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The - Oncologist 2019 Colomer Theoncologist.2018 0228
The - Oncologist 2019 Colomer Theoncologist.2018 0228
Breast Cancer
ABSTRACT
Background. Neoadjuvant treatment is increasingly one of of neoadjuvant therapy has been correlated with long-
the preferred therapeutic options for early breast cancer term clinical benefit, particularly in HER2-positive and
and may have some unique outcomes, such as identifying triple-negative breast cancer. In addition, the neoadjuvant
predictive and prognostic factors of response or increasing setting is a powerful model for the development of new
the knowledge of individual tumor biology. drugs and the identification of prognostic markers. Finally,
Design. A panel of experts from different specialties neoadjuvant therapy has proven to be cost-effective by
reviewed published clinical studies on the neoadjuvant man- reducing nondrug costs, avoiding radical surgery, and
agement of breast cancer. Recommendations were made reducing hospital stays when compared with other treat-
that emphasized the clinical multidisciplinary management ment approaches.
and the investigational leverage in early breast cancer. Conclusion. Neoadjuvant therapy has clinical benefits in
Results. Neoadjuvant therapy has equivalent efficacy to adju- early breast cancer and provides in vivo information of
vant therapy, and it has some additional benefits that include individual breast cancer biology while allowing the investi-
increasing breast conservation, assessing tumor response, gation of new treatment approaches. Access to neoadju-
establishing prognosis based on the pathological response, vant therapy should be an option available to all patients
and providing a “second opportunity” for nonresponding with breast cancer through multidisciplinary tumor man-
patients. Achieving pathological complete remission because agement. The Oncologist 2019;24:1–9
Implications for Practice: Neoadjuvant treatment should be strongly considered as a therapeutic option for localized
breast cancer and is a powerful tool for understanding breast cancer biology and investigating new treatment approaches.
INTRODUCTION
In early breast cancer, neoadjuvant therapy has become one committees before local treatment delivery, and this has
of the preferred treatment options [1–5]. Its efficacy has been been shown to extend the efficacy of neoadjuvant care [8].
proven to be equivalent to adjuvant therapy, in terms of both Systemic medical therapy reduces the risk of distant
overall survival (OS) and progression-free survival (PFS), and it metastasis and increases OS, when initiated either after
has also shown value from research and cost perspectives surgery (adjuvant therapy) or before surgery (neoadjuvant
[6, 7]. In most specialist hospitals, it is standard practice to therapy), because often the same drugs and regimens are
assess patients with early breast cancer in multidisciplinary employed [9]. In general, any patient who is a candidate
Correspondence: Ramon Colomer, M.D., Ph.D., Department of Medical Oncology, Hospital Universitario La Princesa, Calle Diego de León,
62, 28006 Madrid, Spain. Telephone: +34-91-520-22-00; e-mail: rcolomer@seom.org Received April 12, 2018; accepted for publication
November 20, 2018. http://dx.doi.org/10.1634/theoncologist.2018-0228
for adjuvant systemic therapy can be considered for neoad- Table 1. Patient selection criteria for neoadjuvant therapy
juvant therapy [1]. Neoadjuvant therapy has some particu- in early breast cancer
lar advantages that distinguish it from adjuvant treatment. Level of evidence
First, it reduces tumor size, which facilitates surgical resect- Selection criteria [reference]
ability and increases breast-conserving surgery (BCS) rates Clinical lymph node involvement A [1, 2]
[10], and it also can eliminate axillary node metastasis that Size >2 cm B [1, 2]
may be detected in sentinel node biopsy after neoadjuvant
Triple-negative B [22, 23]
treatment [11]. Second, it enables an objective evaluation
HER2-positive B [24, 25]
of treatment efficacy, allowing an in vivo test of cancer
cells’ sensitivity to treatment. If no response occurs, the High proliferative index B [26]
therapy can be modified, thus avoiding side effects from Unresectable tumors A [1, 2]
ineffective treatment [12]. Pathological complete response Inflammatory carcinoma B [1–3]
(pCR) is associated with longer PFS and OS, especially in
the case of triple-negative and HER2-positive tumors (particularly patients with estrogen-receptor [ER]-negative tumors)
[13–17]. Third, it allows the design of clinical trials with by introducing a non-cross-resistant adjuvant therapy [20].
