Episode 068: Breast Cancer Series, Pt. 13- Metastatic Triple Negative Breast Cancer

medicine
Written By TheFellowOnCall HemeOncPodcast

This week, we complete our breast cancer series, focusing on triple-negative breast cancer (TNBC). The last few months have been quite the journey! Please continue to refer to our shownotes to help navigate this complex disease treatment paradigm. 

How should we counsel patients about recurrence risk in triple negative breast cancer? 

  • TNBC has the highest risk of early relapse compared to the other subtypes of breast cancer. 

    • The hazard rate for distant recurrence is close to 15% for the first year 

    • Remains at 10% per year from year 2-4. 

    • Dropping to 5% from year 4-5. 

    • Then lower rates after that time.

Figure 3 from study noted above

When should we think about setting germline BRCA testing for TNBC patients?

  • NCCN guidelines recommend testing any female with breast cancer younger than 50. 

  • All triple negative breast cancer patients should get offered testing given treatment implications in both the adjuvant and metastatic setting.

  • Any male with breast cancer should also get tested. 

  • HIGH YIELD: ENSURE THIS IS BRCA GERMLINE TESTING NOT SOMATIC TESTING

  • Also important to connect to genetic counseling 

Is there a role for immunotherapy given the importance of the tumor microenvironment and possible higher neoantigen expression?

  • Data suggests that there are higher levels of tumor infiltrating lymphocytes and PD-L1 expression for some patients. 

  • This led us to organize trials of immunotherapy in triple negative breast cancer, many of which were enrolled or stratified by PD-L1 status, which is why it is critical to get that PD-L1 testing. 

How do we approach first-line treatment with TNBC? 

  • A historical perspective: 

    • In the 1990’s there were several studies looking at epirubicin alone vs. various combination regimens which all really found that single agent epirubicin was just as good with less toxicities (AKA single agent chemo was just as good as combination therapy

    • In 2003, there was also a pivotal trial run by an cooperative group called E1193; this paper not only informed treatment options, but also highlights (in retrospect) how our view of surrogate endpoints has changed. 

      • Included 739 patients with metastatic breast cancer from 1993-1995

      • Looked at doxorubicin alone vs. paclitaxel alone vs. combination of doxorubicin and paclitaxel

      • Outcomes: 

        • There was improved response rates from 35% to 48% with the combination therapy with improved time to treatment failure 

        • But there was no difference in OS with median close to 20 months in all arms

      • Conclusion: Really no difference between doxorubicin or paclitaxel or combination 

      • Authors conclusion: “Despite superiority in response rate and time to treatment failure, combination therapy failed to improve overall survival. Perhaps more importantly, given the usually fatal nature of the disease, combination therapy did not improve quality of life”

      This is important to keep in mind as we now use things like pathologic CR and PFS as surrogate end points. Is this appropriate? Should we instead be focusing on quality of life? 

  • These studies informed our approach using single-agent chemotherapy sequentially in patients with metastatic TNBC

What other combination or single agent regimens were trialed prior to our current standard of care?

  • Recall that in patients with BRCA-mutations, platinum agents are effective because of the impaired homologous recombination repair mechanisms

  • Many TNBC patients, regardless of BRCA status, also have DNA repair issues.

  • TNT Trial (discussed below) noted that there was no difference between carboplatin and docetaxel BUT in BRCA subgroup, the response rate doubled, therefore suggesting that carboplatin may be a good option for BRCA-mutated patients 

  • There is data suggesting synergy between cisplatin and gemcitabine so this combination was trialed against paclitaxel and gemcitabine for all patients with TNBC (CBCSG006 Trial). 

    • Primary endpoint was PFS

    • Found that cisplatin+gemcitabine had an improved PFS by a little over one month

    • We knew that the toxicity of cisplatin is not worth it, so now we can use carboplatin + gemcitabine for these patients which will be important as we talk about the immunotherapy combination regimens

    • Results not stratified by BRCA status

  • So this informed the use of single-agent therapy (such as paclitaxel) or potentially carboplatin + gemcitabine for patients with TNBC

How does immunotherapy come into play? 

  • Immunotherapy was first looked at in the 2nd or later line setting. 

  • KEYNOTE-119 looked at single agent pembrolizumab vs. investigators choice chemotherapy

    • Chemo options: Capecitabine, gemcitabine, eribulin, or vinorelbine 

    • Included a little over 600 patients and all had prior treatment 

    • No difference in PFS or OS with ORR of only 14% in IO monotherapy

    • Notably did not require high CPS scores and there was a trend for improvement with CPS > 20 in that trial

  • Next step was looking at combination chemoimmunotherapy

    • IMpassion-130 led to the first approval of combination therapy which has now notably been withdrawn 

      • Included metastatic TNBC with no prior treatment for advanced disease and only allowed enrollment for those who progressed greater than 12 months since prior therapy in the early stage setting

      • No requirement for PD-L1 positivity

      • Co-primary endpoints were PFS and OS in ITT 

        • Planned subgroup analysis for PD-L1 positive population

      • Compared atezolizumab + nab-paclitaxel (i.e. abraxane or albumin bound paclitaxel) vs. nab-paclitaxel alone

      • Improved PFS by 2 months in the ITT and PD-L1 positive group from 5 months to 7 months

      • No difference in OS in the ITT

      • Median OS improved from 18 months to 25 months in the PDL-1 positive subgroup but not statistically significant in the ITT population

