Systemic therapy for locoregionally recurrent breast cancer

INTRODUCTION — Aggressive multimodality treatment has the potential to provide long-term disease control for many patients who develop an isolated locoregional recurrence of breast cancer. The data involving the role of chemotherapy, endocrine therapy, or human epidermal growth factor receptor 2 (HER2)-directed therapy are discussed in this topic.

Discussions of patterns of relapse and long-term complications of therapy, clinical manifestations of locoregional recurrence, as well as surgery and radiation for locoregional recurrences are found elsewhere.

●(See "Overview of long-term complications of therapy in breast cancer survivors and patterns of relapse".)

●(See "Clinical manifestations and evaluation of locoregional recurrences of breast cancer".)

●(See "Surgery and radiation for locoregional recurrences of breast cancer".)

Follow-up of patients who have been treated for breast cancer is also discussed elsewhere.

●(See "Approach to the patient following treatment for breast cancer".)

EVALUATION FOR LOCOREGIONAL TREATMENTS — For patients with an isolated, locoregional recurrence in the breast, axilla, or immediate surrounding tissues, locoregional treatments including surgery and/or radiation may be offered as part of potentially curative treatment. These are addressed elsewhere. (See "Clinical manifestations and evaluation of locoregional recurrences of breast cancer" and "Surgery and radiation for locoregional recurrences of breast cancer".)

The role of systemic chemotherapy, either prior to or after locoregional treatment, has been controversial and is discussed in the sections below. (See 'Is there a role for chemotherapy?' below and 'Timing of treatment' below.)

IS THERE A ROLE FOR CHEMOTHERAPY?

Approach — Our approach to patients with an isolated locoregional recurrence (ILRR) after breast-conserving therapy (BCT) or mastectomy depends on the receptor status of the recurrence, as well as the prior treatment history. It is summarized in the sections below.

HER2-negative tumors

ER-negative, HER2-negative tumors — We typically recommend adjuvant chemotherapy following tumor resection in women with estrogen receptor (ER)-negative, human epidermal growth factor receptor 2 (HER2)-negative tumors (triple-negative) cancers (TNBC). The rationale is that, in such patients, endocrine therapy is not an option.

The selection of regimen in ER-negative disease depends on whether the patient had previously received (neo)adjuvant chemotherapy, and if so, what regimen they received. There are no data on the choice of specific regimens; in general, we recommend "standard" adjuvant chemotherapy regimens in chemotherapy-naïve cases (eg, an anthracycline- and taxane-containing regimen), and in situations where prior chemotherapy has been given, attempt to offer different regimens if possible. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'General approach' and "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Choice of regimen'.)

ER-positive, HER2-negative tumors

●Decisions regarding chemotherapy for those with estrogen receptor (ER)-positive disease are individualized, taking into account the patient's prior therapy, disease risk factors, and likely benefit from chemotherapy and/or endocrine treatment.

•By inference from clinical experience, patients without prior adjuvant chemotherapy or specific types of chemotherapy (eg, taxanes), with more extensive recurrent tumor burden, with lower levels of ER expression, and with overt resistance to endocrine therapy are more likely to benefit from chemotherapy for locoregional recurrence.

•Additionally, patients with chest wall recurrences have a higher risk of developing distant disease than those with in-breast recurrences, and therefore may derive a greater benefit from chemotherapy. (See "Surgery and radiation for locoregional recurrences of breast cancer", section on 'Prognosis and prognostic factors'.)

●There are no data on the use of genomic signatures such as the Oncotype DX Recurrence Score for selecting patients for chemotherapy in the setting of locoregional recurrence. However, it may be reasonable to use such scores to estimate the likelihood of major benefit from chemotherapy among patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative recurrences.

Choice of regimen — When chemotherapy is indicated for locoregional recurrence in a patient who has not had prior adjuvant chemotherapy, we suggest regimens such as dose-dense doxorubicin and cyclophosphamide/taxane, or docetaxel and cyclophosphamide (TC).

Patients who have had prior anthracyclines are not usually candidates for additional anthracycline-based treatments. Regimens such as TC; cyclophosphamide, 5-fluorouracil, and methotrexate; or paclitaxel and carboplatin do not have cumulative limits to chemotherapy dose, and can be offered. The side-effect experience of the first round of chemotherapy may affect the treatment choice. For instance, patients with significant neuropathy may wish to avoid taxane- or platinum-based chemotherapy.