novel research approaches for adjuvant treatment, because
Dx risk [28]. In these cases, the use of neoadjuvant chemother- containing EC or AC may be dose-dense in the case of high-
apy would likewise not be of benefit. grade and hormone receptor-negative tumors [33, 34]. There
seems to be insufficient evidence for routinely substituting
Clinical Status paclitaxel for nab-paclitaxel as a component of neoadjuvant
The patient’s general state of health and comorbidities will chemotherapy, given the differing results of the ETNA and
drive the indications for treatment. Age by itself is not a the GBG69 trials [35–37].
contraindication for surgery. A recent review shows that information provided by
Accurate clinical staging at baseline is critical because in genomic platforms may be useful in predicting the response
certain clinical situations, some or all forms of neoadjuvant to chemotherapy, although platforms might not be useful in
systemic therapy might not be the best clinical choice [18]. indicating anti-HER2 therapy [38].
Tumors with extensive involvement of carcinoma in situ, for
example, in which the extent of the invasive component is Anti-HER2 Therapy
not well defined, would better be staged surgically. In HER2-positive breast tumors, neoadjuvant trastuzumab
used in combination with standard chemotherapy is capa-
Patient Information ble of inducing a 30% pCR rate [25, 39, 40].
Neoadjuvant therapy as a treatment option must always More recently, a dual HER2 antibody blockade using
respectively; p = .058) [62]. In a phase II study by the Span- compromising on distant recurrence, breast cancer survival,
ish Breast Cancer Research Group (GEICAM) in luminal or OS [72]. The authors observed a higher local recurrence
tumors, exemestane was compared with chemotherapy rate with breast-conserving therapy over mastectomy, which
(four cycles of epirubicin-cyclophosphamide followed by four is one part of breast-conserving procedures [73].
cycles of docetaxel). The authors reported that response
rates showed nonsignificant differences (48% vs. 66%, respec- Standardization of Pathological Studies
tively; p = .075) and that there were no differences in BCS Neoadjuvant treatment has an important impact for
rates between the two treatment arms (56% vs. 47%, respec- pathologists, as the handling and reporting of breast cancer
tively; p = .23) [63]. specimens in this setting require specific considerations.
A limitation of neoadjuvant endocrine therapy is that Multicenter breast cancer clinical trial studies have indi-
pCR is uncommon and, thus, not an effective surrogate of cated that there is a huge variation in the handling and
clinical outcome [64]. Several phase II studies have evalu- reporting of specimens [74]. The pathologist’s task in asses-
ated the effects of neoadjuvant cyclin-dependent kinase sing post-neoadjuvant therapy specimens may be further
inhibitors in combination with endocrine therapy or endo- complicated by the fact that the definition of pCR is not
crine therapy plus anti-HER2 therapies in ER-positive/ uniformly standardized, which can create further challeng-
HER2-positive breast carcinoma [65–67]. Early evaluation ing issues with the interpretation and reporting of the
of more aggressive tumors. The FDA’s proposed model for by identifying compensatory alternative pathways in resid-
achieving drug approval requires a randomized study, with ual cells. For example, the use of NanoString technology in
the primary objective of demonstrating superiority of the triple-negative tumors identified the DUSP4 gene, a nega-
study drug in terms of pCR, and a subsequent confirmatory tive regulator of ERK, low expression of which was associ-
trial demonstrating a clinically and statistically significant ated with greater proliferation, worse survival, and greater
benefit in RFS, PFS, or OS for the test drug. sensitivity to MEK inhibition [83]. More recently, Karagian-
This proposal became a reality after the pCR results nis et al. observed an increase of the mammalian-enabled
obtained in the NeoSphere and TRYPHAENA studies protein (MENA), which regulates actin structure and cell
[41–43], with the FDA granting approval for pertuzumab motility, in 20 cases of residual tumor after therapy [84].
