Neoadjuvant Therapy for Early-Stage Breast Cancer: Current Practice, Controversies, and Future Directions

Research in the fields of surgical, medical, and radiation oncology has changed the landscape of neoadjuvant therapy in breast cancer, yet many areas of controversy still exist. When considering whether a patient is a candidate for neoadjuvant therapy, ideally the initial assessment should be multidisciplinary in nature and should include clinical, radiographic, and pathologic evaluation. Optimization of systemic therapy is dependent upon identifying the patient’s breast cancer subtype; the best approach may include targeted agents, as well as the determination of eligibility for enrollment into clinical trials that incorporate novel therapeutics or predictive biomarkers. This article will review a variety of surgical and radiation-based strategies for management of early-stage breast cancer, including surgical options involving the breast and axilla, and the role of radiation based on response to systemic therapy. Key areas of controversy include the ideal systemic treatment for different breast cancer subtypes, the surgical and radiotherapeutic approaches for management of the axilla, and the role of pathologic response rates as a surrogate for survival in drug development.

Introduction

Surgical resection of breast cancer remains the cornerstone of therapy for patients diagnosed with early-stage breast cancer. Systemic therapy can reduce the risk of relapse in patients with early breast cancer by killing cancer cells that have escaped the breast or local lymph nodes. Generally, systemic therapy administered either before or after surgery provides equal benefit in terms of disease-free survival (DFS) and overall survival (OS) for patients with early-stage breast cancer.[1] Administration of neoadjuvant therapy has benefits and limitations; therefore, patient selection is crucial for optimizing outcomes. In this review, we will discuss multidisciplinary considerations in treating patients with neoadjuvant therapy and highlight areas of controversy and ongoing research.

Neoadjuvant Therapy: Benefits, Indications, and Limitations

Benefits and indications

Historically, the primary indication for neoadjuvant therapy has been to facilitate breast surgery (see Table).[2] Neoadjuvant chemotherapy has the potential to convert unresectable tumors to resectable ones, and can reduce the extent of surgery needed to achieve adequate resection. For patients with inflammatory breast cancer, neoadjuvant therapy is considered a standard of care (unless a contraindication exists) and may confer a survival benefit in this population.[3] If patients are not candidates for surgery at the time of diagnosis, neoadjuvant therapy can be used as a bridge to operability in selected cases. Similarly, patients who want to undergo breast-conserving surgery (BCS) but are not candidates for this approach at diagnosis may also be considered for neoadjuvant therapy; among such patients, BCS rates as high as 72.3% (odds ratio [OR], 1.7 [95% confidence interval (CI), 1.6–1.8]) have been reported.[4,5]

There are many other instances when neoadjuvant therapy may be considered (see Table). For example, patients with chemoresponsive breast cancers may benefit from this treatment. Of all clinical breast cancer subtypes, human epidermal growth factor receptor (HER) 2–positive breast cancer and triple-negative breast cancer (TNBC) are the most chemosensitive, and therefore are most amenable to neoadjuvant chemotherapy; indeed, patients with HER2-positive disease and TNBC have the highest pathologic complete response (pCR) rates.[6] Patients with aggressive estrogen receptor (ER)-positive breast cancer subtypes, or luminal B–like phenotype breast cancers, tend to have higher pCR rates than those with more indolent ER-positive subtypes (pCR, 15% vs 7.5%), and so may be more suitable for neoadjuvant therapy.[7] Patients with classic invasive lobular breast cancer tend to have inferior responses to neoadjuvant chemotherapy compared with those who have invasive ductal carcinomas (pCR, 11% vs 25%; P = .01), and are therefore less likely to benefit from neoadjuvant chemotherapy.[8] In patients with node-positive disease, for which chemotherapy is the standard of care regardless of the sequencing of drug administration, response to neoadjuvant treatment has a potential impact on locoregional management, including the extent of axillary surgery and the radiation targets selected. In clinical research trials, the neoadjuvant setting is useful for evaluation of the biologic and clinical effects of novel agents, and is thus a powerful research tool. Importantly, because tissue is readily available both before and after therapy in this setting, investigation of tissue-based biomarkers is logistically more feasible.

