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

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


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
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.

Screen Shot 2018-07-13 at 11.12.15 PM
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
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 (preventing/ postponing future symptoms of the disease and palliating/ alleviating cancer symptoms)

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.


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.

Combinations with platinum chemotherapy had been shown to improve pathological complete response (pCR) in neoadjuvant setting [G von Minckwitz – GeparSixto (2014), WM Sikov – CALGB 40603 (‎2014)] and is a logical combination in advanced breast cancer also.


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.


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.
Screen Shot 2018-07-13 at 2.12.56 PM.png
Capecitabine and docetaxel vs docetaxel alone in anthracycline-pretreated patients with advanced breast cancer. O’Shaughnessy (2002)


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.


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).
Screen Shot 2018-07-13 at 3.29.25 PM.png
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).
Screen Shot 2018-07-13 at 3.44.33 PM.png
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 (OS) was 19.3 months in patients treated with olaparib and 17.1 months for patients treated with chemotherapy
    • HR=0.90, p=0.57, meaning no statistical difference in median OS from using standard therapy or with olaparib –> negative trial
  • Median progression-free survival (PFS) was longer in the olaparib group than in the standard chemotherapy group (7.0 months vs. 4.2 months).
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.

Update (1/11/2018):

Impassion130 study (Schmid P, 2018)

  • Atezolezumab (A) + nab-Paclitaxel (P) vs placebo + nab-Paclitaxel (P)
  • Average/ median overall survival (intention to treat population, ALL/ unselected patients) was 21.3 months and 17.6 months (HR=0.84, p=0.084), respectively.
    • In PD-L1+ (>1%) patients only, median OS was 25.0 months vs 15.5 months (HR=0.62), respectively.
  • Median progression-free survival (PFS) was longer also, 7.2 months vs 5.5 months, respectively. Only slightly better in PD-L1+ subgroup, 7.5 months vs 5.0 months.
Screen Shot 2018-11-06 at 12.03.26 AM.png
Impassion130 study (atezolezumab + nab-paclitaxel), showing significant improvement in overall survival only in PD-L1+ (>1%) subgroup patients (Schmid P, 2018).

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.


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

  • Average/ median overall survival (OS) for TNBC subtype ranges from 9.4 months – 19.3 months (now up to 25 months with immunotherapy).
  • Median OS is lower than average life expectancy for all other subtypes of metastatic breast cancer, which is about 26 months (Falkson G, 2002).

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

However, emerging data now showed that immunotherapy can improve further median OS for selected TNBC patients with positive PD-L1 expression.


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