New Strategies for Locally Advanced Breast Cancer: Inflammatory and Non-Responders: A Review

Abstract

This review explores the new strategies around the management of locally advanced breast cancer (LABC), particularly for non-responsive tumors and/or initially unresectable tumors at diagnosis, inclusive of inflammatory breast cancer. Non-responders to neoadjuvant systemic therapy present a unique clinical challenge. Emerging medical therapeutics in this setting as well as considerations for use of radiotherapy and/or surgery in this setting are discussed. In addition, new treatment approaches for LABC such as neoadjuvant radiotherapy and lymphedema prevention with lymphatic reconstruction are reviewed. These new management strategies aim to improve the survival and quality of life for patients with LABC, while minimizing treatment related sequelae.

Introduction

Locally advanced breast cancer (LABC) is comprised of patients with clinical stage III breast cancer, which includes patients with clinical N2 or N3 disease (matted or fixed axillary lymph nodes, ipsilateral infraclavicular, supraclavicular or internal mammary lymph nodes) with any T stage as well as patients with T4 primary tumors regardless of nodal stage. T4 breast cancer describes a unique subset of breast cancers which are defined as a direct extension of the breast tumor to the chest wall or skin. Inflammatory breast cancer (IBC) is a rare, specific type of LABC and is categorized as T4d by the American Joint Committee on Cancer staging guidelines.

IBC is thought to comprise approximately 2–4% of new breast cancer diagnoses annually in the United States. However, IBC is responsible for 7–10% of breast cancer-related deaths in the United States.¹ This rare but aggressive subtype of breast cancer is associated with a 5-year overall survival of 24.3–67.7% and a 10-year overall survival of 17.8–34.8%, and approximately 20–30% of patients have distant metastasis at the time of diagnosis.^2–4

IBC is characterized by the rapid onset (< 6 months) of erythema and/or edema occupying at least one-third of the breast skin with or without an underlying palpable mass. Obstruction of the dermal lymphatics by tumor emboli leads to these characteristics, which are the hallmark of IBC.³ The findings of IBC can mimic findings of mastitis or other inflammatory processes of the breast, such as cellulitis, and can lead to a delayed diagnosis for many patients.^1,5 Initial recommended screening for IBC patients includes mammography and ultrasound followed by magnetic resonance imaging (MRI) and biopsy.⁶ Mammography has low sensitivity in locating the dominant lesion in IBC, but the addition of ultrasound provides more diagnostic information.⁶ MRI with contrast is the most sensitive method of detecting primary breast lesions, especially in cases that were inconclusive on other imaging, guiding biopsy locations, and assessing tumor response to neoadjuvant therapy.^3,6–8 When comparing the molecular subtypes of IBC versus non-IBC, there is a higher incidence of human epidermal growth factor receptor 2 (HER2) positive and triple-negative breast cancer (TNBC) (40% and 30%, respectively) among patients with IBC.^1,5 There is a lower frequency of hormone receptor positivity in IBC compared to non-IBC tumors, and estrogen receptor-negative IBC tumors often have worse prognosis.^1,3

Standard treatment for LABC is neoadjuvant systemic therapy (NST) followed by surgery and radiotherapy. NST allows for downstaging of the axilla and breast. Additionally, patients with IBC are considered unresectable at the time of diagnosis given the extent of dermal involvement. Regardless of response to NST, conventional mastectomy with removal of all involved skin remains the standard of care for IBC. All patients with IBC are encouraged to avoid reconstruction, as it is associated with higher postoperative complications requiring surgical interventions as well as delays to radiotherapy.⁹ Axillary lymph node dissection remains the standard of care for patients with IBC or who are clinical nodal stage II/III. Patients with LABC who are non-responsive to neoadjuvant therapy pose an issue to surgical management given the extent of skin and/or nodal involvement at presentation. Given IBC is initially unresectable, response to neoadjuvant chemotherapy is imperative.

