Episode 063: Breast Cancer Series, Pt. 8-HER2+, Early Stage Breast Cancer

medicine
Written By TheFellowOnCall HemeOncPodcast

We continue on our journey through early stage breast cancer, this time turning our attention to HER2+ disease. There is a lot of data in this episode, as you will both hear and see. To make this easier, we highlight key takeaways to make understanding this even easier.

Background on HER2

Refresher on HER2 status in non metastatic setting:

  • What is HER2?

    • Transmembrane glycoprotein with tyrosine kinase activity belonging to EGFR family; implicated in cell growth and differentiation

    • Implications in breast cancer, amongst other cancers. 

    • Increased risk of disease recurrence and poor prognostic factor (https://www.ncbi.nlm.nih.gov/books/NBK537134/) 

  • Assessed via IHC and FISH (Refer back to breast cancer vocabulary episode)

  • HER2+ simplified if:

    • IHC 3+ or

    • FISH with ratio > 2 or copy number > 6

    • Remember 2, 3, and 6

  • “HER2 low” applies only to the metastatic setting

HER2 is often referred to by different names

  • HER2: The protein product is similar to EGFR, which is also called “HER1,” therefore, this protein as called “HER2”

  • HER2/neu: 

    • In 1984, neu gene was discovered from rat glioblastoma cell line studies that could transform cells into tumor cells

    • Following year, a homologous gene to neu was identified on chromosome 17 in humans; given the similarities, the term “neu” was adopted

  • ERBb2: ERbB is a family of tyrosine kinase proteins structurally similar to EGFR, which was called “ERbB1”; therefore HER2 was also called “ERBb2”

What are some important characteristics about HER2+ disease that we should know about? 

  • Present in 15-20% of invasive breast cancers 

  • Historically aggressive with poor prognosis though this has significantly improved with the advent of HER2 directed therapies in the neoadjuvant and adjuvant settings

  • High risk for metastatic disease to the brain when compared to HR+ tumors that we talked about in prior episodes  

What is the mechanism of HER2? 

  • HER2 is unique in that it activates signaling in a completely “ligand-independent” manner

  • HER2 receptor activated in two ways:

    • Interacts with other HER2 receptors if significant overexpression (i.e. HER2+ breast cancer) to form homodimers (again very interesting that this is ligand-independent)

    • Interacts with other ERbB family receptors to heterodimerize leading to cell proliferation through multiple pathways → PI3K, MAPK 

This then lead to the discovery of trastuzumab

  • Over the next decade after HER2 was discovered, researchers found a murine antibody against the HER2 receptor that slowed cancer cell growth in rats then humanized this antibody which we all now know as “trastuzumab” 

  • Trastuzumab binds the HER2 receptor thereby preventing homodimerization, which subsequently stops downstream signaling (In contrast, pertuzumab, another anti-HER2 monoclonal antibody prevents heterodimerization) 

  • Initial approval Approved in 1998 for treatment of metastatic HER2+ breast cancer 

    • Key trial by Slamon et al. in NEJM in 2001 including women with HER2+ metastatic breast cancer who had not previously received chemotherapy for their metastatic disease:

      • Phase III study of 469 women with HER2+ metastatic disease 

      • Trastuzumab added to standard chemotherapy backbone vs. chemotherapy alone

        • Anthracycline [doxorubicin or epirubicin] + cyclophosphamide 

        • Paclitaxel (for patients who had previously gotten adjuvant anthracycline  

      • Improved RR: 50% with trastuzumab vs. 32% in control

      • Extended time to progression: 7.4m with trastuzumab  vs. 4.6m in control 

      • Improved median OS 25m with trastuzumab vs. 20m in control

As we know by now, since trastuzumab was approved in the metastatic setting with a response rate of 50%, the natural question is can we give it earlier. What were some of the important studies for using trastuzumab in early stage breast cancer?

  • We first looked at the addition trastuzumab to chemotherapy in the adjuvant setting

  • There was a pivotal joint analysis of two concurrent cooperative group adjuvant trials starting in 2000 that showed the efficacy of this approach which looked at AC-T vs. AC-TH

  • Trials included were: 

    • National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31

      • Compared AC-T (T at q3week) vs. AC-TH

        • Trastuzumab (aka Herceptin hence the H) was given for a total of 1 year every 2 weeks starting with taxol. Remember taxol is given for 12 weeks after the AC is completed as we have discussed in prior episodes

    • North Central Cancer Treatment Group (NCCTG) trial N9831

      • Compared AC-T (T at q1week) vs. four cycles of AC-T followed by 1 year of trastuzumab vs. AC-TH (with trastuzumab given for 1 year total and started concurrently with taxol like in B-31 trial)

      • Group B here was excluded in the final analysis because it was not given concurrently with taxol 

      Total patients = 4046

  • In 2014, there was a follow up publication in JCO with mature OS and DFS data (Perez et al. JCO 2014).