Limitations

Neoadjuvant chemotherapy is not recommended routinely for patients with stage I breast cancer[9]-particularly if it is unclear whether to administer chemotherapy, or when third-generation vs first- or second-generation chemotherapy regimens are being considered. In these cases, the final surgical pathology report is often essential to making decisions about the need for chemotherapy and the type of regimen. The extent of tumor as defined by focality may affect BCS rates after neoadjuvant chemotherapy, when multifocal or multicentric tumors have lower chances of achieving eligibility for BCS (unifocal, 71.6%; multifocal, 58.5%; multicentric, 30%).[10] Rates of pCR may also differ slightly depending on tumor focality (unifocal, 19.4%; multifocal, 16.5%; multicentric, 14.4%). Patients with multicentric rather than unifocal tumors may have inferior DFS (P < .001) and OS (P < .009) after neoadjuvant chemotherapy; however, this disadvantage is abrogated if pCR is achieved.[10]

There are insufficient data to support use of BCS after neoadjuvant chemotherapy in multicentric or multifocal disease; therefore, cases should be considered on an individual basis.[2] For patients with multicentric disease (ie, multiple tumors in different quadrants of the breast) at presentation, mastectomy would be the standard of care regardless of response to neoadjuvant therapy. If multifocal disease (ie, multiple distinct tumors in the same quadrant of the breast) is present, BCS may become possible. It is important to bear in mind, however, that although the individual lesions may decrease in size in response to neoadjuvant therapy, the distance between lesions remains the same.

Progression during neoadjuvant chemotherapy is uncommon. While most patients are still able to undergo surgery, studies have reported that up to 12% of patients who started neoadjuvant chemotherapy were not able to undergo definitive surgery.[11] Even more uncommon, distant metastasis has been described in 4% of patients who experience disease progression while receiving neoadjuvant chemotherapy.[11] Factors that predict progression of disease during neoadjuvant therapy include African-American race, advanced tumor stage, high nuclear grade, high Ki-67 levels, and hormone receptor negativity.[12] Patients with breast cancer subtypes that are relatively less chemosensitive, such as luminal A or classic invasive lobular breast cancer, may also be less likely to benefit from neoadjuvant therapy.[7,8] These data underscore the importance of careful patient selection and monitoring during treatment.

In the neoadjuvant setting, therapeutic decisions are largely based on clinical staging; this includes physical examination and results obtained with imaging modalities, which may be less accurate than surgical staging. Nodal staging, in particular, may affect radiation therapy options.[13]

Initial Assessment of the Patient

Breast evaluation

Locoregional assessment should be performed with careful physical examination and the use of mammography and ultrasound as recommended by the National Comprehensive Cancer Network (NCCN) guidelines.[9,14] Magnetic resonance imaging (MRI) of the breast is more sensitive in determining the extent of the tumor but it may also overestimate the tumor size.[15] MRI may be performed if there are other areas of concern on initial imaging that may warrant additional evaluation.[16] A baseline MRI has been shown to decrease re-excision rates, and this procedure also allows for assessment of the contralateral breast, where there is a 3% to 10% likelihood of synchronous disease.[17,18] The decision to pursue an MRI should be tailored to each patient’s specific clinical situation and needs, particularly if BCS is desired.

According to NCCN guidelines, image-guided core needle biopsy with placement of an image-detectable marker of the breast abnormality is necessary to confirm the diagnosis; provide tissue to assess pathologic markers, including ER, progesterone receptor (PR), and HER2 status; and demarcate the tumor bed for post-neoadjuvant management.[9] Tumor grade and Ki-67 levels may also be assessed, as these may estimate a more aggressive phenotype and may predict response to chemotherapy. Other testing on tissue obtained by core needle biopsy, such as Oncotype DX or other commercial genotyping, is not a standard of care in the preoperative setting at this time and should not be obtained routinely outside the context of a clinical trial. Many biomarkers are currently under development, including tumor-infiltrating lymphocytes (TILs), which have been associated with higher likelihood of pCR in HER2-positive disease and TNBC, and the homologous recombination deficiency score, which has been found to be an excellent predictor of pCR in patients with TNBC receiving platinum-based neoadjuvant chemotherapy.[19-21]