Defining Response to NST

Prior to definitive surgery, tumor response to NST is formally assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, based upon comparison of imaging findings before and after NST. The 4 categories of response include complete response, partial response, progressive disease, and stable disease (Table 1).¹⁰ Measurable tumor lesions can range from 1 at minimum to 5 at maximum, and target lesions should be those selected with the longest diameter length that produce reproducible repeat measurements.¹⁰ MRI is the preferred imaging modality for following breast lesions in the neoadjuvant setting; neither computed tomography nor mammography is suggested.¹⁰ Pathologic lymph nodes may be included as target lesions only if their short axis measures ≥ 15 mm.¹⁰ The inclusion of pathological lymph nodes was only added in the 2009 revision of the RECIST guidelines. Patients with progressive disease or stable disease are considered to be “non-responders” to NST.

Table 1.

Revised RECIST [Response Evaluation Criteria in Solid Tumors] Guidelines

Complete Response (CR)	No evidence of target lesions; reduction in size of pathological lymph nodes (short axis to < 10 mm)
Partial Response (PR)	Minimum of 30% decrease in the sum of target lesion diameters, using baseline sum diameters as reference
Progressive Disease (PD)	Minimum of 20% increase in the sum of target lesion diameter, using smallest sum as reference, if not baseline; the sum must also have an absolute increase of 5 mm at least; the presence of 1 or more new lesions also counts as progression
Stable Disease (SD)	Does not meet criteria for partial response nor progressive disease, using smallest sum diameters as reference

A prospective study conducted at The University of Texas MD Anderson Cancer Center spanning 20 years reported the typical tumor response of IBC to induction chemotherapy as follows: 12% had complete response, 62% had partial response, 23% had stable disease and 2% had progressive disease.¹¹ The incidence of IBC tumors non-responsive to NST in this study was 25%.

Some studies may even include their own definitions of clinical response, such as the study by von Minckwitz et al. that examined response-guided chemotherapy, and that defined clinical response as a reduction of ≥ 50% in the product of the 2 largest perpendicular diameters of the primary tumor, assessed by palpation, ultrasound, and mammography (not accounting for axillary nodes).¹² In other studies, clinical response is assessed by the physician with physical examination performed before NST, during NST, and after completion.¹³

Definitive response to NST is assessed based upon surgical pathology results. Pathologic complete response is most commonly defined as the absence of invasive or in-situ cancer in both the breast and axillary lymph nodes. Pathologic complete response is often used as a prognostic metric to determine the effect of neoadjuvant therapy and has been associated with improved overall survival and event-free survival.^14,15 The Residual Cancer Burden (RCB) Index is a prognostic tool to assess the burden of residual disease following NST among breast cancer patients. Patients are categorized as RCB-0 (no residual disease), RCB-I (minimal residual disease), RCB-II (moderate residual disease), or RCB-III (extensive residual disease). Patients with higher residual disease burden have been shown to have poorer distant relapse-free survival. Patients with RCB-III are considered to be largely resistant to the therapy they have received prior to surgery. Among stage II-III patients, an estimated 13% will be categorized as RCB-III or “non-responders.”¹⁶

While pathologic complete response has historically been achieved in approximately 20% of all breast cancer patients post NST, pathologic complete response rates are also largely contingent on cancer molecular subtype.¹⁷ Historical data from The University of Texas MD Anderson Cancer Center (from 1989 to 2011) report IBC pathological complete response rates by molecular subtype as follows: 7.4% estrogen receptor positive/HER2 negative, 12% TNBC, 15% estrogen receptor negative/HER2 positive, and 30% estrogen receptor positive/HER2 positive. However, when comparing pathologic complete response rates in IBC versus non-IBC, higher pathologic complete response rates are seen in non-IBC patients, even when stratified for molecular subtype.¹

