Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• What is the most likely regimen that she received?
  • Dose-dense doxorubicin and cyclophosphamide.
  • Weekly paclitaxel and trastuzumab.
  • Docetaxel.
  • Cyclophosphamide, methotrexate, and 5-fluorouracil.
  • Gemcitabine.
• The regimen in the list that is associated with a high risk for febrile neutropenia (> 20%) is:
  • Dose-dense doxorubicin and cyclophosphamide
• The others listed are associated with a lower (less than 20%) risk of febrile neutropenia and thus do not require growth factor support in an otherwise healthy young patient lacking specific comorbidities

References

1. Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline update. J Clin Oncol. 2015;33(28):199-212.

2. Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21(8):1431-1439.

• The human epidermal receptor (HER) or erbB proteins:
  • Are members of the subclass I of the receptor tyrosine kinase superfamily
    • This group contains four members:
      • Epidermal growth factor receptor (EGFR) / erbB1 / HER-1
      • erbB2 / HER-2 / neu
      • erbB3 / HER-3
      • erbB4 / HER-4
    • These proteins are made up of an:
      • Extracellular ligand-binding domain
      • A membrane-spanning region
      • A cytoplasmic domain with tyrosine kinase activity
    • Ligand binding to these receptors:
      • Leads to their homodimerizartion or heterodimerization:
        • Which promotes signal transduction
    • To date, no ligands have been identified for the HER-2 receptor:
      • However, the HER-2 receptor has been shown to be the preferred heterodimerization for other HER family members

• HER-2 has been shown to be one of the most important oncogenes in human breast cancer
• HER-2 complexes initiate intracellular signaling via the:
  • Mitogen-activated protein kinase (MAPK)
  • Phosphatidylinositol 3-kinase (PI₃K) pathway
  • Phospholipase C pathway
• In breast cell lines and model tumor systems:
  • Overexpression of the gene has been shown to be associated with:
    • Increased mitogenesis
    • Malignant transformation
    • Increased cell motility
    • Invasion
    • Metastasis
• In human breast cancer:
  • Amplification of the gene is found in around 15% to 30% of primary invasive breast tumors:
    • In these cases, up to 100 copies have been demonstrated per cell:
      • Which is equivalent to a 50-fold increase in gene copy number per cell
    • As a result, the number of receptors per cell is increased up to 2 million
    • Overexpression at the messenger RNA or protein level:
      • Occurs in around 15% to 30% of patients with early-stage breast cancer

According to the American Cancer Society, black women have a lower incidence of breast cancer across all age groups older than 40 years of age, although they have a higher incidence rate in women under the age of 40 years. They have a higher mortality rate across all age groups, even when matched for stage and will tend to be ER-negative in phenotype. Black women also are more likely to present with triple-negative (ER-, progesterone receptor-, and HER2-negative) disease and have a higher incidence rate of breast cancer than Hispanic or Latina women.

References:

American Cancer Society. Breast Cancer Facts & Figures 2013-2014. Accessed January 5, 2016.

Daly B, Olopade OI. A perfect storm: How tumor biology, genomics, and health care delivery patterns collide to create a racial survival disparity in breast cancer and proposed interventions for change. CA Cancer J Clin. 2015;65:221-238.

Abstract

BACKGROUND

No single standard treatment exists for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)–positive breast cancers, because most of these patients have been ineligible for the pivotal trials of adjuvant trastuzumab.

METHODS

We performed an uncontrolled, single-group, multicenter, investigator-initiated study of adjuvant paclitaxel and trastuzumab in 406 patients with tumors measuring up to 3 cm in greatest dimension. Patients received weekly treatment with paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy. The primary end point was survival free from invasive disease.

RESULTS

The median follow-up period was 4.0 years. The 3-year rate of survival free from invasive disease was 98.7% (95% confidence interval [CI], 97.6 to 99.8). Among the 12 relapses seen, 2 were due to distant metastatic breast cancer. Excluding contralateral HER2-negative breast cancers and nonbreast cancers, 7 disease-specific events were noted. A total of 13 patients (3.2%; 95% CI, 1.7 to 5.4) reported at least one episode of grade 3 neuropathy, and 2 had symptomatic congestive heart failure (0.5%; 95% CI, 0.1 to 1.8), both of whom had normalization of the left ventricular ejection fraction after discontinuation of trastuzumab. A total of 13 patients had significant asymptomatic declines in ejection fraction (3.2%; 95% CI, 1.7 to 5.4), as defined by the study, but 11 of these patients were able to resume trastuzumab therapy after a brief interruption.

CONCLUSIONS

Among women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of about 2%; 6% of patients withdrew from the study because of protocol-specified adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT00542451. opens in new tab.)

