced breast cancer with HER2-positive who progressed during treatment with transtuzumab were randomised to Capecitabine (X) vs X + Trastuzumab (H).

  • OS: Median overall survival was 20.6 and 24.9 months with X and XH, respectively
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GBG 26/BIG 3-05 study: Overall survival

5. PERTAIN trial (phase 2 trial, ER positive and HER2 over-expressed): pertuzumab (P) + trastuzumab (H) + letrozole/ anastrozole (AI) vs H + AI.

  • PFS: 18.9 vs 15.8 months (HR: 0.65, p=0.007)
  • OS: not reached in both treatment arms
  • Slightly more than 50% in each treatment arm received induction chemotherapy

Third line setting and beyond (heavily pre-treated)

TH3RESA study: T-DM1 vs treatment of physician’s choice (chemotherapy, hormonal therapy) (IE Krop, ‎2017)

  • PFS: 5.2 vs 2.8 months.
  • Average/ median OS: 22.7 vs 15.8 months
  • How can one live more than 20 months when the disease progressed with the above treatment after just 5 months? It’s with subsequent treatments! As long as there is treatment available (chemotherapy, hormonal therapy, radiotherapy, tumor ablation, etc), go for it.
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TH3RESA study: Overall survival

EGF104900 trial: Lapatinib + trastuzumab vs lapatinib alone in heavily pre-treated cohorts.

  • PFS: 2.6 vs 1.9 months
  • Average/ median OS: 14 vs 9.5 months
  • Although the efficacy is not long, good effort by clinicians conducting this study nevertheless for offering patients further treatment options.
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Therapeutic milestones in the management of HER-2-positive advanced breast cancer.


If you can’t afford expensive treatment such as with T-DM1, trastuzumab or lapatinib, other therapies such as palliative chemotherapy, hormonal therapy, radiotherapy and clinical trials are valid options.

I must stressed that treatments are more expensive and less effective as the lines (first-line, second-line, third-line, etc) of treatment increases.

However, any proven therapies are better than no therapy at all, whether to reduce/ delay unpleasant symptoms or to prolong life.

It’s always our hope to delay the inevitable until another breakthrough in cancer treatment arrives or a potential clinical trial become available so that patients’ hope of seeing their children graduate, celebrate anniversary, etc can be achieved.

Optiming HER-2–directed therapy with sequencing of HER2 targeted agents in advanced breast cancer (S Verma)

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