Standard Therapy: Trimodality

NST regimens vary by tumor subtype. Taxane and anthracycline combination regimens in both non-IBC and IBC cancers result in higher pathologic complete response rates and improved prognosis.^1,5 For locally advanced hormone receptor-positive breast cancer, standard first-line therapy includes Adriamycin/cyclosphosphamide/paclitaxel. Moreover, TNBC cancers have shown improved response to platinum-containing agents.¹⁸ For locally advanced TNBC, first-line therapy includes Adriamycin/cyclophosphamide/paclitaxel/carboplatin and pembrolizumab given as per schedule outlined in the KEYNOTE 522 trial.¹⁹ The integration of trastuzumab and pertuzumab in neoadjuvant chemotherapy for HER2 positive tumors has shown higher pathologic complete response.⁵ Currently, first-line therapy for HER2 positive breast cancer includes Adriamycin/cyclosphosphamide/paclitaxel in addition to trastuzumab and pertuzumab. Another second-line chemotherapy backbone for HER2 positive breast cancer includes docetaxel and carboplatin, and may be considered in patients with high risk for cardiac toxicity. For patients with LABC, as many as 25% may have stable disease or progressive disease while on NST. For this reason, it is very important that patients undergoing NST have routine physical examinations to assess response.

Among patients with IBC who respond to NST, modified radical mastectomy without immediate reconstruction followed by postmastectomy radiotherapy remains the standard of care following completion of NST. Aggressive surgical management of IBC with negative margins allows for locoregional recurrence rates comparable to those of non-IBC patients.⁴ Postmastectomy radiotherapy that includes the chest wall and regional nodal basins (axilla, infraclavicular and supraclavicular fossae, and internal mammary chain), reduces local recurrence rates and improves overall survival benefit.²⁰

Breast cancer-related lymphedema (BCRL) is one of the most feared complications among patients with LABC. In a single-institution study of 83 consecutive patients with IBC who were followed for a median of 33 months, 50.6% of patients developed BCRL at a mean time of 13 months following surgery.²¹ LABC patients are highly susceptible to developing lymphedema, as most patients are treated with taxane chemotherapy, axillary lymph node dissection, and regional nodal irradiation—all of which are independent risk factors for developing lymphedema itself.²¹

Recently, an increasing number of patients with IBC have elected to undergo immediate breast reconstruction in spite of lack of evidence supporting the oncologic safety of this approach. In a single-institution study of non-metastatic T4 patients receiving trimodal therapy, 46% of T4d patients who underwent immediate reconstruction experienced a complication requiring reoperation.⁹ And following immediate reconstruction, IBC patients experienced delays in starting adjuvant postmastectomy radiotherapy.⁹ In light of these data, delayed reconstruction should still be advised for patients with IBC as the standard of care. The majority of women with IBC (68%) never undergo reconstruction. Among those undergoing delayed reconstruction, it was performed at a median 40 months following their initial surgery. Furthermore, breast satisfaction has been demonstrated to dramatically increase following delayed reconstruction in women with IBC.²²

Novel Medical Strategies for LABC Non-Responders

Sacituzumab govitecan-hziy is a humanized monoclonal antibody that targets human trophoblast cell-surface antigen 2 (Trop2) and is conjugated with SN-38, an active topoisomerase I inhibitor.^23–26 When compared to irinotecan, a SN-38 prodrug commonly used for metastatic breast cancer, sacituzumab govitecan-hziy delivers higher levels of SN-38 with a better therapeutic index.²⁴

A prospective phase 1/2 trial by Bardia et al. from 2013–2017 administered sacituzumab govitecan-hziy to a sample of 108 metastatic TNBC patients pre-treated with a median of 3 previous regimens (comprising mostly of taxanes and anthracyclines). The response rate was 33.3%, 2.8% had complete response, and 45.4% had stable disease for at least 6 months. The progression-free survival was 5.5 months and overall survival was 13.0 months.²⁵ The most common adverse event was diarrhea (67%) and neutropenia (64%).²⁵ However, due to adverse events, 3 patients discontinued treatment and 4 patients died during treatment.²⁵