plus trastuzumab in the neoadjuvant treatment of patients These findings help identify mechanisms of resistance to
with HER2-positive breast cancer. neoadjuvant chemotherapy, for which experimental drugs
may prove effective in breaking [85]. Because only cases
The Neoadjuvant Setting in Research without a pCR having residual malignant tissue can be eval-
Using the neoadjuvant model in research has brought about uated after neoadjuvant therapy, markers of response to
a paradigm shift in the approval of new drugs for treating therapy cannot be evaluated at the molecular level.
breast cancer. Traditionally, drugs were developed to treat
Table 2. Summary of the most important cost-effectiveness analyses on targeted HER2 therapies
Comparators Country ICER/QALY Conclusion
Neoadjuvant therapy
Pertuzumab + trastuzumab + Canada (pCODR) Can$17,103–Can$27,550 per QALY Yes
taxane vs. trastuzumab +
taxane Spain €637.000 avoided Yes
U.K. (NICE) Not determined because of No (appraisal
uncertainty in neoadjuvant therapy not final)
variation across NHS sites, clinical
benefit, cost, and utility assumptions
Adjuvant therapy
1-year trastuzumab à Canada Can$13,095–Can$127,862 per QALY Yes
standard chemotherapy U.S. U.S. $18,970–$39,982 per QALY Yes
vs. standard chemotherapy
alone U.K. £25,803 per QALY Yes
U.K. (NICE) £18,000 per QALY Yes
Europe €5,828–€41,500 per QALY Yes
cost per quality-adjusted life-years (QALYs) [91]. The Spanish following conclusions regarding the use of neoadjuvant
cost-offset study of Albanell et al. quantified the benefit in therapy in the treatment of breast cancer:
avoiding costs related to disease relapse [92]. An appraisal by • Neoadjuvant systemic therapy involving chemotherapy,
NICE in the U.K. recommends the use of neoadjuvant pertu- targeted therapy, and sometimes hormonal therapy is a
zumab as an option for the neoadjuvant treatment of
preferred therapeutic option in early breast cancer before
HER2-positive breast cancer [93].
definitive breast surgery and has the same indications as
adjuvant treatment.
RECOMMENDATIONS • Multidisciplinary committees play an essential role in
After reviewing the existing scientific evidence, this group the appropriate selection of patients eligible for neoad-
of breast cancer experts, on behalf of SEOM, reached the juvant therapy.
• Concerning chemotherapy, the recommended treatment of the manuscript. This position paper was commissioned
regimen consists of anthracyclines followed by taxanes. by SEOM. Roche Farma provided financial support for medi-
A dose-dense anthracycline regimen may be used in cal writing services.
patients with high-grade or hormone receptor-negative
tumors.
• In patients with triple-negative tumors and mutated AUTHOR CONTRIBUTIONS
BRCA, it is reasonable to supplement the taxane with Conception/design: Ramon Colomer, Cristina Saura, Pedro Sánchez-Rovira,
Tomás Pascual
carboplatin. Provision of study material or patients: Ramon Colomer, Cristina Saura,
• In patients with HER2-positive tumors, neoadjuvant admin- Pedro Sánchez-Rovira, Tomás Pascual
Collection and/or assembly of data: Ramon Colomer, Cristina Saura, Pedro
istration of dual anti-HER2 therapy (trastuzumab and per- Sánchez-Rovira, Tomás Pascual
tuzumab) is indicated together with chemotherapy. Data analysis and interpretation: Ramon Colomer, Cristina Saura, Pedro
• In hormone receptor-positive postmenopausal patients Sánchez-Rovira, Tomás Pascual, Isabel T. Rubio, Octavio Burgués, Lourdes
Marcos, César A. Rodríguez, Miguel Martín, Ana Lluch
not eligible for chemotherapy, neoadjuvant endocrine Manuscript writing: Ramon Colomer, Cristina Saura, Pedro Sánchez-Rovira,
therapy is an appropriate option. Tomás Pascual, Isabel T. Rubio, Octavio Burgués, Lourdes Marcos, César
• Neoadjuvant treatment can significantly impact surgical A. Rodríguez, Miguel Martín, Ana Lluch
Final approval of manuscript: Ramon Colomer, Cristina Saura, Pedro
treatment by downstaging the tumor without compromis- Sánchez-Rovira, Tomás Pascual, Isabel T. Rubio, Octavio Burgués, Lourdes
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