Abstract

Despite the ever-changing breast surgeon’s technical role, the surgeon forms an indispensible link between imaging, diagnostics, pathology, and the medical oncologist. Biomarkers of prognosis, prediction of response, and resistance to treatments, including imaging, tissue and circulating markers apply to the primary diagnostic and treatment settings as well as scenarios which include disease recurrence, both in the early and advanced settings. Whether it is via the diagnostic clinic referred by the primary care physician or via a breast screening service, primary early breast cancer is referred for initial treatment and/or diagnosis and currently remains the domain of the surgical oncologist. The surgeon is privileged by this unique “window of opportunity” to consider the biological aspects of the diagnosis and guide the patient appropriately toward initial therapy, only one of which is primary surgery. Options of neoadjuvant endocrine, cytotoxic, or targeted therapy as either standard of care or else in the clinical trial context should be considered to optimize treatment in all patients.

Precision therapy in medicine is a novel concept encompassing personalized medicine for all available treatment modalities including surgery, radiotherapy as well as systemic therapies.

Precision chemotherapy was used to describe agents like the antibody–drug conjugate T-DM1, where trastuzumab selectively delivers a very effective cytotoxic agent directly to HER2-positive tumor cells, thereby sparing normal cells.

Precision as a concept in treatment should also imply selecting the patient population most suitable for a particular treatment which is then personalized depending on the individual’s pharmacogenetic and tumor characteristics to maximize effectiveness (1).

Surgery should be similarly tailored to match the patient’s preferences, the tumor’s biology, and predicted response to systemic treatment.

Traditionally surgery has been the mainstay of breast cancer treatment. However, despite increasing realization of limitations of such an approach at the exclusion of other treatments, surgeons have commanded the domain of initial diagnosis and definitive treatment decisions. Until recently, surgeons played a key role in utilizing neoadjuvant endocrine therapy (initially tamoxifen and now aromatase inhibitors) in the postmenopausal patient unsuitable for surgery due to advanced disease or significant comorbidity precluding surgery (2). Increasingly, in a multidisciplinary care environment (ie, the breast unit) it behooves the surgeon to consider neoadjuvant systemic therapy (cytotoxic, endocrine, and targeted) as standard practice in selected circumstances and particularly in a research setting to examine the effect of novel treatments on a given tumor biology.

Diagnosis

A full history including a detailed family history, menopausal status, and current exogenous hormonal treatments (contraception, and hormone replacement) and examination is followed by “triple-assessment” using mammography, ultrasound, and ultrasound-guided core biopsy in most instances. While in the primary systemic therapy (PST) population, the majority of cancers will be symptomatic this is not exclusively the case. Care must be taken in the situation where a patient is referred from a screening unit to assess tumor characteristics and perform appropriate staging—even if repeat biopsy is sometimes necessary. The initial diagnostic biopsy should where possible include performance of estrogen receptor (ER), progesterone receptor (PR), HER2 immunohistochemistry (IHC) (+/− in situ hybridization) and Ki-67 in an accredited facility. The reliable determination of receptor phenotype as an approximation of intrinsic subtype is a prerequisite to decision making in PST. Further biopsies as part of standard operating procedure or research protocols should be considered for at least DNA sequencing and RNA expression analysis. Such tissue sampling is facilitated by using a vacuum-assisted device (increased tissue volume obtained) which can obtain multiple samples in a single pass and should be 14G or larger (3).

In selected cases (eg, invasive lobular carcinoma [ILC]) magnetic resonance imaging should be considered to more accurately estimate true extent of disease. The surgeon’s decision to advise PST depends on several patient, tumor, and treatment factors and is facilitated in a breast unit setting with a multidisciplinary team discussion before initial treatment where an integrated decision with the medical oncologist takes place. Staging investigations such as computed tomography +/− bone scan should be reserved for patients with clinical stage III disease (either cN2 or cT3, cN1, or for any cT4) where occult metastases are detected in up to 14% of patients (4).

Biological Evaluation—Selecting Patients for Standard Care

Neoadjuvant chemotherapy was compared directly with adjuvant chemotherapy in the National Surgical Adjuvant Breast and Bowel Project (NSABP)-B18 trial and shown to give patients equivalent outcomes, both for disease-free survival and overall survival (5). In addition, patients aged under 50 years demonstrated a trend toward increased survival (disease-free survival and overall survival) for the neoadjuvant group (6) suggesting a subgroup who might benefit from the PST approach. It may well be that for certain breast cancer subtypes (not examined in B18) delay in chemotherapy initiation may have contributed. De Melo Gagliato et al. (7) showed that for HER2+ and triple-negative tumors such a delay (>60 days) results in poorer overall survival.