Axillary evaluation

Patients being considered for neoadjuvant chemotherapy should undergo careful physical examination of the axilla and review of mammography and ultrasonography.[16] If the clinical or breast imaging results are notable for lymphadenopathy, a dedicated axillary ultrasound is recommended for further evaluation. Fine needle aspiration (FNA) or core needle biopsy should be performed on any suspicious-appearing lymph nodes (Figure). Core needle biopsy is more accurate, particularly in invasive lobular carcinomas, and when feasible, it may be preferred to FNA; either procedure is acceptable, however, according to the NCCN guidelines.[9,22] The placement of a biopsy clip should be strongly considered when performing an FNA or core needle biopsy, because use of the clip can improve the rate of successful surgical resection of biopsy-proven metastatic axillary lymph nodes. This allows for more accurate assessment of pathologic response in the axilla, and decreases the false-negative rate when performing a sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy in patients with known axillary nodal involvement prior to systemic treatment.[23,24]

For patients with clinically node-negative breast cancer at diagnosis, the role of performing an SLNB prior to or following neoadjuvant chemotherapy is controversial. In the SENTINA study, 35% of clinically node-negative patients were found to have pathologically node-positive disease on SLNB performed prior to neoadjuvant chemotherapy.[25] Among these patients, repeat SLNB after neoadjuvant chemotherapy detected additional sentinel lymph nodes (SLNs) in 61% of patients, with a high false-negative rate of 51.6%. Thus, SLNB performed after excision of a positive node prior to neoadjuvant therapy has poor reliability.

In another study, compared with the same procedure performed prior to treatment, SLNB following neoadjuvant chemotherapy resulted not only in lower SLN identification rates (98% vs 95%, before vs after neoadjuvant therapy, respectively; P = .032), but also in less frequent axillary dissections or radiation (45% vs 33%; P = .006); therefore, performing an SLNB after neoadjuvant therapy potentially reduced morbidity.[26] Furthermore, one key limitation of SLNB prior to neoadjuvant therapy is that removal of affected nodes prior to treatment precludes the ability to assess pathologic response and decreases the significance of achieving a pCR.[27] Given that compelling data on routine SLNB before neoadjuvant therapy are lacking, our preference is to perform SLNB after neoadjuvant therapy in patients with a clinically node-negative axilla at presentation; however, patient management in this setting must be individualized.

Evaluation of distant disease

Patients with stage I and II disease who are asymptomatic at presentation do not require routine systemic imaging; however, patients with stage III disease should be considered for systemic imaging even in the absence of symptoms, since they are at higher risk for harboring systemic disease.[9] According to NCCN guidelines, however, routine systemic imaging in the absence of symptoms is not indicated, but any patient experiencing systemic symptoms should undergo laboratory testing and systemic staging as indicated.[9] Nuclear bone scan and computed tomography (CT) scans with contrast of the chest, abdomen, and pelvis can adequately assess for systemic disease, and should be considered as a first step unless a contraindication exists. Additional imaging, including positron emission tomography (PET) scans and MRI, may be required in select cases. Areas suspicious for distant metastasis should undergo biopsy to confirm metastatic disease. Patients with central nervous system symptoms should undergo brain MRI.

Additional considerations

The treatment of breast cancer requires a multidisciplinary approach. Although initial evaluation may be performed by a surgical or medical oncologist, there are several additional factors that should be considered during the initial assessment. In complex cases, the use of a multidisciplinary tumor board, in which pathologists; radiologists; and surgical, medical, and radiation oncologists review the case, can facilitate the development of a treatment strategy. An early referral to radiation oncology as part of the initial assessment should be recommended, particularly when clinical trials are available or there are questions of disease burden, since response to treatment may impact radiation planning. Early involvement of plastic surgery can aid in surgical planning, particularly as it may pertain to cosmetic outcomes. Genetic counseling early in the process can also be helpful, since this may inform final surgical treatment decisions. In cases of patients whose subsequent cancer risk is affected by hereditary mutations, such as BRCA1 or BRCA2, the decision to perform mastectomy and/or prophylactic mastectomy may be considered. In addition, the neoadjuvant setting also provides numerous opportunities for research and clinical trial participation, and these opportunities should be discussed with all eligible patients.