HER2-positive tumors

●Women with human epidermal growth factor receptor 2 (HER2)-positive tumors at locoregional recurrence should receive a HER2-directed therapy. While there are no large clinical experiences to prove the value of anti-HER2 treatment and chemotherapy in this clinical context, the known value of such therapies in both early- and late-stage breast cancer argue for benefit here, too. (See "Adjuvant systemic therapy for HER2-positive breast cancer".)

•Patients without prior adjuvant chemotherapy or anti-HER2 therapy should receive standard regimens such as docetaxel, carboplatin, trastuzumab, and pertuzumab or docetaxel, trastuzumab, and pertuzumab as for early-stage breast cancer.

•Patients with prior chemotherapy and anti-HER2 treatment should receive different regimens than previously. Those who had not received pertuzumab should have that added to the combination of trastuzumab and chemotherapy. We try to use different chemotherapy regimens, if appropriate, than were given in the initial cycles of treatment.

An alternative would be the use of trastuzumab emtansine. In the KATHERINE trial, trastuzumab emtansine improved on outcomes in women treated with neoadjuvant chemotherapy and trastuzumab but with residual disease at the time or surgery [1]. By inference, such therapy is likely to be beneficial in local recurrence, too. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Patients who were treated with neoadjuvant therapy'.)

Rationale — There are relatively few trials of chemotherapy as "adjuvant" type treatment after surgery and/or radiation therapy (RT) for locoregional breast cancer recurrence [2]. Data from a randomized trial suggest there is a benefit to postexcision chemotherapy for women with ER-negative tumors [3]. However, the role of chemotherapy in this setting for ER-positive disease is less clear. Our approach to such patients is discussed above. (See 'ER-positive, HER2-negative tumors' above.)

In the CALOR trial, 162 patients who experienced ILRR after their initial treatment for breast cancer (including BCT for approximately three-quarters and mastectomy for one-quarter) underwent surgical excision of their recurrent breast cancer and were randomly assigned to postexcision chemotherapy (with the regimen determined by the patient's treating oncologist) or to no chemotherapy (control group) [3]. While all patients were advised to undergo RT, RT was mandatory for women with microscopically involved surgical margins. Patients with ER-positive ILRR received adjuvant endocrine therapy; anti-HER2 therapy was optional.

Of the patients enrolled, the majority had a hormone receptor-positive recurrence (68 percent). Compared with the control group, more women in the treatment group were chemotherapy naïve (42 versus 32 percent, respectively) and premenopausal at the time of recurrence (24 versus 18 percent). A similar proportion of women underwent RT for their ILRR (36 versus 38 percent).

At a median follow-up of nine years, results were as follows:

●Chemotherapy improved ten-year disease-free survival in patients with ER-negative ILRR (70 versus 34 percent in patients treated with or without chemotherapy, respectively; hazard ratio [HR] 0.29, 95% CI 0.13-0.67), but not in patients with ER-positive disease (50 versus 59 percent in patients treated with or without chemotherapy, respectively; HR 1.07, 95% CI 0.57-2.00) [4].

●Overall survival (OS) at ten years in patients with ER-negative ILRR was 73 percent with chemotherapy versus 53 percent without chemotherapy (HR 0.48, 95% CI 0.19-1.20); among patients with ER-positive ILRR, ten-year OS was 76 versus 66 percent, respectively (HR 0.70, 95% CI 0.32-1.55).

These data support the use of chemotherapy in women with breast cancer following resection for locoregional, ER-negative recurrence. However, interpretation of the study is affected by the small sample size, and by the variety of different treatments patients had prior to locoregional recurrence [5]. In addition, there were relatively few events, especially in the ER-positive breast cancer cohort. Therefore, questions about the benefits of treatment based on tumor location (eg, chest wall versus regional nodal recurrence), prior treatment with chemotherapy or RT, or breast cancer subtype (eg, triple negative, HER2 positive, or hormone receptor positive) remain unresolved.