It is well accepted that the pathological complete response (pCR) rates attained depend on receptor phenotype as well as the treatment regime (8).

Subtype-specific pCR rate was: 8.3% in hormone receptor (HR)+/HER2−, 18.7% in HR+/HER2+, 31.1% in triple negative, and 38.9% in HER2+/HR− (9). One of the guiding principles of patient selection is to use the same pathological selection criteria as for adjuvant chemotherapy. It is interesting to reflect that recurrence score (OncotypeDx), validated in NSABP-B14, B-20, and SWOG-8814 has been shown to predict response in patients with HR+, HER2− disease to paclitaxel and doxorubicin (10), to docetaxel (11), and to ixabepilone and cyclophosphamide (12) in the PST setting.

Tumor size is clearly a determinant. Down-sizing, which may convert the need for a mastectomy into breast conserving therapy is one of the clear indications for considering PST. For cT2/3 tumors it has been shown that a reduction in tumor volume excised (13) and re-excisions can be achieved (14).

For cT1 tumors (<2cm) this aspect is not as clear as there has not been shown to be a benefit in terms of breast volume excised (13). In fact, the tumor bed must still be removed given that current imaging cannot reliably predict pCR (15). Patients to be considered are those with high-grade tumors, HER2+ or triple negative as well as those with cN1/N2 disease or fine needle aspiration (FNA)-positive nodal metastasis despite small primary tumor size.

Surgery following PST is still recommended for all patients given higher local recurrence rates when radiotherapy was given after omitting surgery despite a clinical complete response (16,17). A radio-opaque or ultrasound-detectable marker should be deployed early in the treatment course, especially in cases where biology predicts high rates of pCR. It remains to be seen whether definitive surgery can be avoided for those with clinical complete response and a biopsy-proven pCR.

The significance of PST however are far wider-reaching than mere cosmetic outcome. The “window of opportunity” for in vivo chemosensitivity testing of the efficacy of treatment on the primary (and nodal disease) and knowledge of therapy resistance can provide much valuable information, in addition to being prognostic for the patient and facilitating translational research. The question of down-staging axillary nodal disease is now a focus of ongoing study (18) and importance for minimizing surgery-associated arm morbidity but is beyond the scope of this paper.

Modification of Surgery Based on Response and Phenotype

There is evidence that phenotype based on receptor status affects risk of loco-regional recurrence in the adjuvant setting (19) and at least in retrospective comparisons is no different in the PST setting (20). For example, triple-negative receptor status for a patient with a poor response or progressive disease in the PST setting should lead to a more aggressive surgical approach to margin clearance as the risk of loco-regional recurrence is higher (21). Intraoperative ultrasound and/or multiparametric magnetic resonance imaging with single or multiple marker placement can be used to guide surgical excision more precisely in the PST setting. Careful mapping of any visible residual tumor, which is often irregular in distribution, should be undertaken. Where there is doubt about conservability, full use of oncoplastic techniques to maximize aesthetic outcome and margins should be made. This may involve “re-staging” the local extent of disease, particularly in the assessment of microcalcification. Close liaison with the radiologist and rebiopsy of microcalcification to determine the extent or presence of ductal carcinoma in situ (DCIS) is essential for surgical planning. Despite pCR definitions not including the presence of DCIS as its presence does not influence prognosis, it will affect surgical margins and therefore the approach to resection.

Research Setting

The ideal schema for the study of novel therapeutic agents or combinations was agreed at the previous consensus (22) and involves tissue sample collection ideally at the time of initial diagnostic biopsy for lesions which are suspicious on clinical and/or imaging criteria. Extra biopsies should be taken for both expression analysis and genomic analysis (eg, next generation sequencing) and epigenetic studies (DNA methylation) at this time. Studies will increasingly demand a genetic screen or selection to enrich the study population likely to respond to a given treatment. Blood for germline (genomic) DNA should also be collected at this time.