• A 60-year-old female with a 0.9 cm invasive ductal carcinoma, ER 70%, PR 30%, HER2 3+ by immunohistochemistry, grade 2, with 0/3 sentinel lymph nodes involved with tumor
  • The APT trial showed a 3-year rate of survival free from invasive disease of 98.7% for node negative tumors up to 3 cm in size with use of weekly paclitaxel / trastuzumab

References

1. Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. New Engl J Med. 2015;372(2):134-141.

2. Tolaney SM, Guo H, Pernas S, Barry WT, Dillon DA, Ritterhouse L. Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2-positive breast cancer.J Clin Oncol. 2019;37(22):1868-1875.

• For node-positive triple negative breast cancer:
  • The best choice for chemotherapy would be dose-dense doxorubicin and cyclophosphamide, followed by paclitaxel:
    • Each given for 4 cycles 2 weeks apart:
      • With growth factor support
  • This regimen is supported by results of the CALGB 9741 study
• For triple negative breast cancer and node positive disease:
  • The use of an anthracycline-containing regimen is favored compared to a non-anthracycline containing regimen

References

1. Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21(8):1431-1439.

2. 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.

A 59-year-old postmenopausal female underwent a partial mastectomy and sentinel lymph node biopsy (SLNB) for a 1.5 cm right breast moderately-differentiated invasive ductal carcinoma, ER 100%, PR 90%, HER2 positive (3+), with 0/1 positive lymph nodes.

What would you do next?

The 21-gene signature is only indicated for HR+ / HER2 negative tumors.

For small node-negative HER2 positive tumors, paclitaxel and trastuzumab are recommended

References

1. Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. New Engl J Med. 2015;372(2):134-141.

2. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673-1684

Patients with a significant family history for breast and ovarian cancer in first- and second-degree relatives it is important to recognize that genetic testing does not identify mutations in all high-risk families and it is not always possible to test the most informative (best testable) individual in the family.

Consequently, the Society of Surgical Oncology and the American Society of Clinical Oncology have affirmed that risk reducing surgery is an appropriate consideration when a significant family history exists, even when genetic testing does not demonstrate a mutation or when the proband does not wish to have genetic testing. However, if there is a known mutation in the family accounting for the affected individuals and the proband is unaffected and without a genetic mutation, then the result is interpreted as a true negative, and therefore risk reducing mastectomy would not be indicated on the basis of the genetic information alone.

In women undergoing risk reducing mastectomy, the likelihood of a positive sentinel node is low, especially if the appropriate preoperative imaging is negative; hence, bilateral sentinel node biopsy is not mandatory. Reconstruction, however, is safe and may be performed concurrently at the risk-reducing surgery.

Risk reducing mastectomy does not completely eliminate the risk of breast cancer. Some tissue must remain under the skin flaps to preserve the blood supply and viability of the skin; however, this procedure has been found to lower a woman’s risk of breast cancer by over 90%.

Once a woman has bilateral risk reducing mastectomy, no annual breast diagnostic imaging for screening is required, as there should be very little breast tissue remaining to image. Physical examination is the mainstay of follow-up to assess recurrence by examining the skin flaps and nodal basins.

References:
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Available at http://www.nccn.org.

Czyszczon IA, Roland L, Sahoo S. Routine prophylactic sentinel lymph node biopsy is not indicated in women undergoing prophylactic mastectomy. J Surg Oncol. 2012;105:650-654.

Guillem JG, Wood WC, Moley JF, et al. ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. Ann Surg Oncol. 2006;13:1296-1321.

Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med. 1999;340:77-84.

Newman LA, Kuerer HM, Hung KK, et al. Prophylactic mastectomy. J Am Coll Surg. 2000;191:322-330.

• In the Suppression of Ovarian Function Trial (SOFT) trial:
  • Ovarian function suppression given for 5 years reduced disease-free survival (DFS) events when added to 5 years of adjuvant tamoxifen:
    • 78.9% to 83.2% DFS at 8 years, hazard ratio (HR) of 0.76, P = .009)
  • One-third of women entered in the SOFT trial:
    • Were randomized to receive the aromatase inhibitor exemestane plus ovarian function suppression and they had an even better disease-free survival

References

1. Francis PA, Pagani O, Fleming GF, Walley BA, Colleoni M, Lang I, et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Eng J Med.2018;379(2):122-137.

2. Francis PA, Regan MM, Fleming GF, Lang I, Ciruelos E, Bellet M, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372(5):436-446.

• Neutropenia is found in up to 79.5% of patients on palbociclib
  • Neutropenia and the risk for infections must be discussed with patients prior to initiation of treatment
• Other common adverse effects of this drug include:
  • Fatigue (37.4%)
  • Nausea (35.1%)
  • Alopecia (32.9%)

References

1. Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and Letrozole in advanced breast cancer. New Engl J Med. 2016;375(20):1925-1936.

2. Finn RS, Crown JP2, Lang I3, Boer K4, Bondarenko IM5, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25-35.