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• Failure to achieve pathologic complete response (pCR):
  • Is associated with poorer prognosis:
    • Particularly for triple negative breast cancer
• In the CREATE-X trial:
  • 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy were randomized to receive standard postsurgical treatment with capecitabine or control
  • Adjuvant capecitabine:
    • Resulted in improved disease-free survival and overall survival:
      • With the bulk of the benefit seen only in the patients with triple negative disease
        • Based on this study, adjuvant capecitabine can be considered for patients with triple negative breast cancer and residual disease after neoadjuvant chemotherapy

References

1. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164-172.

2. Masuda N, Lee S-J, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant Capecitabine for breast cancer after preoperative chemotherapy. New Engl J Med. 2017;376(22):2147-2159.

• Neoadjuvant chemotherapy:
  • Is often given in early stage triple negative breast cancers
  • It has the benefit of:
    • Increased rates of breast conservation
    • As well as the prognostic value of assessing tumor response to systemic therapy
• Overall survival is equivalent with chemotherapy:
  • Administration either adjuvantly or neoadjuvantly
• The dosing of the chemotherapy in breast cancer:
  • Should be given in a dose-dense fashion:
    • For example every 2 weeks instead of every 3 weeks
  • In a meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG):
    • Dose-dense delivery of chemotherapy was found to improve:
      • 10-year recurrence risk
      • Breast cancer mortality
      • All-cause mortality
  • If there are no medical contraindications:
    • The preferred delivery of chemotherapy should be dose-dense
• The chemoregimen docetaxel plus cyclophosphamide (TC) is not the preferred regimen for a patient with lymph node positive and triple negative disease:
  • In the Anthracyclines in Early Breast Cancer (ABC) trials:
    • Three cooperative group trials underwent a combined analysis to determine the activity of TC compared to regimens containing anthracycline, cyclophosphamide and taxane in HER2-negative early breast cancers
    • The primary endpoint was:
      • Invasive disease-free survival (IDFS)
    • This trial enrolled over 4,000 patients and was stopped early due to inferior IDFS in the TC group
    • Exploratory subgroup analysis:
      • Suggested benefit of an anthracycline regimen was particularly meaningful with triple negative tumors

References

1. Mougalian SS, Soulos PR, Killelea BK, Lannin DR, Abu-Khalaf MM, DiGiovanna MP, et al. Use of neoadjuvant chemotherapy for patients with stage I to III breast cancer in the United States. Cancer. 2015;121(15):2544-2552.

2. Gray R, Bradley R, Braybrooke J, Liu Z, Peto R, Davies L, et al. Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials. Lancet. 2019;393(10179):1440-1452.

3. Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, et al. Anthracyclines in early breast cancer: the ABC Trials—USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017;35(23):2647-2655.

4. Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278-2284.

• The CDK 4/6 inhibitors:
  • Are a class of oral drugs:
    • That have been approved for HR+, HER2-negative metastatic breast cancer in the first-line setting or after progression on prior aromatase inhibitor
• In the MONALEESA-3 trial:
  • Ribociclib in combination with fulvestrant:
    • Showed progression-free survival (20.5 months vs. 12.8 months) and overall survival benefit over fulvestrant alone in HR+, HER2-negative metastatic breast cancer:
      • That was either treatment naïve or had up to one prior line of endocrine therapy
• Everolimus:
  • Is an mTOR inhibitor with evidence of benefit in the metastatic setting after prior aromatase inhibitor
  • However it is FDA-approved in combination with exemestane per the BOLERO-2 trial
• Chemotherapy is an effective treatment strategy in metastatic disease of the breast of any subtype:
  • But is not first line treatment in patients with limited disease asymptomatic
• In the metastatic setting:
  • Radiation is generally pursued to palliate symptoms or control isolated disease that is not responding to systemic therapy

References

1. Slamon DJ, Neven P, Chia S, Fasching PA1, De Laurentiis M1, Im SA, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465-2472.

2. Slamon DJ NP, Chia S, et al. Overall survival (OS) results of the phase III MONALEESA-3 trial of postmenopausal patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) advanced breast cancer (ABC) treated with fulvestrant (FUL) + ribociclib (rib). Paper presented at: ESMO; September 27 to October 1, 2019, 2019; Barcelona, Spain.

3. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor–positive advanced breast cancer. N Engl J Med. 2011;366(6):520-529

• Tamoxifen is indicated for:
  • Premenopausal patients with:
    • Node-negative, hormone receptor–positive, HER2-negative breast cancer with low-risk recurrence scores
• Tamoxifen:
  • Is a selective estrogen receptor modulator (SERM) with antiestrogenic activity in breast tissue:
    • Reducing epithelial cell proliferation
• Hot flashes are one of the most common and bothersome side effects of tamoxifen:
  • Up to 80% of women prescribed tamoxifen complain of hot flashes:
    • About 30% rate them as severe
  • Premenopausal women have a greater increase in hot flashes after starting tamoxifen compared with perimenopausal or postmenopausal women
  • Hot flashes are believed to be due to:
    • A central nervous system antiestrogenic effect:
      • Causing thermoregulatory dysfunction
  • Additionally, some data suggest that polymorphisms in drug metabolizing enzymes:
    • Cytochrome P450 enzyme, CYP2D6):
      • Decrease the conversion of tamoxifen to its most active metabolite (endoxifen), and they may influence the likelihood of tamoxifen-related hot flashes
  • Coadministration of drugs that inhibit the activity of CYP2D6:
    • Such as the selective serotonin reuptake inhibitors (SSRIs):
      • Can reduce tamoxifen-related hot flashes
    • Among SSRIs, there is a gradient of potency for inhibition of CYP2D6:
      • For example, paroxetine and fluoxetine are strong CYP2D6 inhibitors, while sertraline and duloxetine are moderate inhibitors
      • While the strong CYP2D6 inhibitors have the potential to adversely affect drug efficacy:
        • The data to suggest that this issue decreases tamoxifen effect are very weak
      • Venlafaxine:
        • Is a weak CYP2D6 inhibitor with proven efficacy against hot flashes without risk of significantly interfering with tamoxifen metabolism
• Black cohosh is a substance with purported efficacy treating menopausal symptoms:
  • It is not FDA regulated with reported rare incidence of hepatotoxicity
  • Its use would be contraindicated in a patient on tamoxifen:
    • As it may interfere with CYP2D6 activity

References

1. Aiello Bowles EJ, Boudreau DM, Chubak J, Yu O, Fujii M, Chestnut J, Buist DS. Patient-reported discontinuation of endocrine therapy and related adverse effects among women with early-stage breast cancer. J Oncol Pract. 2012;8(6):e149-e157.

2. Ramaswami R, Villarreal MD, Pitta DM, Carpenter JS, Stebbing J, Kalesan B. Venlafaxine in management of hot flashes in women with breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat. 2015;152(2):231-237.

3. Johns C, Seav SM, Dominick SA, Gorman JR, Li H, Natarajan L, Mao JJ, et al. Informing hot flash treatment decisions for breast cancer survivors: a systematic review of randomized trials comparing active interventions. Breast Cancer Res Treat. 2016;156(3):415-426.