Tissue biomarkers predictive of early response or resistance (such as Ki67) taken at 2 weeks or in some cases even earlier following commencement of treatment are an established need (23). Biomarkers should to be tailored to the specifics of the (on target) mechanism of action of agents being trialed (eg, cleaved caspase 3 for proapoptotic agents). For many studies this will be of an exploratory nature. Finally, the surgical specimen should have the residual cancer burden characterized and quantified using a validated index such as that of Symmans et al. (24). Tissue sampling and handling is critical and representative biopsies at the time of surgery to maximize quality and ensure adequate quantity for both DNA and RNA analysis should be ensured.

Intratumoral Heterogeneity

We propose a model based on the premise that intratumoral heterogeneity (ITH) is responsible for treatment resistance in a significant proportion of primary tumors (25). Partial response to PST may be due to the preexistence of a subclonal population within the primary which is selectively favored by the successful treatment of a competing subpopulation.

Ten subtypes in 2000 primary breast cancer samples based on an integrated analysis of whole genomic copy number aberration and gene expression were described (26) and accounted for interpatient variation in breast cancer type. However, breast cancer heterogeneity has also been recognized to exist within patients when the molecular phenotype of the primary cancer is compared with metastatic deposits at sites remote to the breast (27). Several studies comparing receptor expression between paired biopsies have shown an altered phenotype at metastatic sites including axillary nodes, with either a reduction or loss of ER expression in up to 35% of tumors, and gain of HER2 in up to 10% of ER-positive breast cancers (28–30). By the time of clinical diagnosis, a primary breast cancer may comprise at least three or four detectable significant subclonal populations of cancer cells (31–34). The clinical significance of such underlying genetic ITH, is that it is postulated to be the main source for heterogeneity across different (metastatic) sites and to be a major mechanism of acquired resistance to treatment (25,35). While it was thought that treatment might lead to clonal selection of a resistant cell population which then metastasizes, it is more consistent with current evidence that ITH at the primary site, present before treatment, arising during cancer evolution, already exists (36,37). Particular subclones metastasize, survive, and develop into manifest recurrence at distant sites. The primary cancer site may act as a clonal “source” from which different subclones originate and disseminate to form heterogeneous metastases.

Changes in clonal composition could be monitored during treatment to predict and anticipate development of drug resistance (38) and allow early modification of treatments before clinical progression occurs.

Next generation sequencing techniques may provide detailed analysis of a single or multiple tumor core biopsies performed at different times (eg, before, during, and after treatment) on any number of patients, particularly those with rapidly acquired and clinically recognized treatment resistance—manifest by residual disease.

Biopsy with a view to DNA sequencing and resolution of cellular (subclonal) populations will lead to an understanding of not only the primary tumor characteristics at diagnosis, but also the effect of drug treatments on the dominant populations and the proportional distribution of subclonal populations which the effects of drug treatments may alter.

Genetic ITH has been described in human breast cancer through investigation of ex-vivo cancer specimens, cell lines and mouse xenografts (31). In a study of ITH in 20 breast cancers, almost half (n = 9) were found to be monogenomic (defined as a homogenous population of cells with similar genomic profiles throughout the tumor), the remainder polygenomic (32). In the latter group, the anatomical distribution of the clonal subpopulations was either segregated (localized to one region) or intermixed throughout the tumor. It can be speculated that the latter may account for the “scattered” response seen with PST irrespective of receptor phenotype. For some tumors a single biopsy may be representative of the genetic make-up of the entire lesion whereas for the “segregated” polygenetic tumors, multiple biopsies from different regions may be required.

Currently used indices such as tumor grade, ER, PR, HER2, and Ki-67 and their distribution within a tumor do not necessarily correspond to the presence and distribution of genetic heterogeneity (32).

We suggest that tissue collection taken before treatment and at the time of surgery undergo analysis to compare possibly heterogeneous populations of cells and their relative abundance, by various techniques including fluorescent-activated cell sorting and next generation sequencing with deep exome sequencing. This applies when there is a lack of a complete response to treatment. The nature of the residual tumor and the possible emergence of new subclones is of particular interest. Involved axillary nodes could also be sampled, particularly in the situation where there is a differential treatment response between the primary breast tumor and the axillary nodal metastases.