In the phase 3 ASCENT trial from 2017–2019, a sample of 468 relapsed or refractory metastatic TNBC patients were randomized to receive either sacituzumab govitecan-hziy (n = 235) or single-agent chemotherapy (n = 233). All patients included in the trial previously had taxane-based treatment, and 82% had received anthracyclines; the single-agent chemotherapy control was either eribulin, vinorelbine, capecitabine, or gemcitabine based on physician choice. Similar to the phase 1/2 trial by Bardia et al., the phase 3 ASCENT trial saw a significant difference in progression-free survival of 5.6 months for the sacituzumab govitecan-hziy group compared to 1.7 months for the control group (p < 0.001).²³ Overall survival was also significantly longer for the sacituzumab govitecan-hziy group than the control group—12.1 months and 6.7 months, respectively.²³ Objective response in the treatment group was 35% compared to 5% in the control group.²³ Adverse events were consistent with the phase 1/2 trial, most commonly being myelosuppression and diarrhea; the most common adverse event of grade 3 or higher was neutropenia, occurring in 51% of the treatment group and 33% of the control group.²³ Based on these data, consideration for sacituzumab govitecan-hziy in patients with TNBC who are progressing on standard therapy is appropriate.

Trastuzumab deruxtecan (Enhertu) consists of a humanized monoclonal antibody that targets HER2, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor.²⁷ When compared to trastuzumab emtansine, Enhertu has a higher drug-to-antibody ratio while maintaining beneficial pharmacokinetic profile.²⁷

A prospective phase 2 trial from 2017–2019 by Modi et al. investigated the efficacy of trastuzumab deruxtecan in 184 patients with HER2 positive metastatic breast cancer previously treated with trastuzumab emtansine. Objective tumor response by independent central review was 60.9% (6.0% complete response and 54.9% partial response).²⁷ Median progression-free survival was 16.4 months, and estimated overall survival was 86.2% at 1 year.²⁷ 57.1% of patients experienced an adverse event of grade 3 or higher, with the most common being neutropenia.²⁷ Per independent review, 13.6% of patients had interstitial lung disease resulting from treatment, which accounted for 4 deaths.²⁷ Investigators recommended careful pulmonary monitoring during treatment.

In the phase 3 DESTINY-Breast03 trial from 2018–2020 by Cortes et al., a sample of 524 HER2 positive metastatic or unresectable breast cancer patients, non-responsive to previous treatment of trastuzumab and/or taxane, were randomized to receive either trastuzumab deruxtecan (treatment group, n = 261) or trastuzumab emtansine (control group, n = 263). There was a statistically significant difference between both groups in the percentage of patients alive without disease progression at 1 year: 75.8% in the trastuzumab deruxtecan group and 34.1% in trastuzumab emtansine group (p < 0.001).²⁸ Per independent review, 79.7% of treatment patients achieved overall response (either complete or partial), compared to 34.2% of control group patients.²⁸ Among the treatment group, 45.1% of patients had an adverse event of grade 3 or higher, compared to 39.8% of patients among the control group.²⁸ Similar to the findings of the phase 2 trial by Modi et al., the treatment was associated with development of interstitial lung disease and pneumonitis, occurring in 10.5% of patients.²⁸ The ongoing DESTINY-Breast11 trial is currently enrolling patients with early HER2 positive breast cancer, including IBC, to receive either neoadjuvant trastuzumab deruxtecan, trastuzumab deruxtecan followed by Paclitaxel/trastuzumab/pertuzumab, or Adriamycin/cyclophosphamide, followed by Paclitaxel/trastuzumab/pertuzumab.²⁹ The primary outcome of the trial is pathologic complete response.

These new antibody-drug conjugates have shown promise in improving response and survival in patients with previously treatment refractory tumors. Given the increase of adverse effects in these new treatments, an important area of future research is to understand the patient perspective on these treatments regarding tolerability and adherence.

Radiotherapy Strategies for LABC Non-Responders

Patients with IBC and LABC who progress on systemic therapy and are not operable remain candidates for consideration of palliative-intent radiotherapy. Patient with symptoms such as breast pain, bleeding, ulceration, and discharge could be considered for such an approach to improve overall symptom burden. In a single-institution retrospective series of 22 patients with IBC who underwent hypo-fractionated palliative radiotherapy between 2010 and 2016, 59.1% of patients experienced > 70% relief in symptoms after radiotherapy compared with pre-radiotherapy symptoms, 31.8% experienced 30–70% symptom relief, and 9.1% experienced < 30% symptom relief.³⁰ 81.9% of patients demonstrated an objective clinical tumor response to palliative radiation. Similarly, in a retrospective series of 26 women with LABC undergoing palliative radiotherapy. Among those who were able to complete radiotherapy as prescribed, 95% experienced improvement in symptoms and 28.6% experienced a World Health Organization-level reduction of analgesics.³¹

