Online Appendix

Historical Trials

In the first Milan trial, patients with stage IIIA or IIIB breast cancer were given four cycles of doxorubicin and vincristine, followed by 60 Gy to the breast and a 10-Gy boost to the area of residual tumor. Patients who demonstrated a complete response were randomized to either no further treatment or six more courses of chemotherapy. The objective response rate to this neoadjuvant chemotherapy regimen was 89%, the complete response rate was 15.5%, the major (≥50% tumor size reduction) response rate was 54.5%, and the minor (<50% tumor size reduction) response rate was 19%. Of the patients responding to neoadjuvant chemotherapy, 83% had a complete response with the addition of radiotherapy. This combined chemotherapy-radiotherapy approach resulted in an overall 3-year survival rate of 53%.

In 1975, the Milan group began a second trial that ultimately enrolled 277 consecutive patients with stage IIIA and IIIB disease. In this trial, patients received three courses of doxorubicin and vincristine preoperatively. They were randomized to radiotherapy or surgery (radical or modified radical mastectomy) followed by six additional cycles of chemotherapy. The best local control was achieved when surgery rather than radiotherapy was interposed between chemotherapy courses (82.3% vs. 63.9% complete local control rate). Freedom from disease progression was maintained for 5 years or longer in 25% of the patients who received chemotherapy and surgery but in only 4.9% of the patients who received chemotherapy and radiotherapy. Likewise, the overall 5-year survival rate was higher for the chemotherapy and surgery group (49.4% vs. 19.7%).

In 1974 a multimodality treatment protocol for LABC was initiated at MD Anderson Cancer Center to explore whether the combined use of chemotherapy, surgery, and radiotherapy would improve control of micrometastases and reduce local tumor burden in patients with stage III disease, thereby avoiding the need for either radical radiotherapy or radical mastectomy, both of which were standard of care for stage III patients at that time. Between 1974 and 1985, 174 patients with stage III noninflammatory (operable and inoperable) breast cancer were initially treated for three cycles with combination systemic therapy consisting of 5-fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (Cytoxan) (FAC); up until 1978, bacillus Calmette-Guerin (BCG) was also included in this regimen.

After three cycles of neoadjuvant chemotherapy, patient response was assessed with a combination of clinical examination and mammography, and patients were assigned to one of three treatment arms based on clinical response: (1) those who had minimal or no residual disease (i.e., complete responders ) were assigned to radiotherapy only (although it is important to note that, in the early years of the trial, complete responders with large breasts sometimes underwent postchemotherapy, preradiation mastectomy to facilitate delivery of radiation); (2) those who had a moderate response (i.e., moderate responders ) went on to modified radical mastectomy followed by radiotherapy (beginning in 1978, moderate responders also received adjuvant chemotherapy, the regimens for which varied over time, after undergoing surgery and before receiving radiation); and (3) those who had no response or progressive disease (i.e., nonresponders ) went on to radiotherapy, with subsequent surgical resection if their disease was operable. In addition, although surgery alone was not a predetermined treatment arm, a subset of 40 patients underwent surgical resection alone for a variety of reasons including patient preference, patient comorbidities that precluded radiation, development of distant disease before receiving radiation, and provider preference or judgment.

With a median follow-up of 59 months, complete remission was achieved in 16.7% of patients and was more common in stage IIIA patients than in stage IIIB patients (17% vs. 8%); 70.7% of patients had a moderate response after the initial three cycles of neoadjuvant chemotherapy, again with higher rates of response among stage IIIA patients. All but 6 of the 174 treated patients were eventually rendered disease-free after neoadjuvant chemotherapy and local treatment; all 6 of the patients with residual/progressive disease had stage IIIB disease at presentation. Five-year overall and disease-free survival rates for stage IIIA patients were both 84%, whereas for stage IIIB patients, overall and disease-free survival rates were 44% and 33%, respectively. These findings demonstrated significant improvement over historical 5-year survival rates of 30% to 45% for stage IIIA and only 10% to 28% for stage IIIB patients and illustrated the efficacy of a multimodal approach in which systemic therapy mitigated the need for radical local therapy.

