Living Longer: Advanced Breast Cancer (ABC) – Hormone positive; ER (+ve), HER2 (-ve)

Introduction

In patients with advanced breast cancer AND ER positive AND HER2 negative AND no presence/ impending visceral crisis, the recommended treatment by various international guidelines is hormonal therapy.

  • Chemotherapy is only for rapidly progressive disease OR in the setting of visceral crisis OR no more response from available hormonal therapy.
  • HER2 directed treatment is applicable only when HER2 is positive (3+)/ overexpressed/ amplified

Visceral metastasis is spread of cancer to internal organs including liver, lungs, brain and body cavities like the pleura and peritoneum. Non-visceral metastasis are spread to bone and/ or skin.

Visceral crisis is defined as severe organ dysfunction as assessed by signs and symptoms, laboratory studies, and rapid progression of disease.

Types of hormonal treatments depend on menopausal status. Most hormonal therapy requires patient to be in post-menopausal status such as:

  • Aromatase inhibitors (letrozole, anastrozole, exemestane)
  • Fulvestrant
  • Or any combination treatment with agents above

For pre-menopausal patients with advanced breast cancer, there are few ways to induce menopause:

  • Medically via hormonal therapy with GnRH agonist (Zoladex, Lucrin)
  • Surgically via bilateral oophorectomy
  • Radiotherapy

The Good

Hormonal monotherapy commonly used in first-line setting for women in advanced breast cancer setting depend on which hormonal therapy had been used previously in adjuvant (non-metastatic setting).

  • If tamoxifen was used for 5 – 10 years in adjuvant setting, aromatase inhibitors (AI) such as letrozole, anastrozole or exemestane can be used as first line monotherapy in metastatic setting.
  • Else, if AI was used earlier during non-metastatic setting, tamoxifen can be used as first line monotherapy.
  • How long can monotherapy with tamoxifen or AI can control advanced breast cancer before disease progression?
    • Around 5.6 – 6 months disease control for tamoxifen and 9.4 – 11.1 months disease control for AIs (Nabholtz 2000, R Paridaens 2004, Mauridsen HT 2007)
    • Advantages: Cheap (from RM50 to few hundreds), well tolerated, minimal side effects, oral tablets
    • Disadvantage: Not really long disease control but still valid options and commonly practiced.
  • Some patients who had adjuvant sequential hormonal treatments earlier; 2-3 years of tamoxifen and then followed by 2 years of AI. Options for these patients are:
    • They can still try back tamoxifen in second line setting but disease control will be shorter than 6 months
    • Single agent fulvestrant used in second-line setting, average/ median time to disease progression was 7.9 months (Di Leo, 2018)

The Better

  • Fulvestrant as first line setting:
    • FIRST trial (phase 2 trial, fulvestrant 500mg vs anastrozole), average/ median time to disease progression was 23.4 months and 13.1 months
  • Screen Shot 2018-06-23 at 1.26.01 AM
    FIRST trial: Also showed improved survival of 54.1 months vs 48.4 months with fulvestrant and anastrozole, respectively.
    • In confirmatory first-line setting FALCON phase 3 trial (fulvestrant 500mg vs anastrozole), average/ median time to disease progression was 16·6 months vs 13·8 months
    • Advantage: Longer disease control, good compliance (once a month injections), minimal side effects.
    • Disadvantage: More expensive (around RM3000, if I’m not mistaken)
  • It doesn’t take long before someone tried combining both fulvestrant + anastrozole vs anastrozole alone, in SWOG S0226 study.
    • Average/ median time to disease progression was 15.0 months versus 13.5 months.
  • Fulvestrant alone is good enough and for best results, to use in first line setting.

The Even Better

Starting from 2015, a new class of treatment, inhibitor of CDK4/6 which prevents cellular DNA synthesis was introduced.

  • Palbociclib (2015), ribociclib and abemaciclib (2018)
  • Advantages: longer disease control
  • Disadvantages: Newer side effects (still tolerable), expensive

Palbociclib

First inhibitor of CDK4/6 approved for use in Malaysia

Price: New patient assistance programme soon (3 weeks on, 1 week off)

PALOMA-1 (phase 2 study, first line treatment)

  • palbociclib + letrozole vs letrozole alone;
    • progression free survival was 20.2 months vs 10.2 months, respectively.
    • average/ median overall survival was 37.5 months vs 33.3 months, respectively

Screen Shot 2018-06-23 at 2.06.15 AM

Finn RS (2015): Overall survival for PALOMA-1

PALOMA-2 (phase 3 confirmatory study, first line treatment)

  • palbociclib + letrozole vs letrozole alone;
    • progression free survival was 24.8 months vs 14.5 months, respectively.
    • no overall survival data yet

PALOMA-3 (phase 3 study, second line treatment/ previously failed hormonal therapy)

  • palbociclib + fulvestrant vs fulvestrant alone;
    • progression free survival was 9.2 months vs 3.8 months, respectively.
    • no survival data yet

Abemaciclib

MONARCH-2 (phase 3, second line treatment)

  • Abemaciclib + fulvestrant vs fulvestrant alone
    • progression free survival was 16.4 months vs 9.3 months, respectively.
    • no survival data yet

MONARCH-3 (phase 3, first line treatment)

  • Abemaciclib + letrozole/ anastrozole vs letrozole/ anastrozole alone
    • progression free survival was NR (not reached yet) vs 14.7 months, respectively.
    • no survival data yet

Ribociclib

MONALEESA-2 (phase 3, first line treatment)

  • Ribociclib + letrozole vs letrozole alone
    • progression free survival was 25.3 months vs 16 months, respectively.
    • no survival data yet
    • UPDATE (25/6/2018): Approval obtained to use in Malaysia (3 weeks on, 1 week off)

MONALEESA-3 (phase 3, first/ second line treatment)

  • Ribociclib + fulvestrant vs fulvestrant alone
    • progression free survival was 20.5 months vs 12.8 months, respectively.
    • no survival data yet
    • Screen Shot 2018-07-02 at 12.17.00 AM.png
      DJ Salmon (2018): Progression free survival for MONALEESA-3

The Best

The best treatment strategy can be summarised by image below:

  • It’s hormonal therapy all the way unless there is impending/ presence of visceral crisis, rapidly progressing disease or no more response from available hormonal therapies.
Screen Shot 2018-06-22 at 11.35.52 PM.png
Endocrine treatment strategy

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