Most of the locally advanced tumors are clinically evident and often have been noticeable for a long period, representing a neglected lesion rather than an aggressive cancer. Psychic fragility, fear and refusal make women avoid seeking medical attention. Sometimes aggressive lesions may have a rapid and subtle growth. Inflammatory signs may initially be misleading and diagnosis of an aggressive tumor may thus be challenging in the absence of a palpable or imaging detectable mass.

Initial work up, after a careful history and complete physical exam, always include bilateral mammography and breast ultrasound to evaluate the extension of the disease within the breast and the presence of multicentric lesions or malignant microcalcifications.

Magnetic resonance may be helpful in determining the extent of the disease, although it may overestimate the real size of the tumor [46], and should always be performed for baseline evaluation if induction chemotherapy is planned [47].

Tissue diagnosis is a priority and requires histological confirmation of an infiltrating lesion, as an extensive ductal carcinoma in situ may be palpable and mislead to the planning of induction chemotherapy, which is not appropriate in this setting. Thus needle core biopsy is preferred over fine needle aspiration cytology. In addition, microhistology by needle core biopsy allows evaluation of hormone receptor status and HER2/neu expression, which are essential for the medical oncologist to plan the chemotherapy regimen.

At the time of needle core biopsy, it may be wise to leave a clip in place which may serve as a marker for future resection, should a complete clinical response occur. Another useful practice is a visual record of the size and site of the lesion with pictures.

Rarely, a large necrotic lesion with a negative needle core biopsy forces an open biopsy to be performed. If skin involvement is present a punch biopsy may prove useful.

Axillary status may be evaluated with ultrasound, which is helpful in detecting apical and infraclavicular involved nodes, which in turn has a relevant prognostic significance. In addition axillary ultrasound may provide a guide for fine needle aspiration cytology of a suspected node, thus providing a clear diagnosis of a positive axilla. Even in experienced hands, ultrasound has at least a 20% false negative rate, because small tumor deposits in a normal node are not detected.

An FDG-PET scan may be useful in determining the extent of axillary involvement and in revealing involvement of internal mammary nodes, that may be involved in as much as 20% of cases, especially in IBC [48].

The best way to stage the lymph node status in the presence of a clinically and imaging negative axilla is to perform a sentinel node biopsy. Sentinel node biopsy accurately stages the axilla even in patients with large or multicentric lesions. It is not indicated in women with IBC due to a very low localization rate. When performed as a single procedure it may be easily performed under local anesthesia and in an outpatient setting. Correct staging of the axilla prior to the pathological changes induced by chemotherapy results in optimal staging and avoids difficulties in lymphatic mapping and possible higher false negative rate of sentinel node biopsy performed after primary chemotherapy [2, 49].

Sentinel node biopsy prior to induction chemotherapy in patients with clinical and imaging negative axilla is the procedure of choice at our institution.

Additional imaging to evaluate for metastatic disease is not standardized and practices vary accordingly. But in the presence of a clinically diagnosed stage III breast cancer, subsequent work-up should always include a bone scan, liver ultrasound and chest x-ray, as about 10% of patients may present distant disease and then would be restaged as a stage IV [50].

Work-up after neoadjuvant chemotherapy is important to estimate the residual disease, but the extent of residual disease may be difficult to assess after induction chemotherapy. Tumor shrinkage after neoadjuvant chemotherapy is better assessed with sonography compared to mammography, but the former exam is operator dependent and not reproducible. Although ultrasound correlates well with complete remission, residual ultrasound abnormalities are not always indicative of residual disease. When both imaging modalities demonstrate no residual disease, likelihood of a complete pathological response has been reported as high as 80%.

Magnetic resonance imaging has been shown to correlate well with pathological findings after neoadjuvant chemotherapy, as it represents the best and most reproducible imaging study to accurately document the occurrence of a downstaging of the tumor [51].

Positron emission tomography is under investigation as an indicator of tumor response [52]. However, current imaging modality is insufficient for assessing complete pathological response.

Primary surgery is an option only in those patients with operable disease, although primary systemic therapy has gained wide favor in locally advanced breast tumors. Patients with inoperable LABC may occasionally require a salvage surgical resection as initial treatment.