Neoadjuvant Chemotherapy

A retrospective study in Nottingham, England, compared outcomes in 106 consecutive patients with LABC who received one of two neoadjuvant chemotherapy regimens: an anthracycline-based regimen (5-fluorouracil, epirubicin/Adriamycin, cyclophosphamide; i.e., FEC/FAC) or a regimen consisting of mitoxantrone, methotrexate, and mitomycin (MMM). End points of locoregional recurrence, metastasis, and survival were analyzed after a median follow-up of 54 months. All patients underwent neoadjuvant chemotherapy as part of a multimodal approach, which included subsequent mastectomy, radiotherapy, and adjuvant endocrine therapy if tumors were estrogen receptor (ER)-positive. More patients in the anthracycline-based treatment group than in the MMM group had a complete clinical response (24% vs. 9%, P = 0.035). In addition, patients in the anthracycline group had a lower incidence of locoregional recurrence (6% vs. 19%) and distant metastasis (20% vs. 53%) and a higher survival rate (82% vs. 45%), findings that supported the use of anthracycline-based neoadjuvant regimens in LABC.

Although the effectiveness of anthracyclines and taxanes in treating breast cancer has now been demonstrated in multiple trials, these agents are associated with significant morbidity including, but not limited to, neurologic and cardiac toxicities. Thus increasing attention has been devoted to maximizing cure at the population level while preventing overtreatment of the individual through a shift in focus from standardized chemotherapy treatment protocols to patient-specific treatments based on gene-expression signatures. This personalized approach to systemic therapy has been furthered greatly by the development and clinical use of commercially available genomic assays such as Onco type DX, MammaPrint, Mammostrat, and Prosigna, which were developed to assess the appropriateness of chemotherapy in the adjuvant setting in patients with early-stage breast cancer whose initial presentation did not suggest a need for chemotherapy. With increasing confidence in these genomic assays to tailor systemic therapy decisions among early-stage breast cancer patients, these assays are increasingly being tested for utility in tailoring treatment in patients with more advanced disease, in particular in those LABC patients with the ER-positive, HER2/neu-nonamplified disease.

Neoadjuvant Endocrine Therapy

In a phase III trial launched by the European Organization for Research and Treatment of Cancer (EORTC), 410 patients with LABC were randomized to receive radiotherapy alone, radiotherapy plus chemotherapy, radiotherapy plus endocrine therapy, or radiotherapy plus endocrine therapy and chemotherapy. Endocrine therapy consisted of ovarian irradiation for premenopausal women and tamoxifen 10 mg twice daily for 5 years for postmenopausal women. After an 8-year follow-up, the combination of adjuvant chemotherapy with endocrine therapy produced a significant reduction in the risk of locoregional recurrence (from 60% to 47%) and distant progression of disease. Although the combined treatments provided the greatest therapeutic effect, patients who received adjuvant endocrine therapy appreciated a significant improvement in survival with a 25% reduction in the death hazard ratio. Thus current recommendations dictate that premenopausal patients with hormone receptor–positive breast cancer receive at least 5 years of adjuvant tamoxifen, whereas postmenopausal women should receive an aromatase inhibitor, unless otherwise contraindicated based on each agent’s described risk profile (discussed elsewhere in this book). It is important that the clinical team factor patient- and tumor-specific features factor into the complex multimodal treatment equation.

In addition to tamoxifen and aromatase inhibitors, antiestrogen therapies including fulvestrant (which blocks ER and promotes its degradation) and aromatase inhibitors in combination with other agents (e.g., letrozole and palbociclib, a selective inhibitor of cyclin-dependent kinases [CDKs] 4 and 6) have been shown to improve progression-free survival in advanced breast cancer and are used in treatment of locally recurrent and/or treatment-resistant, hormone-sensitive cancers. Furthermore, pharmacologic suppression of ovarian function has also proven to be an important component of endocrine therapy: results published in 2015 from the Suppression of Ovarian Function Trial (SOFT) trial demonstrated that in young women with ER-positive breast cancer who remained premenopausal (determined by estradiol levels) after receiving chemotherapy, ovarian suppression with triptorelin, a gonadotropin-releasing hormone (GnRH) agonist, given in combination with tamoxifen or with an aromatase inhibitor reduced the risk of recurrent breast cancer compared with tamoxifen alone.

Reconstruction Techniques