Systemic Therapy Considerations

Hormone receptor (HR)-positive breast cancer

Unless in the context of a clinical trial, patients with aggressive phenotype HR-positive breast cancer who are candidates for chemotherapy should be treated with neoadjuvant chemotherapy rather than endocrine therapy, since compared with indolent HR-positive subtypes they have superior rates of response.[7] There are data, however, that suggest that neoadjuvant endocrine therapy may be effective. Studies comparing neoadjuvant endocrine therapy with chemotherapy have shown similar clinical response rates (48% to 67% vs 63% to 66%, respectively), and pCR rates were comparable but low (0% to 3% vs 1% to 6%, respectively).[28,29] Of note, the majority of patients included in these studies had ER and PR positivity and had grade 1/2 histology, suggesting that these may be less aggressive in nature and more likely to be sensitive to endocrine therapy. Since these studies demonstrated low pCR rates with chemotherapy in HR-positive breast cancer, primary surgery should be considered, unless there is an indication for neoadjuvant therapy. Several studies investigating neoadjuvant aromatase inhibitors (AIs) vs tamoxifen have also been conducted, demonstrating either equal efficacy or superiority of AIs, with clinical response rates ranging from 38% to 70% for AIs and 36% to 51% for tamoxifen.[30-33] In a phase II study comparing different AIs, clinical response rates were highest with letrozole (74.8% [95% CI, 66.3–82.1]) and anastrozole (69.1% [95% CI, 60.1–77.1]), and lowest with exemestane (62.9% [95% CI, 53.8–71.4]); however, future studies are needed to definitively demonstrate that one AI is superior to another.[34] The duration of therapy is also an important factor, with several studies suggesting treatment duration in excess of 3 to 4 months is optimal.[35-37] In patients who are unable to undergo surgery or receive chemotherapy, neoadjuvant endocrine therapy may be an appropriate alternative. Assays that reflect tumor biology may be useful in determining who is a good candidate for neoadjuvant chemotherapy vs hormonal therapy.

HER2-positive breast cancer

The addition of the anti-HER2 monoclonal antibody trastuzumab to chemotherapy has resulted in an increase in pCR rates, from 20% to 43% (relative risk [RR], 2.07 [95% CI, 1.41–3.03]; P = .0002), and a decreased relapse rate, from 20% to 12% (RR, 0.67 [95% CI, 0.48–0.94]).[38] Furthermore, event-free survival (EFS) and OS benefits (hazard ratio [HR], 0.64; P = .016 and HR, 0.66; P = .055, respectively) have been demonstrated in the NOAH study, which was presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting.[39]

The success of lapatinib, a tyrosine kinase inhibitor (TKI) targeting the intracellular domain of HER2, in the metastatic setting motivated several studies investigating this drug in the neoadjuvant setting. Investigators from the European Organisation for Research and Treatment of Cancer (EORTC) 10054 study, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-41 study, the Cancer and Leukemia Group B (CALGB) 40601 study, and the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) study reported that the addition of lapatinib to trastuzumab-based neoadjuvant chemotherapy improved pCR rates by 4% to 21%.[40-43] NeoALTTO randomized patients to paclitaxel and either lapatinib, trastuzumab, or a combination of lapatinib and trastuzumab. Following completion of chemotherapy, the patients underwent definitive surgical treatment and then received adjuvant anthracycline-based chemotherapy. While this study demonstrated a striking improvement in pCR rate with the addition of lapatinib to trastuzumab (pCR, 30% for the trastuzumab arm vs 51% for the trastuzumab/lapatinib arm), combination treatment was not associated with improved EFS (HR, 0.78 [95% CI, 0.47–1.28]; P = .33) or OS (HR, 0.62 [95% CI, 0.30–1.25]; P = .19). The study was not powered to detect small differences in survival outcomes, however.

The confirmatory Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) study, presented at the 2014 ASCO Annual Meeting, failed to demonstrate that adding lapatinib to trastuzumab-based chemotherapy improves DFS (HR, 0.84 [95% CI, 0.70–1.02]; P = .048, with P ≤ .025 needed to achieve statistical significance).[44] The discordant results between NeoALTTO and ALTTO may be explained in part by the timing of the anthracycline-based therapy, since in NeoALTTO this regimen was given after surgery, and therefore did not have an impact on pCR rates. The findings inform future study designs, suggesting that all chemotherapy should be given upfront before surgery. Given that there is no survival benefit to adding lapatinib to neoadjuvant trastuzumab-based chemotherapy, at this time it is not considered a standard of care for patients with early HER2-positive breast cancer, and should not be routinely prescribed except in the context of a clinical trial.