  • At the same time, we had another trial called IMpassion-131

    • Same design as prior trial except it was atezolizumab + “plain old” paclitaxel vs. paclitaxel alone

    • No difference in PFS or OS in the ITT or PD-L1 population

    • Important negative confirmatory study that resulted in withdrawal of prior atezolizumab approval

    • Published in Annals of Oncology while the positive likely spurious IMpassion 130 trial was published in NEJM

Given the negative follow up trial, atezolizumab approval was withdrawn 

  • This gets to our current standard of care trial called KEYNOTE-355

    • Compared pembrolizumab + chemotherapy vs. chemotherapy alone

      • Chemotherapy could be carboplatin + gemcitabine, nab-paclitaxel, or paclitaxel

    • Prespecified analysis for PFS and OS in CPS 10 or more, CPS 1 or more, and ITT population

    • Outcomes: 

      • PFS improved in CPS > 10 CPS > 1, and ITT!

      • The effect size was highest in CPS > 10 with improvement in PFS by roughly 4 months compared to 2 months in the other subgroups

      • OS only improved in CPS > 10 with median 23 months compared to 16 months

    • This led to the approval of pembro + chemo in metastatic TNBC for CPS ≥10

What is our standard of care for CPS <10? 

  • Single agent chemotherapy would be the preferred approach 

    • Many options but often think paclitaxel or capecitabine (oral so convenient)

  • If a germline BRCA mutation: Consider chemotherapy or PARP inhibitor (NCCN guidelines - Page 82)

    • Remember that platinum agents work well against cancer cells with DNA repair deficiency (i.e. BRCA mutated cancer cells) so the chemotherapy preference is carboplatin

      • Phase III trial called TNT (mentioned above), which compared carboplatin vs. docetaxel in first line treatment of metastatic TNBC or metastatic BRCA mutated breast cancer

      • No difference in PFS or OS

      • But higher response rates in the BRCA mutated subgroup (roughly doubled to 68% from 33%)

      • This is why carboplatin is preferred if using chemotherapy for BRCA mutated patients

  • Two trials phase III trials looked at the use of PARP inhibitors in BRCA mutated patients

    • OLYMPIAD (olaparib) and EMBRACA (talazoparib)  

      • Included all HER2 negative patients (HR positive and TNBC)

      • Powered for PFS

      • Total of 54 patients with TNBC in OLYMPIAD

      • Total of 150 patients with TNBC in EMBRACA

    • So what did the control arm get?

      • Patients enrolled had prior treatment with taxane, anthracycline, or both

      • capecitabine, eribulin, gemcitabine, or vinorelbine 

    • Active drug with ORR ~60% compared to ~20% with standard chemo

      • Caveat is that this was investigator assessed so prone to bias

    • PFS improved from 4-5 months to about 7-8 months

      • These numbers included both HR positive and TNBC

      • The TNBC subgroup seemed to derive more benefit

    • No difference in OS and more hematologic toxicities with PARP inhibitors (also financial toxicity)

    • There was improved QOL with PARP inhibitors over chemotherapy; however, this was not assessed during the cancer journey but just during the trial period 

      • Brings in the question of whether QOL would improve over the whole journey if they just got PARP at progression and chemotherapy first

  • If patient has CPS <10, then first line is single-agent chemotherapy

  • If they have BRCA mutation, then consider single-agent platinum therapy or PARP inhibitor 

What are second-line therapy options? 

  • So remember that single agent chemotherapy and clinical trial is always an option but we have good data for the use of antibody drug conjugates

  • First question: is this patient HER2 low?

  • If patient is HER2 low:

    • We discussed the HER2 low data in the HR+ breast cancer episode from the DESTINY Breast-04 trial using trastuzumab-deruxtecan

      • Remember that this is an option for patients with HER2 1+ or 2+ by IHC

      • In the TNBC subgroup, there was improved PFS and disease control rates

        • Caveat it was comparing 40 patients who got trastuzumab-deruxtecan to 18 patients who got chemotherapy so small numbers but nonetheless promising

  • If patient is NOT HER2 low: 

    • Proceed with the ADC called sacituzumab-govitecan which we discussed previously in HR+ metastatic disease

      • This is an ADC to trop-2 which is universally expressed on breast cancer cells

      • Approved based on the phase III ASCENT trial

      • Randomized patients in the second line or greater to sacituzumab govitecan vs. single agent chemotherapy

      • Primary endpoint PFS

      • Median PFS improved to 5.6 months from 1.7 months

      • ORR was 35% compared to 5% which is great activity as we think about potentially moving it up in lines of therapy

Let’s put this all together (our approach based on the data): 

  • Is the CPS score >10: Chemo+Pembro

  • If CPS score <10: 

    • If BRCA+: Single agent platinum or PARP-inhibitor

    • If not: Single agent sequential chemotherapy

  • Second line 

    • Clinical trials

    • If HER2 low: trastuzumab deruxtecan 

    • If not HER2 low: sacituzumab-govitecan

    • Continue cycling through single agent chemotherapy

References

The crew behind the magic:

  • Show outline: Vivek Patel

  • Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath

  • Editing: Resonate Recordings

  • Shownotes: Ronak Mistry

  • Social media management: Ronak Mistry

We are proud to partner with HemOnc.org!

Want to learn more about the trials that lead to the regimens discussed today? What about dosing schedules? See links in the show notes for a link to HemOnc.org

TheFellowOnCall HemeOncPodcast
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Episode 067: Breast Cancer Series, Pt. 12- A Patient's Perspective