Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

My name is Rodrigo Arrangoiz I am a breast surgeon/ thyroid surgeon / parathyroid surgeon / head and neck surgeon / surgical oncologist that works at Center for Advanced Surgical Oncology in Miami, Florida. I was trained as a surgeon at Michigan State University from (2005 to 2010) where I was a chief resident in 2010. My surgical oncology and head and neck training was performed at the Fox Chase Cancer Center in Philadelphia from 2010 to 2012. At the same time I underwent a masters in science (Clinical research for health professionals) at the University of Drexel. Through the International Federation of Head and Neck Societies / Memorial Sloan Kettering Cancer Center I performed a two year head and neck surgery and oncology / endocrine fellowship that ended in 2016. Mi nombre es Rodrigo Arrangoiz, soy cirujano oncólogo / cirujano de tumores de cabeza y cuello / cirujano endocrino que trabaja Center for Advanced Surgical Oncology en Miami, Florida. Fui entrenado como cirujano en Michigan State University (2005 a 2010 ) donde fui jefe de residentes en 2010. Mi formación en oncología quirúrgica y e n tumores de cabeza y cuello se realizó en el Fox Chase Cancer Center en Filadelfia de 2010 a 2012. Al mismo tiempo, me sometí a una maestría en ciencias (investigación clínica para profesionales de la salud) en la Universidad de Drexel. A través de la Federación Internacional de Sociedades de Cabeza y Cuello / Memorial Sloan Kettering Cancer Center realicé una sub especialidad en cirugía de cabeza y cuello / cirugia endocrina de dos años que terminó en 2016.

Dosing of Chemotherapy in Breast Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • The dosing of the chemotherapy:
    • Should be given in a dose-dense fashion:
      • 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 and all-cause mortality:
        • If there are no medical contraindications, the preferred delivery of chemotherapy should be dose-dense
  • References:
    • 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.

Regimen of Choice of Triple Negative Breast Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • The regimen of choice for a locally advanced triple negative breast cancer is:
    • Doxorubicin and cyclophosphamide every 2 weeks cycle with growth factor support followed by taxane chemotherapy
  • Neoadjuvant chemotherapy is often given in early stage triple negative breast cancers (> 2 cm or lymph node positive):
    • It has the benefit of increased rates of breast conservation as well as the prognostic value of assessing tumor response to systemic therapy
  • References
    • 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.
    • 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.
    • 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.
    • 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.

Oncotype Dx Provided Prognostic Information that Guided Therapy In Early Hormone Receptor Positive Breast Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • In women with HR+, HER2-negative early breast cancer:
    • The 21-gene signature score provides prognostic information that is independent of clinicopathological features
    • A high score (on a scale of 0 to 100):
      • Indicates a higher rate of distant recurrence and is predictive of chemotherapy benefit
  • The prospective Trial Assigning Individualized Options for Treatment (TAILORx):
    • Showed that endocrine therapy alone was noninferior to adjuvant chemotherapy plus endocrine (chemoendocrine) therapy in women with:
      • HR+, HER2-negative, axillary node-negative breast cancer:
        • And a 21-gene recurrence score of 11 to 25
    • An exploratory analysis indicated:
      • Some benefit of chemotherapy in women 50 years of age or younger:
        • Who had a recurrence score of 16 to 25
      • In this analysis there was a small (~1.6%) chemotherapy benefit in distant disease-free survival for patients with recurrence score results from 16 to 20, and a modest (~6.5%) chemotherapy benefit for patients with recurrence score results from 21 to 25
  • References
    • Sparano JA, Gray RJ, Ravdin PM, Makower DF, Pritchard KI, Albain KS, et al. Clinical and genomic risk to guide the use of adjuvant therapy for breast cancer. New Engl J Med. 2019;380(25):2395-2405.
    • Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. New Engl J Med. 2018;379(2):111-121.

Treatment of Hot Flashes in Women Taking Tamoxifen for Breast Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Tamoxifen:
    • Is indicated for premenopausal patients:
      • With node-negative, hormone receptor positive, HER2-negative breast cancer:
        • With low-risk recurrence scores (Oncotype Dx)
    • 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
  • References
    • 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.
    • 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.
    • 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.