Pertuzumab is a monoclonal antibody against HER2 and HER3. It has demonstrated a survival benefit for patients with metastatic HER2-positive breast cancer, and has also been studied in the neoadjuvant setting.[45] The NeoSphere trial found that the addition of pertuzumab to trastuzumab and docetaxel improved pCR rates from 29% to 45.8%.[46] A recent update reported at the 2015 ASCO Annual Meeting suggested a trend for improved DFS, but this was not statistically significant (HR, 0.60 [95% CI, 0.28–1.27]).[47] The TRYPHAENA study compared a combination regimen of pertuzumab, trastuzumab, docetaxel, and carboplatin vs two other pertuzumab-based regimens (both including epirubicin), and showed an unprecedented pCR rate of 66.2% in the non–anthracycline-containing arm.[48] Based on the results of NeoSphere and TRYPHAENA, the US Food and Drug Administration (FDA) granted approval for the use of pertuzumab in the neoadjuvant setting.

The results of the APHINITY study will confirm whether the addition of pertuzumab improves survival outcomes in early HER2-positive breast cancer. Until then, the strict approval for use of pertuzumab in early breast cancer remains in the neoadjuvant setting, but the NCCN guidelines have made provisional statements to also consider its use in the adjuvant setting.[9] The success of several novel therapeutics in the metastatic setting has led to studies in the neoadjuvant setting. The effects of neoadjuvant trastuzumab emtansine (T-DM1) with or without hormone therapy in HR-positive, HER2-positive early breast cancer were reported at the 2015 ASCO Annual Meeting. Compared with trastuzumab administered with endocrine therapy, pCR rates were substantially higher in the T-DM1 arms (6.7% vs 40.5% and 45.8%, respectively; P < .001).[49] The novel TKI neratinib, which irreversibly inhibits HER2, was studied in the I-SPY 2 trial, in which it demonstrated overall pCR rates of 32% (95% CI, 28–36); a larger registration trial is planned.[50]

Triple-negative breast cancer

Although there are no approved drugs specifically indicated for TNBC, this subtype is associated with relatively high pCR rates following chemotherapy, with many novel agents under investigation. The addition of the anti–vascular endothelial growth factor receptor (VEGFR) monoclonal antibody bevacizumab to chemotherapy has been studied extensively in the setting of neoadjuvant treatment for breast cancer. The German Breast Group (GBG) 44 study and the Avastin Randomized Trial With Neoadjuvant Chemotherapy for Patients With Early Breast Cancer (ARTemis) found that in TNBC cohorts, the addition of bevacizumab improved the rates of ypT0N0 pCR by 11.4% (P = .003) and 14% (P = .03), respectively.[51,52] The recently presented Austrian Breast and Colorectal Cancer Study Group (ABCSG) 32 study and the Southwestern Oncology Group (SWOG) S0800 study have also reported improvements in pCR rates, especially in patients with TNBC.[53,54] The NSABP B-40 and CALGB 40603 studies found statistically significant improvements in ypT0Nx pCR in the breast with the addition of bevacizumab, but differences in ypT0N0 rates were not statistically significant (P = .08 and P = .057, respectively).[55,56] While these neoadjuvant studies demonstrated improvements in pCR, three large randomized studies in multiple breast cancer subtypes in the adjuvant setting have failed to demonstrate a survival advantage.[57-59] These data demonstrate no role for bevacizumab at this time in unselected populations with early-stage breast cancer.

Platinum agents such as carboplatin have been investigated in the neoadjuvant setting-administered at different dosing schedules and in a variety of combinations with other agents-and have consistently been shown to improve pCR rates. The CALGB 40603 study found rates of ypT0N0 pCR improved from 41% to 54% (P = .0029); in GeparSixto, pCR rates in the TNBC cohort improved from 36.9% to 53.2% (P = .005); and in the I-SPY 2 study reported at the 2013 San Antonio Breast Cancer Symposium, the estimated pCR rate with carboplatin/veliparib was 52%.[55,59,60] Notably, these studies used various doses and schedules of carboplatin, and in combinations with non–standard-of-care agents such as bevacizumab and veliparib. The addition of carboplatin is associated with significant myelosuppression and nausea. Grade 3/4 hematologic adverse events ranged from 59% to 82% in the GeparSixto study.[59] In the CALGB 40603 study, patients who received carboplatin were more likely to miss more than two doses of paclitaxel (36% vs 16%). Additionally, 20% of patients did not receive all planned doses of anthracyclines and taxanes, and many required dose reductions.[55] This is an important factor to consider, since long-term survival data for anthracyclines and taxanes are robust.[61] In summary, given the significant toxicity of carboplatin, its incorporation into the neoadjuvant management of breast cancer requires additional studies, which should use consistent doses and schedules of carboplatin, integrate it into standard treatment regimens, and provide long-term survival data. Furthermore, adjuvant studies have been initiated to study the benefit of adding platinum drugs to treatment regimens for early-stage TNBC.

