Living Longer: Advanced Breast Cancer (ABC) – Triple Negatives; ER/PR/HER2 (-ve)

Introduction

Breast cancer is not a single disease but comprised of distinct biological subtypes with different prognosis and treatment options:

  • Luminal A: ER/PR+ve, Her2-ve
  • Luminal B: ER/PR+ve, Her2+ve
  • HER2 over-expressed: Her2+ve
  • Triple negatives/ basal-like: ER/PR-ve, Her2−ve
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Breast cancer 4 subtypes

Among the different subtypes above, triple negative breast cancer (TNBC) accounts for 10%-15% of breast cancer diagnosed.

TNBC carries the worst prognosis and shortest progression free survival (PFS) compared to other subtypes.

  • Also, 15% of TNBC also developed brain metastasis.
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Survival data for different metastatic breast cancer subtypes with triple negative breast cancer (TNBC) faring the worst (SEER, 2017).

TNBC, in turn, is heterogenous and can be further divided into more different subtypes:

  • Basal-like – associated with BRCA, higher pathological complete response
  • Immunomodulatory
  • Mesenchymal
  • Luminal androgen receptor

 

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Triple negative breast cancer (TNBC) subtypes

Despite multiple subtypes of TNBC, there are still no targeted therapy for each of the subtypes.

The current recommended treatments are still chemotherapy, chemotherapy and more chemotherapy because the lack of targets (ER and HER2 negative) for hormonal and targeted therapy to act on.

Palliative chemotherapy aims are to prolong survival AND to maintain quality of life (alleviation of symptoms/ postponing future symptoms of the disease).

Patients shouldn’t fear chemotherapy because it’s not as bad as shown in TV series or movies. With adequate hydration, balance dietary intake and avoidance of alternative medications, most of the chemotherapy side effects can by avoided or lessened.

Chemotherapy

There are many types of chemotherapy that are effective in advanced triple negative breast cancer. Which is the best?

The choice of chemotherapy is based on whether the chemotherapy had been used before in earlier/ curative/ adjuvant/ neoadjuvant setting.

I

Anthracycline-based (epirubicin, doxorubicin) combination chemotherapy had been proven to be beneficial and superior since 1970s and is most often used in the first-line/ adjuvant/ neoadjuvant/ curative setting.

  • If it’s not used before or patient presented initially as advanced triple negative breast cancer, anthracycline-based combination chemotherapy should be used first.
  • If it’s used before, it’s cannot be used again. Anthracycline chemotherapy had maximum cumulative dose that cannot be exceeded or the risk of congestive heart failure increases.
  • Combination FEC is more superior than single agent anthracycline.

II

Secondly, taxanes group (paclitaxel, docetaxel) is also effective in advanced TNBC. Although it’s also commonly used in first-line/ adjuvant/ curative setting, there is no maximum cumulative dose and rechallenging with taxane chemotherapy is possible if long disease free interval > 1 year.

  • Combination with capecitabine offer higher overall survival than taxane (docetaxel) alone.
  • Average/ median overall survival with combination capecitabine and docetaxel is 14.5 months vs 11.5 months with docetaxel alone.
  • Median time to disease progression was 6.1 months in the combination arm and 4.2 months with docetaxel alone.
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Capecitabine and docetaxel vs docetaxel alone in anthracycline-pretreated patients with advanced breast cancer. O’Shaughnessy (2002)

III

Capecitabine is also effective as single agent (average/ median overall survival 9.4 months, see below) in advanced TNBC but results are not as robust as combination chemotherapy. The advantages of capecitabine are convenient (oral administration) and tolerable with minimal side effects.

IV

Eribulin have data that support its use in both second and third line-setting for advanced breast cancer.

  • In second-line Study 301 (C Twelves, ‎2016) setting, eribulin increases survival specifically in TNBC by 5 months (14.4 months vs 9.4 months in eribulin and capecitabine, respectively).
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Study 301: Subset analysis overall survival results for triple negative breast cancer (TNBC)
  • In third-line Embrace study (J Cortes, ‎2011) setting, which patients are fairly heavily pre-treated, eribulin still maintain respectable average/ median overall survival – 13.1 months vs 10..6 months using eribulin vs treatment of physician’s choice (TPC; most often are vinorelbine, gemcitabine, or capecitabine).
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EMBRACE study: Overall survival results comparing eribulin vs treatment physician’s choice (TPC)

Newer Treatment Options

I. PARP Inhibitor

In basal-like breast cancer, which is a subset of TNBC, some patients have BRCA-mutated/ dysfunction. These BRCA1-deficient cells are sensitive to PARP1 inhibition treatment (olaparib, niraparib, talazoparib).

  • In OlympiAD Trial (M Robson, ‎2017), patients with inherited/ germline BRCA-mutated (gBRCAm) and metastatic breast cancer that was either hormone receptor–positive and HER2 negative or triple-negative are treated with olaparib vs standard chemotherapy (either capecitabine, vinorelbine, or eribulin).
  • Average/ median overall survival was 19.3 months in patients treated with olaparib and 17.1 months for patients treated with chemotherapy.
  • Average/ median progression-free survival was longer in the olaparib group than in the standard chemotherapy group (7.0 months vs. 4.2 months).
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OlympiAD Trial: Olaparib vs standard chemotherapy in patients with inherited/ germline BRCA-mutated (gBRCAm) and metastatic breast cancer with triple negative or ER positive and HER2 negative.

II. Immunotherapy

TNBC subset, immunomodulatory, is currently vigorously tested in clinical trials with various types of immunotherapy (pembrolizumab, nivolumab, atezolizumab, etc) +/- combination with chemotherapy. More results in the coming years to come.

III. Anti-androgen

In luminal androgen (TNBC subset), anti-androgen treatment (bicalutamide, enzalutamide, abiraterone) might be effective treatment for those with androgen receptor positive.

However, results are still preliminary and mainly for clinical activity (response rate, clinical benefit rate, etc) and tolerability to anti-androgen treatment.

High hopes? Not really, early phase 2 study only showed progression free survival around 3 months (T.A. Traina, 2018). More results in the coming years to come also.

Finally

Prognosis for advanced triple negative breast cancer remain poor compared with other subtypes of breast cancer.

So far, chemotherapy is still the best option while we wait for more results from multiple clinical trials using newer treatments such as immunotherapy, PARP inhibitors or anti-androgen.

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Half glass full or half glass empty?

Average/ median overall survival for TNBC subtype ranges from 9.4 months – 19.3 months. Different perspectives, depend on how you want to see them, either with half glass full or half glass empty.

  • Half glass full – the increase in average/ median overall survival with treatment is 2 – 3 times longer compared to just best supportive care/ no treatment.
  • Half glass empty – average/ median overall survival is lower than average life expectancy for all other subtypes of metastatic breast cancer, which is about 26 months (Falkson G, 2002).

Palliative chemotherapy had clearly proven to improve survival in patients with TNBC.

Live longer.

 

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