Indications for Neoadjuvant Chemotherapy (NAC) in Breast Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Neoadjuvant chemotherapy (NAC):
    • Is appropriate for many patients with locally advanced breast cancer regardless of subtype:
      • Because a response may allow both less extensive surgery and improved surgical outcomes
    • Locally advanced disease is defined as:
      • Stage III cancers
      • As well as the subset of IIB cancers with T3 disease
    • In addition, patients with earlier stage, HER2+ disease (stage I or II) may also be candidates for neoadjuvant therapy, if one or more of the following criteria apply:
    • The patient desires breast-conserving surgery (BCS) but is not a candidate for BCS or is likely to have a suboptimal cosmetic outcome with BCS due to tumor location or size relative to the size of the patient’s breast, and may be a better candidate if neoadjuvant therapy decreases the extent of her tumor
    • The patient has limited axillary nodal involvement (N1), for which axillary lymph node dissection would be standard surgical management, but could be a candidate for sentinel lymph node sampling alone if converted to node-negative disease with neoadjuvant therapy
    • Surgery must be postponed awaiting consultation with plastic surgery regarding breast reconstruction, results of genetic testing, or resolution of an intercurrent illness, including pregnancy, and the patient and treating clinicians do not wish to delay initiation of treatment
    • Postoperative treatment with ado-trastuzumab emtansine (T-DM1) would be considered if the patient were found to have residual invasive disease in the breast or axillary nodes following NAC with single or dual HER2-targeted therapy
  • Pertuzumab:
    • Is a monoclonal antibody that binds to a different epitope on HER2 than trastuzumab:
      • Blocking the formation of HER2:HER3 heterodimers:
        • Which is believed to be an important mechanism of resistance to trastuzumab
    • While single-agent pertuzumab has demonstrated antitumor activity in patients with HER2-positive metastatic disease who progressed on trastuzumab:
      • It is typically given in combination with trastuzumab to maintain suppression of signaling initiated by HER2 homodimers
    • In 2013, the FDA granted accelerated approval for the addition of pertuzumab to NACT and trastuzumab:
      • For patients with HER2+ locally advanced, inflammatory, or early-stage (either greater than 2 cm in diameter or node positive) breast cancer
    • We routinely add pertuzumab in patients receiving NACT and trastuzumab:
      • Given evidence that pertuzumab enhances locoregional responses:
        • Even though it increases the incidence and severity of treatment-related diarrhea as well as modestly increasing the frequency of hematologic toxicities
  • NeoSphere trial:
    • In the phase II NeoSphere trial:
      • 417 HER2+ patients received 12 weeks of neoadjuvant therapy composed of either 4 cycles of single-agent docetaxel with trastuzumab, pertuzumab, or both, or the combination of trastuzumab and pertuzumab without concurrent docetaxel
      • After surgery, all patients received anthracycline-based adjuvant chemotherapy (those randomized to trastuzumab and pertuzumab alone also received adjuvant docetaxel) and completed a year of treatment with trastuzumab
      • Those randomly assigned to docetaxel with pertuzumab and trastuzumab had a higher pathologic complete response (pCR) rate (46%):
        • Compared with those receiving docetaxel with just trastuzumab (29%) or just pertuzumab (24%)
      • Patients receiving pertuzumab and trastuzumab without docetaxel:
        • Had a pCR rate of 17%
  • References
    • Hayes DF. HER2 and breast cancer — a phenomenal success story. N Engl J Med. 2019;381(13):1284-1286.
    • Gianni L, Pienkowski T, Im Y-H, Tseng LM, Liu MC, Lluch A, et al. 5-Year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016;17(6):791-800.

Triple Negative Breast Cancer in Elderly Women Adjuvant Therapy Options

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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
  • References
    • 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).
    • 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.

Cleopatra Study HER2 Positive Metastatic Breast Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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
    • 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.
    • 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.

21-Gene Recurrence Score in Breast Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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
  • References
    • 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.
    • 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.

APHINITY Trial in HER2 Positive Breast Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Updated results from the adjuvant APHINITY trial in HER2-positive early breast cancer:
    • Now with a median follow-up of 10.4 years:
      • Confirmed the benefit of adding pertuzumab to trastuzumab plus chemotherapy:
        • In preventing invasive disease recurrences, but as yet no statistically significant overall survival benefit has emerged
  • The long-term outcomes of both arms remain very good:
    • With more than 92% of patients alive at 8 years:
      • The overall survival analysis remains immature:
        • But the difference of 0.7% numerically favors the pertuzumab arm
  • Key Findings of Aphinity trial:
    • In the third interim analysis, fewer deaths were seen in the pertuzumab arm compared with the placebo arm:
      • By January 10, 2022, deaths totaled 168 in the pertuzumab arm (7.0%) and 202 in the placebo arm (8.4%)
      • The 8-year overall survival percentages were 92.7% vs 92.0%, respectively – a 0.7% difference (hazard ratio [HR] = 0.83; P = .078; 95% confidence interval [CI] = 0.68–1.02)
    • For invasive disease–free survival, the primary endpoint:
      • The updated descriptive analysis revealed a 2.6% absolute benefit for pertuzumab (HR = 0.77; 95% CI = 0.66–0.91):
        • Consistent with the 2.8% increase from the 6-year analysis, she further reported
    • Of note, the sustained benefit with pertuzumab was driven by its impact on the node-positive cohort:
    • The absolute benefit of dual HER2 blockade in this cohort was 1.9% for overall survival and 4.9% for invasive disease–free survival
    • In contrast, patients with node-negative disease derived no additional benefit:
      • From the second anti-HER2 agent
    • Interestingly, although not shown in previous analyses:
      • The addition of pertuzumab conferred an advantage in both hormone receptor negative and positive patients
  • Two key takeaways from the latest findings:
    • The node-positive cohort derives benefit from adding pertuzumab
    • And with longer follow-up beyond the first 3 years, the data clearly show that hormone receptor status should not guide pertuzumab treatment decisions
  • REFERENCES
    • Loibl S, Jassem J, Sonnenblick A, et al: Updated results of APHINITY at 8.4 years median follow-up. ESMO Virtual Plenary. Abstract VP6-2022l. Presented July 14, 2022.
    • Piccart M, Procter M, Fumagalli D, et al: Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer in the APHINITY Trial: 6 years’ follow-up. J Clin Oncol 39:1448-1457, 2021.
    • Von Minckwitz G, Procter M, de Azambuja E, et al: Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 377:122-131, 2017.

HER 2 Positive Breast Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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 trastuzumab emtansine (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
    • 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.
    • 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.