Beyond symptom control, radiotherapy can also be considered to facilitate operability in patients who are not responding to systemic therapy but continue to have no evidence of distant disease. In a single-institution retrospective series of 18 patients with IBC refractory to NST and considered “inoperative”, 12 patients (67%) became operative candidates.³² Similarly, in a prospective series of 14 patients with LABC who remained inoperative after NST, 10 patients became operable after radiotherapy.³³ Surgical intervention for patients with poor response to chemotherapy and/or radiotherapy has been associated with high rates of locoregional recurrence, and wound complication rates of 71%.³⁴ Surgical intervention in this setting should be discussed in a multidisciplinary setting with a focus on the patient’s goals of care.

Recently, neoadjuvant radiotherapy for breast cancer has been proposed as an alternative sequencing approach to allow for immediate breast reconstruction, and to potentially minimize toxicity of radiotherapy and enhance efficacy of systemic therapy. Thiruchelvam et al. conducted a prospective feasibility study (the PRADA study) from 2016–2017 of 33 patients undergoing mastectomy and deep inferior epigastric perforator flap reconstruction in the United Kingdom who received preoperative radiotherapy.³⁵ Of note, these patients were all classified as tumor stage T2, T3, or T4b; patients with IBC were excluded. Eligible patients required mastectomy because they had either aggressive disease with inadequate neoadjuvant chemotherapy response, or positive margins after breast-conserving surgery. At the primary endpoint of 4 weeks post-surgery, 12.1% (4 patients) had an open breast wound larger than 1 cm; only 1 patient had a grade 3 moist desquamation. At 12 weeks post-surgery, no patients had an open breast wound > 1 cm.³⁵

There were no treatment-related deaths, no flap failures, and no local or regional node recurrences within the median follow-up of 23.6 months.³⁵ Breast pathologic complete response was achieved in 21% of patients, and axillary pathologic complete response was achieved in 26%; overall survival was 93.9% and disease-free survival was 84·8%.³⁵ Hence, even in these high-risk patients receiving novel preoperative radiotherapy, morbidity and mortality outcomes were preserved. Furthermore, patient satisfaction, measured by scoring on the BREAST-Q, a validated breast surgery-specific patient-reported outcome measure of satisfaction and health-related quality of life following breast surgery at various follow-up intervals, was 48.0 at baseline, 73.0 at 3 months post-surgery and 77.0 at 1 year post-surgery (with scoring based on a scale of 0 to 100, with 0 indicating low satisfaction and 100 indicating high).³⁵ Given these acceptable outcomes for NART, current clinical trials are evaluating expanded criteria for neoadjuvant radiotherapy to include women with IBC who are not typically offered immediate breast reconstruction.³⁶

New Surgical Strategies

Axillary lymph node dissection in addition to taxane chemotherapy and regional nodal irradiation are all commonly required for LABC, and these treatments greatly increase susceptibility to BCRL. The incidence of BCRL in IBC patients has been reported to be as high as 50.6%.²¹ BCRL is initiated by a disruption in the lymphatic system leading to swelling, interstitial fluid accumulation, chronic inflammation, and fibroadipose tissue deposition; it often develops variably within the first 3 years post-surgery.³⁷ Patients with BCRL complain of pain, impaired mobility and reduced quality of life.³⁷ While lymphedema has no cure, there are several palliative tools to reduce its severity: weight loss and exercise, lymphatic drainage massage, compression bandages, low-level laser therapy, direct excision, and liposuction. Surgical interventions for the management of BCRT include lymphovenous bypass and vascularized lymph node transplantation.