ADDITIONAL SYSTEMIC THERAPY CONSIDERATIONS

Endocrine therapy in hormone receptor-positive disease — There are no randomized trials to address the value of ongoing anti-estrogen therapy in women with locoregional recurrence. However, women with estrogen receptor-positive disease should be treated with endocrine therapy (irrespective of whether chemotherapy was administered), typically a different endocrine regimen than they have been receiving in the past. For example, women previously on tamoxifen may be offered an aromatase inhibitor (AI), if postmenopausal, or ovarian suppression and an AI, if premenopausal. Women previously treated with an AI may be offered fulvestrant, although resuming an AI may be an option for women who wish to avoid monthly injections, particularly those with smaller, node-negative local recurrences that did not occur while on AI therapy.

Although there are limited data to support the benefit of treatment in this clinical setting, treatment is based on the benefits of endocrine therapy observed both in the adjuvant setting and among patients with evidence of measurable metastatic breast cancer. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer" and "Adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer" and "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer".)

The only randomized trial evaluating the benefit of endocrine therapy in the local recurrence setting assigned 167 women with hormone receptor-positive or hormone receptor-unknown, locally recurrent breast cancer (all of whom underwent resection of disease) to tamoxifen or observation [6]. With a median follow-up of 11 years, the median disease-free survival (DFS) following the initial locoregional recurrence was longer with tamoxifen compared with observation (6.5 versus 2.7 years, respectively). This translated into an improvement in the five-year DFS rate favoring tamoxifen (61 versus 33 percent). However, there was no difference in median overall survival in the overall population (11.5 versus 11.2 years, respectively).

Timing of treatment

●While in many cases chemotherapy, if indicated, is administered following surgery and prior to radiation therapy (RT), in certain instances it may be appropriate to administer induction treatment. As examples:

•An initial trial of systemic therapy in patients who have an apparently isolated supraclavicular nodal recurrence can help cytoreduce the tumor burden prior to surgical resection or regional RT. (See "Surgery and radiation for locoregional recurrences of breast cancer", section on 'Isolated supraclavicular recurrence'.)

•For patients with sizable chest wall recurrence that would require an extensive surgical resection, a response to neoadjuvant therapy may simplify the extent of surgery.

●For patients who may receive RT in addition to systemic therapy (eg, following resection of disease), we prefer to administer chemotherapy prior to initiation of RT, as in the adjuvant setting (and in the CALOR trial).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast cancer".)

SUMMARY AND RECOMMENDATIONS

●Systemic therapy can further reduce recurrence risk following successful surgical or radiotherapy treatment of a locoregional recurrence without established metastases. (See 'Is there a role for chemotherapy?' above.)

●The addition of chemotherapy to endocrine therapy in patients with estrogen receptor (ER)-positive disease is less well supported by the limited data available. Addition of a standard adjuvant regimen of chemotherapy to anti-human epidermal growth factor receptor 2 (HER2) therapy is considered appropriate. (See 'ER-positive, HER2-negative tumors' above and 'HER2-positive tumors' above.)

●For patients who have undergone successful treatment of a locoregional recurrence after either breast-conserving therapy or mastectomy, our approach depends on the tumor characteristics and patient preferences:

•For patients with ER-negative disease, we recommend postexcision chemotherapy rather than observation (Grade 1B), and suggest use of a different chemotherapy regimen than was used for the initial cancer (Grade 2C). (See "Overview of the approach to metastatic breast cancer".)

•For patients with ER-positive breast cancer, we recommend endocrine therapy rather than observation (Grade 1B). In general, we suggest use of a different endocrine agent than was used in the initial adjuvant setting (Grade 2C).

The role of additional systemic chemotherapy should take into account patient preferences, given the uncertain benefits of treatment in this situation. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Factors influencing chemotherapy choice' and "Overview of the approach to metastatic breast cancer".)

•For patients with HER2-positive breast cancer, we recommend the administration of a HER2-directed agent (Grade 1B) and suggest use of a different chemotherapy backbone (Grade 2C), when possible. (See "Systemic treatment for HER2-positive metastatic breast cancer".)

●As in the adjuvant setting, we prefer to administer chemotherapy prior to radiation therapy (if indicated) following surgery.

●In some circumstances (eg, an apparently isolated supraclavicular recurrence, a large or initially unresectable chest wall recurrence), we suggest neoadjuvant systemic therapy rather than upfront locoregional therapy (Grade 2C). (See "Overview of the approach to metastatic breast cancer".)