Residual disease

Patients treated with neoadjuvant chemotherapy who have residual disease at the end of treatment are at increased risk of recurrence. This relationship is particularly true of patients with TNBC (DFS HR, 6.02 [95% CI, 3.92–9.25]; P < .001), HER2-positive disease (DFS HR, 8.74 [95% CI, 3.17–24.12]; P < .001), and luminal B breast cancer (DFS HR, 5.95 [95% CI, 1.46–24.25]; P = .013).[62] Because of the complexities of assessing pathologic characteristics of residual disease, the Breast International Group and the North American Breast Cancer Group have set forth guidelines that focus on a multidisciplinary approach, rigorous pathologic sampling, use of biopsy clips, and the consideration of receptor retesting when it may affect clinical management (ie, patients with initial receptor-negative status).[27]

Receptor status has been demonstrated to change with neoadjuvant chemotherapy, and may be associated with prognosis when there is loss of the ER.[63] In one series examining receptor status after neoadjuvant therapy, 10.3% of patients with tumors that were ER-positive and HER2-negative on core needle biopsy became ER-negative on excision, whereas 34.5% of patients with TNBC on core needle biopsy became ER-positive at the time of surgical resection. This study is limited because it did not report the change in percentage of ER labeling in tumors with discordant ER status results, and the differences may reflect tumor heterogeneity, tissue sampling, or technical issues with the assays. Nevertheless, changes did correspond with outcomes, as patients whose tumors were ER-negative on excision had inferior recurrence-free survival (RFS; HR, 3.54 [95% CI, 1.60–7.85]), while patients whose tumors became ER-positive had a trend toward improved RFS (HR, 1.32 [95% CI, 0.64–2.74]).[63]

In addition to standard American Joint Committee on Cancer/Union for International Cancer Control TNM staging, the Residual Cancer Burden (RCB) system can be used for patients who have residual disease. The RCB system incorporates not only residual disease, but also the primary tumor size and nodal burden, and it can be used to determine the risk of recurrence.[64] Biomarkers are under development to further characterize patients with residual disease after neoadjuvant therapy. For instance, the presence of TILs has been found to be a favorable prognostic factor for metastasis-free survival and OS in patients with TNBC who have residual disease after neoadjuvant chemotherapy.[65] Furthermore, biomarkers such as multigene assays may be useful in the development of targeted therapies for patients with an increased risk of recurrence. Unfortunately, there is no standard additional therapy at this time for patients who have residual disease after neoadjuvant chemotherapy.

The KATHERINE study is investigating the role of T-DM1 in HER2-positive breast cancer with residual disease (ClinicalTrials.gov identifier: NCT01772472). For TNBC patients with residual disease, the role of cisplatin is being evaluated by investigators from the Eastern Cooperative Oncology Group (ECOG)/American College of Radiology Imaging Network (ACRIN) (ClinicalTrials.gov identifier: NCT02445391). A deeper molecular understanding of tumor biology is needed to help identify and overcome mechanisms of resistance to standard therapy.

Interpreting Pathologic Complete Response

For patients who achieve a pCR, numerous data demonstrate that they are more likely to experience a survival benefit when pCR is defined as ypT0/is ypN0.[66] Naturally, pCR achieved in a single patient may not correlate to the pCR rate in a population of patients as a function of a therapy. To date, only our experience with trastuzumab has demonstrated that improvements in pCR are linked to improved survival; investigations of lapatinib and bevacizumab have failed to show this, and we await results from the APHINITY trial to see if pertuzumab will demonstrate a correlation between pCR and survival endpoints.[39,44,58,59] Similarly, studies are ongoing in the neoadjuvant and adjuvant settings to investigate the role of carboplatin in early TNBC. Certainly the anticancer potency of the drug under investigation matters, and perhaps the degree of change in pCR rate may also matter. When considering neoadjuvant therapy, a clinician must weigh the potential benefits of agents with no proven survival benefit against their potential toxicity. The impact of toxicity on the ability of patients to complete standard-of-care therapy should also be considered. Furthermore, clinicians should be cautious in extrapolating neoadjuvant data to the adjuvant setting in the absence of survival data.