Lymphovenous bypass (Figure 1a and Figure 1b) allows microsurgeons to anastomose lymphatic channels to nearby veins, creating an exit for the lymphatic fluid and thereby decreasing lymphedema symptoms. This procedure has been proven to be safe and tolerable for patients.³⁷ More recently, lymphovenous bypass has been studied in the prophylactic setting in patients at high risk for lymphedema prior to the development of lymphedema. Boccardo et al. termed this approach LYMPHA [lymphatic microsurgical preventative healing approach].³⁸ In their study, which enrolled 74 patients from 2008 to 2012, only 4% patients undergoing LYMPHA developed BCRL. Postoperative lymphoscintigraphy showed patency of the lymphovenous anastomoses lasting 1 to 4 years postoperatively. These findings are further supported by early results from the first randomized control trial examining immediate lymphatic reconstruction versus no immediate lymphatic reconstruction (control group), which enrolled 144 patients between 2020 and 2023. This study found that the cumulative incidence of BCRL was significantly lower among the immediate lymphatic reconstruction group (9.5% at 24 months) versus the control group (32% at 24 months).³⁹

Figure 1.

(A) Lymphovenous bypass under white light: pictured are 2 lymphatic structures anastomosed to a top vein and lower vein branch, respectively. (B) The same lymphovenous bypass under a fluorescein filter: the dye flows through the anastomosis into the vein; the valve of vein is present, which prevents the backflow of blood. (Images courtesy of Dr. Michelle Coriddi of Memorial Sloan Kettering Cancer Center, New York, NY, USA)

Vascularized lymph node transplantation is the transfer of healthy lymph nodes to the affected lymphedematous area; spontaneous lymphangiogenesis then occurs and reconnects the lymphovenous system.^37,40 The transplanted lymph node can be orthotropic (from the region where the dissection was) or heterotopic (from a distal site). Typically, a heterotopic node transplant is either inguinal or omental.^37,40 Inguinal nodes require reverse lymphatic mapping to mitigate the risk of donor site lymphedema.^37,41 Vascularized omentum lymph node transfers (VOLT) have promising outcomes in reducing infectious complications, such as cellulitis, in addition to reducing lymphedema circumferentially.^42,43 There is variability in how some studies have measured lymphedema outcomes, either circumferentially or volumetrically; regardless, a systematic review found that those who used circumferential measurements saw > 90% improvement post-surgery, and that those who used volumetric measurements saw > 86% improvement.³⁷ Like lymphovenous bypass, vascularized lymph node transplantation may have some promise in being used prophylactically, though large studies are yet to explore this.

While it is important to mitigate lymphedema risk among this high-risk population of patients, hope remains for oncologically safe de-escalation of axillary surgery among patients with LABC. Three studies have examined the accuracy of sentinel lymph node biopsy among patients with IBC who have no residual palpable adenopathy after completion of neoadjuvant systemic therapy.^44–46 The false-negative rate of sentinel lymph node biopsy in these studies ranged from 18–25%. Based upon this high-false negative rate, axillary lymph node dissection remains standard for patients with IBC. Similarly, little data regarding the safety of sentinel lymph node biopsy for patients with clinical stage N2/N3 exist.^47–49 Larger prospective studies are needed to explore whether axillary de-escalation is feasible in a subset of patients with LABC who have an excellent response to NST. An ongoing multicenter trial is actively accruing patients with cT4 or N2–3 disease examining the false-negative rate of sentinel lymph node biopsy among patients with no residual clinical adenopathy on examination after NST.⁵⁰

Conclusion

Overall, future advancements—whether they be new antibody-drug conjugates improving neoadjuvant chemotherapy, altering the sequence of trimodality therapy through the use of NART, lymphedema prevention through microsurgical methods, or the possibility of axillary surgery de-escalation —will aim to increase the survival and quality of life for patients while minimizing treatment related sequelae for patients with LABC.

Abbreviations:

LABC

locally advanced breast cancer

IBC

inflammatory breast cancer

MRI

magnetic resonance imaging

HER2

human epidermal growth factor receptor 2

TNBC

triple-negative breast cancer

NST

neoadjuvant systemic therapy

RECIST

Response Evaluation Criteria in Solid Tumors

RCB

Residual Cancer Burden

BCRL

breast cancer-related lymphedema