    • Median follow up: 8.4 years

    • OS: 84% in trastuzumab arm vs. 75.2% in control arm → ~10% improvement

    • DFS: 73.7% in trastuzumab arm vs. 62.2% in control arm → ~10% improvement

  • The Fellow on Call Key Takeaway: 

    • Addition of trastuzumab in adjuvant setting improved OS and DFS compared to control in patients with operable HER2-positive breast Cancer

We often use HER2-directed therapies in the neoadjuvant setting now. How did we get here? 

  • We have discussed previously in the HR+ setting we use neoadjuvant chemotherapy for inoperable tumors and to downstage some tumors in certain situations but that overall pathologic CR and ORR rates are not ideal and some of these women would never need chemotherapy based on their oncotype score 

  • The HER2+ setting is different:

    • First off, it is important to know that overall survival outcomes for patients are essentially the same whether we give neoadjuvant or adjuvant chemotherapy for breast cancer patients based on a meta analysis published in 2005 (Article here)

    • We also know that achieving a pathologic CR (which we believe is favorable, but not a validated endpoint yet!) to neoadjuvant chemotherapy is prognostic for overall survival 

    • So why neoadjuvant chemotherapy + trastuzumab for HER2 positive disease:

      • Downstage tumors for better surgical outcomes

      • Possibly downstage the axilla to prevent axillary lymph node dissection

      • Pathologic complete response is an important prognostic marker; and after status of pathologic CR after surgery, we can give another HER2-directed agent if pathologic CR is not achieved to further improve survival 

  • This is why neoadjuvant treatment is standard of care for women with HER2 positive breast cancer that is T2 (>2 cm) and/or node positive 

  • Adjuvant chemotherapy + trastuzumab approach can be considered for patients with smaller tumors which we will discuss 


How did we get to where we are today? 

Role of neoadjuvant trastuzumab with the NOAH Trial (Lancet 2010)

  • International phase 3 trial in women with newly diagnosed high risk HER2+ breast cancer

  • Enrolled 235 patients 

    • T3N1 (moveable axillary), T4, or any T+ N2 or N3 (fixed axillary or other nodes)

  • Study design: 

    • Arm 1: HER2+; neoadjuvant trastuzumab + chemotherapy followed by adjuvant trastuzumab

    • Arm 2: HER2+; neoadjuvant chemotherapy; initially not offered adjuvant treatment, but positive results of adjuvant trastuzumab were released, therefore given 1 year of adjuvant trastuzumab post-surgery 

    • Chemotherapy backbone: AT-T followed by CMF (cyclophosphamide, methotrexate, 5-FU)

  • Primary endpoint was EFS

  • Key Secondary endpoint was pathologic CR rates (breast and axilla reported separately)

  • Outcomes in updated analysis published in 2014: 

    • EFS: 

      • 5 year EFS was 58% in trastuzumab arm vs. 43% that was statistically significant

      • 5 year OS not different

        • Authors conducted a sensitivity analysis to account for cross over

        • Remember that arm 2 initially got no trastuzumab but crossed over to adjuvant trastuzumab based on the NSABP-B31 trial we talked about above

        • Improvement in OS if you just look at patients who got no trastuzumab but that doesn’t make sense because we should be asking do we need trastuzumab neoadjuvant and adjuvantly or adjuvantly alone

    • Pathological response: 

      • Improved rates of pathological response in HER2+ patients treated with neoadjuvant trastuzumab 

        • Breast: 43% vs. 22% (improvement of 20%)

        • Both breast and axilla: 38% vs. 19% (improvement of ~20%)

  • The Fellow on Call Key takeaway:

    • Pathological complete response improved in both breast and axilla with addition of neoadjuvant trastuzumab to chemotherapy by about 20%

    • OS not improved if you use neoadjuvant + adjuvant trastuzumab vs. adjuvant trastuzumab only

What is the data to support the use of pertuzumab? 

