Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• 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
• In the metastatic setting:
  • Radiation is generally pursued to palliate symptoms or control isolated disease that is not responding to systemic therapy
• References
  • 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.
  • 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.
  • 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 Med. 2011;366(6):520-529

• In the SOFT / TEXT trials:
  • Premenopausal women were given ovarian function suppression with adjuvant aromatase inhibitor or tamoxifen:
    • Outcomes were compared to tamoxifen alone for 5 years
  • The SOFT / TEXT trials showed a:
    • Disease-free survival benefit of 2.1%
    • Overall survival benefit of 4.3%:
      • At 8 years with GnRH agonist and tamoxifen over tamoxifen alone in the cohort of women who had prior chemotherapy
    • Premenopausal patients with high-risk disease and who received prior chemotherapy:
      • The most effective adjuvant endocrine therapy would include ovarian function suppression with a GnRH agonist per the SOFT / TEXT trials
• Tamoxifen alone:
  • Is still an effective endocrine therapy and would be appropriate if the patient chooses not to use ovarian function suppression
• In premenopausal patients an aromatase inhibitor would be ineffective unless she was rendered post-menopausal
• Raloxifene is a selective ER modulator similar to tamoxifen:
  • It is FDA-approved only for breast cancer risk reduction in post-menopausal women
• Oophorectomy alone is not as effective without additional endocrine therapy

• References
  • Francis PA, Regan MM, Fleming GF, Lang I, Ciruelos E, Bellet M, et al. Adjuvant ovarian suppression in premenopausal breast cancer. New Engl J Med. 2015;372(5):436-446.
  • Francis PA, Pagani O, Fleming GF, Walley BA, Colleoni M, Lang I, et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379(2):122-137.
  • Vogel VG. The NSABP Study of Tamoxifen and Raloxifene (STAR) trial. Expert review of anticancer therapy. 2009;9(1):51-60.

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• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.