Resampling and sequencing the residual cancer burden for clonal characterization may eventually lead to rational trialing of additional therapies by switching or combining treatments with those already given. Instead of surgery at the time of either completion of a predetermined number of chemotherapy cycles or after stable disease/progressive disease has been detected, rebiopsy of the residual or resistant tumor to guide further treatment might be the next stage in the evolution of the neoadjuvant testing paradigm (Figure 1).

Figure 1.

A generalized, hypothetical schema for neoadjuvant testing of multiple novel agents. Drug A is a standard therapy (eg, endocrine therapy) and Drug B is a novel agent tested in combination with A. Both drugs have a lead-in period (alone) for 2 weeks to permit biomarker study. They are then combined and the four arms are randomized for this purpose. The three combination arms can then be recombined after the initial biomarker analysis. Rebiopsy at the end of the regime is undertaken instead of definitive surgery. If residual disease is present, the patient can be further randomized to test one or more agents (or against a standard agent). Tissue biopsy may include study of tumor heterogeneity and blood is taken at multiple time points for circulating markers (circulating tumor cells and plasma nucleic acids). pCR = pathological complete response; RAN = randomization.

Figure 1.

A generalized, hypothetical schema for neoadjuvant testing of multiple novel agents. Drug A is a standard therapy (eg, endocrine therapy) and Drug B is a novel agent tested in combination with A. Both drugs have a lead-in period (alone) for 2 weeks to permit biomarker study. They are then combined and the four arms are randomized for this purpose. The three combination arms can then be recombined after the initial biomarker analysis. Rebiopsy at the end of the regime is undertaken instead of definitive surgery. If residual disease is present, the patient can be further randomized to test one or more agents (or against a standard agent). Tissue biopsy may include study of tumor heterogeneity and blood is taken at multiple time points for circulating markers (circulating tumor cells and plasma nucleic acids). pCR = pathological complete response; RAN = randomization.

Tissue Collection for Research

Modern biopsy devices, particularly those capable of single-pass multiple biopsy acquisitions with vacuum assistance to minimize patient discomfort and maximize accuracy of biopsy placement (and avoidance of multiple passes which require relocalization for each one) should be utilized in this setting. Such devices may increase patient compliance and reduce risk compared with devices such as the older spring-loaded single fire biopsy ones. Use of such devices at diagnosis may reassure patients regarding the need for further biopsies, particularly when consenting to clinical trials of PST.

Patient Decision Making

With the surgeon as the initial team member at or after diagnosis of breast cancer, patients will be guided by advice given, as they perceive the surgeon to be the pivotal member of the team. The surgeon who not only supports but also advocates chemotherapy as initial treatment instead of surgery might find greater patient acceptance of chemotherapy compared with the adjuvant setting (39).

This is an opportunity to educate patients about the potential advantages of PST. These include conversion of mastectomy into breast conservation or a reduction in the extent of surgery in BCT resulting in enhanced oncoplastic outcome and aesthetic results. Furthermore, a neoadjuvant approach for patients who are still advised to undergo mastectomy (eg, germline carriers of BRCA1 or 2 mutations) may be subject to reduction in complications from immediate reconstruction if chemotherapy is completed before surgery and adjuvant radiotherapy is deemed unnecessary. Patient acceptance may in part be due to the clinical and radiological objective responses seen with PST which in the adjuvant setting is difficult for patients to comprehend. In fact, adjuvant systemic therapy is a “blind” procedure as it is given after the only opportunity to monitor treatment effectiveness has been eliminated.

The effect on potential micrometastatic disease can still be emphasized in the PST setting especially when objective tumor response is seen. Furthermore if tumor progression or lack of objective response occurs, switching agents (eg, from the standard anthracycline-based to taxane-based regime) may provide some reassurance. The early truncation/cessation of a full regime which is seen to be ineffective may also reassure patients that they are not receiving excessive potentially solely toxic treatment.

A surgeon endorsing such an approach to treatment and supporting the medical oncologist may give patients the reassurance to participate and comply more fully.

Conclusion

Despite the aim of minimizing the extent of surgery and its unwanted side-effects, surgeons need to adopt an increasingly active and interactive role in the PST setting. This includes patient selection, biological assessment of the tumor, monitoring response to standard regimes and newer agents in the clinical trial context as well as determining the most efficacious form of definitive surgery on completion of treatment. Closer engagement and regular collaboration with radiologists, pathologists, and medical oncologists will greatly facilitate this to optimize long-term patient outcomes.

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