• Neoadjuvant chemotherapy (NAC):
  • Has traditionally been the standard approach in patients with locally advanced and inflammatory breast cancer:
    • Allowing for a reduction in disease volume and therefore optimizing surgical resection of the disease in the breast
• The use of NAC has evolved over time to include:
  • Large operable cancers in patients who desire breast conservation and now is commonly used in patients with early-stage breast cancer based on tumor biology:
    • Especially in HER-2-positive and triple-negative tumors
  • Delivery of chemotherapy in the neoadjuvant setting:
    • Allows assessment of response to therapy
      • Pathologic complete response (pCR):
        • Which indicates eradication of invasive disease in the breast and the lymph nodes:
          • Has been shown to correlate with outcome
        • The achievement of a pCR in HER-2-positive breast cancer with the use of trastuzumab in combination with chemotherapy:
          • Has been shown to correlate with improved survival and patient outcome
• Neoadjuvant trials of anti-HER-2 therapy have included:
  • Single-arm trastuzumab or lapatinib trials
  • Trials investigating the addition of trastuzumab to NAC
  • Trials that compare HER-2 targeted approaches:
    • Individually or in combination
• The earliest study of trastuzumab in the neoadjuvant setting was published in 2005:
  • This trial from MD Anderson Cancer Center (MDACC) randomized women (N = 42) to:
    • Treatment with taxane with trastuzumab and sequential taxane and anthracycline chemotherapy with or without trastuzumab
  • The pCR rate was 65% in the combination arm compared with 26% in women who received chemotherapy alone
  • This study was closed early due to the remarkable response seen
• The Neoadjuvant Herceptin (NOAH) trial:
  • Was a larger trial of 235 women with locally advanced HER-2-positive breast cancer who were randomized to receive:
    • Neoadjuvant anthracycline– and taxane-based chemotherapy with or without trastuzumab
  • The study reported an increase in the pCR rates in the breast and axilla with the addition of trastuzumab to chemotherapy compared with no trastuzumab:
    • 38% and 19%, respectively, p = .001
  • Of note, patients in the NOAH trial had more advanced disease compared with the MDACC trial:
    • Accounting for the lower pCR rate
• Similar results have been demonstrated in the:
  • Phase II Remagus 02 trial:
    • pCR rates with trastuzumab therapy 26%
  • The Austrian Breast and Colorectal Cancer Study Group (ABCSG-24) trial:
    • pCR rates with trastuzumab therapy 40%
  • GeparQuinto:
    • pCR rates with trastuzumab therapy 30.3%
• Furthermore, the role of dual HER-2 targeted therapy in the neoadjuvant setting was addressed in several trials:
  • The NeoALLTO trial investigated the addition of the reversible tyrosine kinase inhibitor lapatinib to trastuzumab and chemotherapy:
    • This resulted in an increase in pCR rates compared with treatment with trastuzumab and chemotherapy alone:
      • 46.8% versus 27.6%, p = .0007
    • In study arms with single-agent trastuzumab or lapatinib:
      • pCR rates were 27.6% and 20%, respectively
    • Around one third of patients in the lapatinib arm did not complete treatment:
      • Due to grade 3 diarrhea and alterations of liver enzymes
  • Similar results were demonstrated in the CHER-LOB trial (Chemotherapy, Herceptin and Lapatinib in Operable Breast cancer):
    • Which also investigated trastuzumab and lapatinib alone or in combination with chemotherapy
    • The rates of pCR were 25% in the trastuzumab arm, 26% in the lapatinib arm, and 47% in the combination arm
• Furthermore, the NSABP-B41 trial:
  • Reported and showed rates of breast and axillary pCR with AC-T in combination with either trastuzumab or lapatinib:
    • As high as 62%
  • There was no statistically significant difference in the pCR rates with trastuzumab and chemotherapy alone or in combination with lapatinib (p = .095)
• Pertuzumab is a humanized monoclonal antibody:
  • Is a second-generation anti-HER-2 agent that binds to HER-2 and prevents its dimerization with itself or other members of the EGFR family:
    • Resulting in inactivation of downstream signaling pathways
• The results from the NeoSphere trial:
  • Demonstrated a pCR rate of 45.8% in patients receiving pertuzumab plus trastuzumab and chemotherapy compared with a pCR of 29% in patients who received trastuzumab and chemotherapy
• Similar results were demonstrated in the Trastuzumab plus Pertuzumab in Neoadjuvant HER2-Positive Breast Cancer (TRYPHAENA) trial:
  • Where  treatment with the dual HER-2 targeting agents resulted in pCR rates up to 52%
• Furthermore, the addition of pertuzumab was not found to be associated with an increased rate of cardiac dysfunction when used in conjunction with trastuzumab and chemotherapy
  • These remarkable results demonstrated by the addition of pertuzumab to trastuzumab and chemotherapy resulted in the FDA approval of pertuzumab in the neoadjuvant setting in September 2013
  • Many patients today with HER-2-positive breast cancer are treated with chemotherapy together with both trastuzumab and pertuzumab.
• Novel anti-HER-2 agents are currently being investigated in ongoing neoadjuvant trials these include:
  • Neratinib (oral dual-activity irreversible PNA inhibitor of EGFR tyrosine kinases)
  • Trastuzumab-emtansine (trastuzumab linked to emtansine, a microtubule inhibitor)
  • Afatinib (an irreversible receptor tyrosine kinase inhibitor targeting HER-1 and HER-2) 
• A question regarding the optimal duration of neoadjuvant therapy remains unclear:
  • The results from recent trials have suggested that shorter treatment durations are effective and feasible. However, further work and study in this area are essential