  • Approval of Pertuzumab in neoadjuvant setting (NeoSphere, Lancet Oncology 2012):

    • Multi-centered, randomized, phase II study with locally advanced, inflammatory, or early HER2-positive breast cancer

    • Inclusion criteria: 

      • IHC 3+ or 2+ with positive FISH

      • Notably excluded patients with tumors less than 2 cm (i.e. T2)

    • 417 patients randomized to four treatment groups (1:1:1:1)

      • Neoadjuvant trastuzumab + docetaxel (TH)

      • Neoadjuvant pertuzumab + trastuzumab + docetaxel (THP)

      • Neoadjuvant pertuzumab + trastuzumab 

      • Neoadjuvant pertuzumab + docetaxel

      • Total 12 weeks of treatment followed by surgery; all patients received FEC x 3 (5-FU, epirubicin, cyclophosphamide) and trastuzumab x 1 year adjuvantly 

  • The Fellow on Call Key Takeaways: 

    • Improved rates of pCR: 45.8% in THP vs. 29.0% in TH

    • pCR and node negative at time of surgery: 39% vs. 22%

    • Less path CR when substituting pertuzumab for trastuzumab at 16%

    • Another important result: lower path CR rates for ER+, HER2+ compared to ER-, HER2+ (roughly cut in half)

The regimen we often use today is “TCHP”. Where did that come from? 

  • One of the more common regimens used today is TCHP: docetaxel + carboplatin + trastuzumab + pertuzumab 

    • Based on TRYPHENA study which was a Phase II looking at cardiac toxicity with the combination of trastuzumab and pertuzumab

    • Total 6 cycles of neoadjuvant therapy given followed by surgery 

  • Why no anthracycline?

    • High rates of congestive heart failure (~4%) when combining anthracycline with trastuzumab in multiple studies

    • The disease free survival of TCHP was also better numerically compared to these more toxic regimens. 

How long do we continue the patients on trastuzumab?

  • Total 1 year of trastuzumab is the generally accepted duration of treatment based on results of the HERA trial

    • An updated 11 year follow study published in 2017 

    • Compared to observation, 1 year of trastuzumab improved DFS HR 0·76, 95% CI 0·68–0·86) and death (0·74, 0·64–0·86) 

    • No significant difference in outcomes between 1 year and 2 years of treatment (HR 1·02, 95% CI 0·89–1·17)

Can we do shorter duration of trastuzumab given cardiotoxicity? No!

  • There were four studies that looked into shorter durations: 

    • Short-Her: 9 weeks (Conte et al. 2018)

    • PERSEPHONE: 6 months (Earl et al. 2016)

    • HORG: 6 months (Mavroudis et al. 2015)

    • PHARE: 6 months (Pivot et al. 2013)

  • Trials had mixed results. However meta-analysis performed in 2017 by Gyawali and Niaula found that non-inferiority could NOT be established and that there were improved OS and DFS rates with one year of treatment compared to shorter durations of trastuzumab 

But how do you decide when to add pertuzumab? Patients with nodal involvement!

  • APHINITY Trial (NEJM 2017): Does the addition of pertuzumab to trastuzumab in adjuvant setting improve outcomes in patients with HER2 positive early breast cancer. 

  • Randomized patients with or without nodal disease to

    • adjuvant chemo + trastuzumab and pertuzumab vs.

    • adjuvant chemo + trastuzumab alone 

  • Primary endpoint: 

    • Invasive disease free survival

  • Secondary endpoint:  

    • OS

  • Results: 

    • Only 1% improvement by adding pertuzumab in iDFS at 3 years for whole cohort: 94% vs. 93%

    • When stratified by nodal status for iDFS at 3 years:

      • Node positive: iDFS 90% vs. 88%

      • Node negative: no difference

    • Updated analysis with 6 years of follow up:

      • Node positive: iDFS 88% vs. 83%

      • Node negative: no benefit in iDFS

  • The Fellow on Call Key Takeaways: 

    • APHINITY Trial shows most benefit for pertuzumab in patients with nodal involvement. 

    • So for patients with HER2+ disease with node involvement, add pertuzumab (TCHP)!

    • For node-negative disease, use trastuzumab alone (TCH). 

So how do we pick the right regimen in the adjuvant setting? 

  • If you only administered trastuzumab  in neoadjuvant setting, continue just trastuzumab adjuvantly

  • If you administered trastuzumab and pertuzumab neoadjuvantly, then continue both adjuvantly if pathologic complete response was achieved. If not, see below!

What if pathologic complete response is not achieved after patient has received neoadjuvant HER2-directed therapy? 