Surgical Considerations

Additional imaging following neoadjuvant therapy prior to surgery

In addition to clinical examination, imaging at the conclusion of neoadjuvant therapy can aid in the assessment of treatment response. Particularly when the patient desires BCS, critical to surgical decision making is the determination of whether neoadjuvant therapy has downstaged the tumor to the point where lumpectomy is feasible. MRI of the breast has been shown to be more accurate than mammography for evaluation of treatment response. Although the sensitivity of MRI is high (0.92), the specificity tends to be lower (0.6).[67] Correlation of MRI performed after neoadjuvant chemotherapy with pathology obtained from surgery has shown that MRI can both underestimate and overestimate pathologic size, although the discrepancy may be particularly related to HR-positive disease.[67-69] MRI alone, however, may not be adequate to assess for residual disease after neoadjuvant therapy. In one study, MRI alone correctly predicted suitability for BCS in 88% of patients, but MRI plus mammography improved this to 92%. Mammography after neoadjuvant therapy is important to assess the patient for extensive residual calcifications that may preclude BCS.[70] Close collaboration between surgery and radiology departments is crucial for assessing response to neoadjuvant therapy and surgical planning.

Partial vs complete mastectomy

Surgery after neoadjuvant therapy can be performed safely despite the potential toxicities associated with the therapy.[71] A primary objective of neoadjuvant therapy is to enhance surgical options for patients. One key measure of this is a decrease in mastectomy rate, and studies have found that mastectomies can be decreased by 16.6% to 27% after neoadjuvant therapy.[72,73] Interestingly, as pCR rates have increased with the use of modern neoadjuvant regimens, rates of BCS have not.[74,75] Reasons for this discrepancy may be related to tumor focality and centricity, patient preference, and residual ductal carcinoma in situ.[2] While, in general, BCS can be performed safely after neoadjuvant therapy, advanced nodal involvement, residual tumor > 2 cm, multifocal residual disease, and lymphovascular invasion predict higher rates of locoregional and ipsilateral breast tumor recurrence.[76]

Surgical axillary approach

The approach to initial evaluation of the axilla is discussed in an earlier section of this article. In women with clinically negative axillary lymph nodes, SLNB after neoadjuvant therapy yields similar identification rates compared with those of women who undergo primary surgery (97.4% vs 98.7%, respectively); recurrence rates are statistically similar as well (1.2% vs 0.9%, respectively).[77] Therefore, SLNB after neoadjuvant chemotherapy in patients with clinically negative lymph nodes at diagnosis is acceptable and considered to be the standard of care.[78] The role of SLNB vs axillary lymph node dissection in patients with clinically node-positive disease prior to neoadjuvant chemotherapy is more controversial. The American College of Surgeons Oncology Group (ACOSOG) Z1071 investigators found that in women with clinically node-positive breast cancer (cN1) who received neoadjuvant chemotherapy and then underwent SLNB, the false-negative rate was 12.6% (90% Bayesian credible interval, 9.85–16.05) when two or more SLNs were examined, and 9.1% (95% CI, 5.6–13.7) when three or more SLNs were examined; notably, in this study, false-negative rates > 10% were considered to be unacceptable.[79]

Additional analysis revealed that radiolabeled colloid alone or with blue dye, compared with blue dye alone, led to improved SLN identification rates.[80] The SENTINA study found that in women with clinically node-positive disease at diagnosis who converted to clinically node-negative status after neoadjuvant chemotherapy, SLNB following neoadjuvant chemotherapy resulted in a false-negative rate of 14.2% (95% CI, 9.9–19.4). If three or more lymph nodes were removed, the false-negative rate dropped to 7.3%, and the addition of blue dye to radiocolloid decreased the false-negative rate from 16% to 8.6%.[25] The Sentinel Node Biopsy Following Neoadjuvant Chemotherapy in Biopsy Proven Node Positive Breast Cancer (SN FNAC) study also found that increasing the number of SLNs removed decreased false-negative rates (with removal of one lymph node associated with a false-negative rate of 18.2% vs a rate of 4.9% for removal of two lymph nodes), as did mandatory use of immunohistochemistry and a broad definition of lymph node positivity with metastasis of any size, including isolated tumor cells.[81] While the NCCN guidelines state that axillary lymph node dissection should be performed in patients with clinically positive lymph nodes, the previously discussed data suggest that SLNB after neoadjuvant therapy is a feasible option for patients with initial node-positive disease when the procedure yields three or more lymph nodes, and dual radiotracer and dye techniques are used.[9] Alternative approaches are under investigation-for example, “targeted axillary dissection,” which includes SLNB in combination with targeted removal of biopsy-proven positive lymph nodes that were clipped at the time of initial core needle biopsy or FNA.[82] Furthermore, additional studies are needed to identify breast cancer subtypes for which patients with biopsy-proven nodal disease at presentation may derive the most benefit from SLNB after neoadjuvant therapy.