• Trastuzumab in the adjuvant setting:
  • Has been shown to significantly improve DFS and OS and has become the standard of care for patients with HER-2-positive breast cancer
• Newer agents and combination dual anti-HER-2 therapy have been investigated:
  • The Adjuvant Lapatinib and / or Trastuzumab Treatment Optimisation (ALLTO) trial:
    • Investigated the role of lapatinib, a dual tyrosine kinase inhibitor of both EGFR and ErbB2:
      • As a single agent or in combination with trastuzumab compared with trastuzumab as a single agent in the treatment of HER-2-positive tumors
    • The study failed to show a statistically significant improvement in:
      • DFS with dual HER-2 blockade compared with trastuzumab alone
    • Patients who received lapatinib experienced:
      • More diarrhea, cutaneous rash, and hepatic toxicity
    • The results of this trial were unexpected:
      • As dual therapy with trastuzumab and lapatinib in the neoadjuvant setting showed promising results
  • A Study of Pertuzumab in Addition to Chemotherapy and Trastuzumab as Adjuvant Therapy in Participants With Human Epidermal Growth Receptor 2 (HER2)-Positive Primary Breast Cancer, the APHINITY trial:
    • Assessed  the outcomes and effectiveness of incorporating the second generation anti-HER-2 monoclonal antibody, pertuzumab, together with trastuzumab in the adjuvant setting)
    • The study revealed that pertuzumab added to trastuzumab and chemotherapy:
      • Significantly improved the rates of invasive-disease-free survival among patient with HER-2 positive breast cancer:
        • This was most apparent in patients with node positive disease or hormone receptor negativity
      • Specifically, dual anti-HER-2 therapy increased the:
        • 3-year disease-free survival from 93.2% to 94.1% (HR 0.81, 95% CI 0.66-1.00, p=0.045):
          • This difference is clinically modest
        • In women with clinically node positive disease:
          • The improvement was also modest, increasing from 90.2% to 92% (HR0.77, 95%CI 0.62-092, p=0.02)
      • These studies highlight the importance of considering extent of benefit and risk of associated side effects from treatment
      • Future studies are needed to stratify patients into those that benefit from standard treatment and those that benefit from more intensive treatment

• Paclitaxel monotherapy:
  • It is recommended as one of the first lines of therapy for metastatic triple negative breast cancer:
    • Safety data are reported for its use in the elderly
  • In addition, because it is administered weekly:
    • It is easy to reduce the dose in the presence of toxicities
  • Local therapy:
    • Is not indicated for most patients with distant metastatic disease in the absence of symptoms
  • HER2 therapies:
    • Are not indicated in the treatment of HER2 negative tumors
  • Dose-dense doxorubicin and cyclophosphamide is often part of the regimen for early-stage triple negative breast cancer:
    • Not metastatic disease
  • Testing for PDL1 to see if she is a candidate for immunotherapy with chemotherapy would be indicated if the patient is interested in this treatment option

References

1. Li X, Kwon H. Efficacy and Safety of Nanoparticle Albumin-Bound Paclitaxel in Elderly Patients with Metastatic Breast Cancer: A Meta-Analysis. J Clin Med. 2019 Oct 15;8(10).

2. Biganzoli L, Wildiers H, Oakman C, Marotti L, Loibl S, Kunkler I, et al. Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA). Lancet Oncol. 2012;13(4):e148-e160.

• The CLEOPATRA study:
  • Showed that the combination of docetaxel, trastuzumab, and pertuzumab:
    • Led to improved progression free survival (PFS) compared to docetaxel, trastuzumab, and placebo:
      • 18.5 months vs. 12.4 months
• Surgery for the primary site is not indicated for patients with distant metastatic disease in the absence of symptoms

References

1. Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. New Engl J Med.2012;366(2):109-119.

2. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734.

• The 21-gene recurrence score estimates the likelihood of distant recurrence:
  • In women with ER+ breast cancer with up to 3 lymph nodes positive
• It also predicts who is more likely to benefit from adjuvant chemotherapy:
• Patients with more than 3 lymph nodes:
  • Usually receive adjuvant chemotherapy and 21-gene signature assay is not routinely ordered

References

1. Dowsett M, Cuzick J, Wale C, Forbes J, Mallon EA, Salter J, et al. Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study. J Clin Oncol. 2010;29(11):1829-1834.

2. Roberts MC, Miller DP, Shak S, Petkov VI. Breast cancer-specific survival in patients with lymph node-positive hormone receptor-positive invasive breast cancer and Oncotype DX Recurrence Score results in the SEER database. Breast Cancer Res Treat.2017;163(2):303-310.

• All patients with HER2 positive breast cancer who require systemic therapy:
  • Should complete 1 year of HER2-targeted therapy:
    • Including those who achieve pathologic complete response after neoadjuvant chemotherapy
• One could also consider continuing adjuvant pertuzumab in addition to trastuzumab based on results from the phase III Aphinity trial:
  • Although patients who received neoadjuvant chemotherapy were not included in this trial
• For patients who have residual disease and do not achieve complete pathologic response at the time of surgery:
  • Completion of 1 year of T-DM1:
    • Decreased the risk of recurrence of invasive breast cancer or death by 50% than with trastuzumab alone:
      • Based on results from KATHERINE trial
    • The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group

References

1. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, et al. Adjuvant Pertuzumab and Trastuzumab in early HER2-positive breast cancer N Engl J Med. 2017;377(2):122-131.

2. von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628.