  • We know that patients with high risk breast cancer, namely HER2+ or TNBC, have high risk of recurrence and metastasis if there is residual disease after neoadjuvant therapy (prognostic marker)

  • Changing adjuvant therapy for residual disease was evaluated in the Phase III KATHERINE Study (NEJM 2019)

  • Evaluated the use of an antibody-drug conjugate known as trastuzumab emtansine (T-DM1)

    • links a cytotoxic microtubule inhibitor called emtansine to trastuzumab

  • Randomized those with residual disease in breast or lymph nodes after neoadjuvant systemic therapy to:

    • T-DM1 q3week x 14 cycles

    • Trastuzumab q3week x 14 cycles

  • Primary endpoint: invasive disease free survival 

  • Outcomes:

    • 3 year iDFS: 88.3% for T-DM1 vs. 77.0% for Trastuzumab

    • 3 year freedom from distant recurrence: 89.7% for T-DM1 vs. 83% for trastuzumab

    • No difference in OS

  • Limitation:

    • Only 20% of patients got neoadjuvant pertuzumab despite nodal disease in ~60% of patients and these patients should get both trastuzumab and pertuzumab adjuvantly

    • Nonetheless, results promising and this is now standard of care for residual disease

The side effects of the drug and outcomes are unique and worth noting; these were analyzed in a follow up study published in Annals of Oncology in 2021

  • Incidence of peripheral neuropathy:

    • Greater in TDM1 (32.3%) vs. Trastuzumab (16.9%) arm

    • Between the two groups, there was a similar amount of baseline peripheral neuropathy

      • However, there were still slightly more patients who had no baseline neuropathy that developed it with TDM1 vs. trastuzumab 

      • How long does it last?

        • TDM1 arm: 

          • W/ baseline neuropathy 352 days; resolution rate 66%

          • w/o baseline neuropathy 243 days; resolution rate 81%

        • Trastuzumab: 

          • w/ baseline neuropathy 337 days; resolution 64%

          • w/o baseline neuropathy 232 days; resolution rate 83%

      • Neoadjuvant taxane choice did not influence this

  • Incidence of Thrombocytopenia: 

    • 28.5% of patients in TDM1 compared to 2.4% of patients in trastuzumab

  • Incidence of Pulmonary Toxicity: 

    • Only seen in patients who received adjuvant radiation therapy; slightly higher in TDM1 group vs. trastuzumab (3.4% v. 1.0%)

  • The Fellow on Call Key Takeaway: 

    • Adding TDM-1 adjuvantly in patients with residual disease had improvements in invasive disease free survival and freedom from distant recurrence 

    • Important caveat: <20% of patients in trial received pertuzumab (despite APHINITY data); however, we still follow KATHERINE study as standard of care

    • Discontinuation rate of TDM-1 was about 20% due to neuropathy and pulmonary toxicity:

      • Incidence of neuropathy higher in T-DM1

      • Incidence of thrombocytopenia higher in T-DM1

      • Incidence of CNS mets: incidence of CNS mets was similar compared to trastuzumab (5%)

What about stage I breast cancer? 

  • Single arm multi-centered phase II study investigating small node-negative HER2+ breast cancer

  • Eligibility:

    • Patients with HER2+ disease who had invasive tumor </= 3 cm and were node negative

    Regimen:

    • weekly adjuvant paclitaxel + trastuzumab x 12 weeks followed by 1 year of trastuzumab

  • Results: 

    • Median follow up 4 years

    • 3 year rate of invasive disease free survival was 98.7%

  • 10 year follow up data continues to show IDFS 91.4%, 10 year recurrence free interval 96.3%, and 10 year OS 94.3%

  • The Fellow on Call Key Takeaway:

    • For small node negative tumors, no need for neoadjuvant therapy

    • Treat with taxol + trastuzumab x 12 weeks followed by trastuzumab weekly

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

  • For HER2+ tumors Stage I (node negative, <2cm):

  • For HER2+ tumors Stage II and III (>2 cm and/or nodal involvement):

    • Treat with neoadjuvant therapy

    • Docetaxel+carboplatin+trastuzumab (TCH) for all

    • if they have nodal involvement, add pertuzumab (TCHP)

  • Follow this after surgery 

    • If patient receives trastuzumab alone neoadjuvantly → continue trastuzumab adjuvantly to complete 1 total year of therapy

    • If patient receives trastuzumab + pertuzumab neoadjuvantly → continue both adjuvantly to complete 1 total year of therapy

    • If pCR is not achieved, give 14 cycles q21 days of trastuzumab emtansine (T-DM1)

References

The crew behind the magic:

  • Show outline: Ronak Mistry, 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

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