Radiation Considerations

For patients who undergo BCS after neoadjuvant therapy, radiation therapy to the breast is considered a standard of care whether or not pCR is achieved, as it is for patients who undergo upfront surgery.[9,83] For patients who undergo mastectomy, the roles of postmastectomy radiation therapy (PMRT) and regional nodal irradiation (RNI) are more controversial, particularly among those who achieve pCR. NCCN guidelines simply state that radiation therapy should be based on the worst stage either prior to or after neoadjuvant therapy.[9] Patients who have negative lymph nodes prior to and following neoadjuvant therapy generally do not require PMRT or RNI, and conversely those with residual node-positive disease are at higher risk of locoregional recurrence (LRR) and require PMRT/RNI.[84] However, studies evaluating the risk of LRR after neoadjuvant therapy have consistently demonstrated a lower risk of LRR in patients who achieve pCR compared with those who do not.[85-88] Subtype of breast cancer may additionally influence LRR rates in those achieving pCR, with TNBC generally associated with a higher LRR rate.[89] A pooled analysis of the NSABP B-18 and B-27 studies demonstrated low rates of LRR in patients with pCR who had mastectomy without PMRT; in these studies, the 10-year risk of LRR was < 10% in patients with pCR, regardless of initial nodal status or tumor size, suggesting that PMRT may not be needed in these patients.[87]

Conversely, a recent meta-analysis of patients treated in the German Gepar trials, presented at the 2015 ASCO Annual Meeting, found that among patients who achieved pCR, the use of PMRT was an independent prognostic factor for locoregional relapse–free survival (HR, 0.54 [95% CI, 0.035–0.82]; P = .004) and DFS (HR, 0.69 [95% CI, 0.51–0.93]; P = .016).[90] To address this conundrum, the Radiation Therapy Oncology Group (RTOG) and the NSABP have designed the randomized phase III NSABP B-51/RTOG 1304 trial (ClinicalTrials.gov identifier: NCT01872975) for patients who have positive axillary nodes before neoadjuvant chemotherapy but convert to pathologically negative axillary nodes. Patients will be randomized to PMRT with RNI vs no radiation in those who had mastectomy, and breast irradiation with or without RNI in those who have undergone BCS. This study will help to determine which patients can safely have PMRT and/or RNI omitted in the setting of nodal pCR.[91] In summary, at this time there are no prospective data to guide clinicians regarding use of radiation after neoadjuvant chemotherapy in the setting of pCR. Outside the setting of a clinical trial, the current NCCN guidelines recommend strong consideration of PMRT or RNI in patients who have positive lymph nodes either before or after neoadjuvant chemotherapy; treatment decisions should be made on a case-by-case basis (Figure).[84]

Conclusions

In carefully selected patients, neoadjuvant therapy can provide improved surgical outcomes, prognostic information, and access to clinical trials investigating novel agents and locoregional therapies. Management involves a multidisciplinary team that should include surgical, medical, and radiation oncologists; pathologists; radiologists; and, in certain cases, plastic surgeons, genetic counselors, and research staff. (A suggested algorithm, based on data presented in this review article, is provided in the Figure.) Since optimization of systemic and local therapies continues to be an evolving field, participation in a clinical trial should be considered for eligible patients.

Financial Disclosure: Dr. Stearns receives research funding from AbbVie, Celgene, MedImmune, Merck, Novartis, Pfizer, and Puma. The other authors have no significant financial relationship with the manufacturer of any product or provider of any service mentioned in this article.

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