Radical mastectomy has long been the treatment of choice, but breast preservation is feasible in some patients who present with LABC. Those with small tumors and clinically advanced nodal disease may be amenable to conservative surgery, as well as those with larger tumor but a good breast to tumor ratio. Patients with poor breast to tumor ratio may still be amenable to breast conserving resection after neoadjuvant chemotherapy has reduced the size of the tumor to a more favorable ratio.

Several studies do report an increase in breast-conservative surgery (BCS) after the administration of neoadjuvant chemotherapy with low recurrence rates, comparable to those after BCS in patients with early stage disease [2, 3, 18, 19, 53]. Still some patients are poor candidates for breast preservation. Patients with multicentric disease, or with extensive malignant or suspect microcalcifications should not undergo breast conservation [49]. Similarly patients with lobular histology, in which the extent of residual disease is difficult to judge, are poor candidates for conversion to breast preserving surgery after neoadjuvant chemotherapy. Moreover, patients with pure invasive lobular carcinoma experience a lesser clinical benefit from induction therapy, presenting a less frequent downstaging and a higher incidence of positive margins after breast conserving surgery, compared with patients having an infiltrating ductal carcinoma.

Among other pathologic characteristics, initial tumor size and nodal status give an increased, but not significant risk of local recurrence, thus do not predict BCS feasibility [18].

Factors mainly associated with an increased risk of local recurrence are advanced lymph node disease (N2 or N3) at initial clinical presentation, residual tumor size > 2 cm, a multifocal pattern of residual disease, and LVI [9, 12]. However, it remains unclear how these factors interact and how to best incorporate these data in the context of clinical decision-making. Differences in reported outcomes between series are likely to be due to a varying selection criteria used to determine BCS eligibility after neoadjuvant chemotherapy. According to their selection criteria, Singletary at the MD Anderson Center found a potential 23% conversion rate in 143 women with LABC who underwent mastectomy having experienced a clinical response (84% partial and 16% complete) after neoadjuvant chemotherapy (Table 12.2) [49].

Careful selection of patients to refer for breast conservation should be undertaken, because downsizing of the tumor may not always allow for a smaller resection. The pattern of tumor regression is somewhat irregular and unpredictable; it does not necessarily shrink concentrically, but it may appear to occur with fragmentation of the mass, either in a concentric or diffuse way. In both cases residual foci of tumor may still be present and occupy an area not smaller then the initial tumor. This phenomenon has been explained as being due to irregular tumor angiogenesis or tumor polyclonality with different exposure and susceptibility of the tumor cells to the drug. Resections that are too limited may be at risk of leaving residual cancer cells, thus an adequate postneoadjuvant surgical resection shall not be much smaller than the initial planned resection. Given this, the real benefit of neoadjuvant chemotherapy in allowing breast conservative surgery is limited and it concerns mainly patients that were borderline for breast conservative surgery before induction therapy.

As a matter of fact, only 5 to 19% of patients deemed as a candidate for mastectomy receive BCS down the line [3, 19, 45]. The randomized study from the NSABP B-18 [19] has demonstrated that only 7% of the women in which a mastectomy would have been the procedure of choice at presentation, were switched to breast partial resection after neoadjuvant chemotherapy. Noteworthy is the observation that, although local relapse was not statistically different in women who had BCS in the adjuvant chemotherapy setting compared to those who had BCS after NACT overall, local relapse was higher among those in whom a BCS was undertaken after an initial indication for mastectomy and after tumor shrinkage by chemotherapy had occurred. Another large randomized trial from EORTC [18a], showed a 23% conversion rate from mastectomy to BCS after NACT. However, at the same time 18% of patients who were planned for BCS prior to NACT, actually underwent mastectomy after treatment. In this trial as well, patients who were initially planned for mastectomy, but were subsequently submitted to BCS because of downstaging of the tumor, had a worse overall survival (HR 2.53; 95% CI, 1.02 to 6.25) compared to patients who underwent BCS accordingly to preNACT planning (Table 12.3).

Other randomized trials comparing preoperative chemotherapy to postoperative chemotherapy reported a similar observation of a higher local recurrence rate in the preoperative chemotherapy treatment arm.

A meta-analysis from nine randomized studies did find a statistically significant 22% increase in the risk for local recurrence associated with neoadjuvant treatment. This risk was greater in those studies where radiotherapy was the only local treatment in patients with apparent complete clinical response [18

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