Multidisciplinary Approach to Treatment, Emerging Techniques Optimize Survival and Quality of Life for Breast Cancer Patients

As the outcomes for breast cancer continue to improve and patients are surviving longer, the morbidity of treatments has become more apparent. The timing and type of surgery both have huge impacts on the systemic therapies and radiation for which a patient is eligible.

Additionally, we continue to learn more about the heterogeneity of breast cancer tumor biology and further understand that different cancer subtypes require dramatically different treatments. Therefore, a multidisciplinary approach to management in the preoperative setting is important to ensure optimal treatments and outcomes. New technologies also are providing exciting potential to further minimize surgical morbidity.

This article examines the importance of a multidisciplinary approach to breast cancer treatment, developments in axillary management, oncoplastic techniques, and emerging technologies such as robotic nipple-sparing mastectomy and tumor ablation.

Multidisciplinary Approach

Neoadjuvant vs. Adjuvant Systemic Therapy

Treatment recommendations for breast cancer vary greatly depending on the biomarker status of the tumor. Most patients with triple-negative breast cancer (TNBC; negative for estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]) and HER2-positive breast cancers are recommended to undergo chemotherapy first (neoadjuvant) followed by surgery. This is contrasted with ER-positive, HER2-negative breast cancers, which rely on molecular assays sent on the surgical specimen to guide chemotherapy decision-making for patients with early breast cancers.

Systemic therapy regimens for breast cancer have continued to improve. The pathologic complete response (pCR) rate for patients with ER-negative, HER2-positive breast cancers undergoing neoadjuvant chemotherapy in combination with dual HER-2 targeted therapy (trastuzumab plus pertuzumab) is a remarkable 81%.¹

TNBC treated with systemic chemotherapy in combination with pembrolizumab (immune checkpoint blockade) has a pCR rate of 65%.² These rates are contrasted with the low pCR rates for ER-positive, HER2-negative cancers, where pCR rates are under 20% with standard chemotherapy. Emerging data show that adding immunotherapy to chemotherapy for ER-positive, HER2-negative cancers improves the pCR rate, but this has not yet entered standard guidelines as survival data are forthcoming.³ These vastly different pCR rates for different types of breast cancers guide management decisions (see Figure 1).

Even if surgical plans would be unchanged by the downstaging of neoadjuvant treatment, patients with TNBC and HER2-positive breast cancers are frequently eligible for treatments that improve survival if they have systemic therapy in the neoadjuvant setting.

Who Should Be Referred to Medical Oncology Prior to Surgery?

Preoperative medical oncology consultation is recommended for all patients with TNBC, HER2-positive, or inflammatory breast cancer (any biomarkers). Patients with TNBC or HER2-positive cancers over 0.5 cm in size will all require systemic therapy in the neoadjuvant or adjuvant setting.

For early TNBC or HER2-positive cancers that are cT1N0 on all imaging modalities (≤2 cm on magnetic resonance imaging [MRI], ultrasound, and mammogram), patients may receive surgery first as this population is sometimes eligible for a less toxic chemotherapy regimen in the adjuvant setting if early disease is confirmed pathologically. Patients with TNBC or HER2-positive cancer >2 cm in size and/or node positive benefit from neoadjuvant chemotherapy. Making these decisions in conjunction with the medical oncologist is vital.

For ER-positive, HER2-negative cancers, all premenopausal patients with lymph node (LN) involvement or locally advanced cancers should be referred for upfront medical oncology evaluation. In this subset, the decision for surgery first versus chemotherapy first is not as clear-cut as with TNBC and HER2-positive cancers and requires joint decision-making.

At the City of Hope Comprehensive Cancer Center in Duarte, California, we typically proceed with surgery first for most resectable ER-positive, HER2-negative cancers given the low pCR rate and lack of survival benefit with neoadjuvant systemic therapy in this group, unless there is extensive nodal involvement or the likelihood of margin-negative surgical resection would benefit from neoadjuvant therapy.

See Figure 2 for a summary of management recommendations by biomarker status.

Who Should Be Referred to Radiation Oncology Prior to Surgery?

For patients to make the most informed decision, we recommend that all patients meet with radiation oncology prior to surgery, in environments with adequate resources. If this is not possible, the following clinical scenarios represent key situations where preoperative consultation with radiation oncology should be sought.

Patients with a history of prior breast augmentation with implants for whom breast conservation is planned benefit from a preoperative evaluation with radiation oncology to discuss radiation plans and potential risks and morbidity of capsular contracture. As external beam accelerated partial breast irradiation (APBI) has increased in use and additional radiation techniques have developed, depending on the tumor location, size, and nodal status there are often options that can limit radiation to the implant and result in excellent cosmetic and oncologic results with breast conservation. Having these discussions upfront is extremely beneficial.

A second area where radiation plans and options are affected by surgical decisions is when oncoplastic surgery is performed, resulting in larger local tissue rearrangements and affecting the ability to accurately boost the cavity or precluding the patient from receiving APBI. These patients benefit from preoperative multidisciplinary planning between the oncologic surgeon, plastic surgeon, and radiation oncologist.

Another area in which preoperative evaluation is beneficial is when deciding to omit axillary surgery. Choosing Wisely guidelines from the Society of Surgical Oncology (SSO) in 2016 recommended against routine use of sentinel node biopsy in clinically node-negative (cN0) women ≥70 years of age with early stage hormone receptor-positive, HER2-negative invasive breast cancer.⁴

This SSO recommendation was made based on several trials that showed sentinel LN biopsy (SLNB) had no impact on breast cancer recurrence or survival in this population. SLNB results are unlikely to alter recommendations for systemic therapy in this group since all patients will be recommended to take adjuvant endocrine therapy, and chemotherapy recommendations will be guided by molecular tumor profiling, even in the presence of limited nodal involvement. 

Several studies have shown that there is no survival advantage to radiation in patients >70 with early stage ER-positive, HER2-negative cancers with cN0 disease, although there is an increased risk of locoregional recurrence when radiation is omitted.^5,6

However, knowledge of LN status can affect radiation recommendations. Since the studies evaluating APBI versus whole breast irradiation required pathologic staging of the axilla and APBI is not recommended for patients with pathologic nodal involvement, there may be some hesitancy for radiation oncologists to offer APBI or omit radiation in patients without axillary nodal sampling, and they may instead offer the traditional fields targeting the whole breast and lower axilla.

We recommend consideration of nodal sampling in patients >70 with more aggressive tumor biology (i.e., ER-low positive, grade 3, multifocal, lymphovascular space invasion) in which pathologic nodal status may help inform adjuvant therapy decisions. Preoperative discussions with radiation oncology will ensure optimal management.

Axillary Management: When to Do SLNB or Complete Axillary Lymphadenectomy

Techniques to Decrease Lymphedema

As surgeons, we see firsthand the morbidity of complete axillary lymphadenectomy (ALND)–including lymphedema, chronic discomfort, and decreased range of motion. Emerging techniques, including axillary reverse mapping (ARM) and lymphovenous anastomosis (LVA), have shown promise in ongoing and recently reported studies to decrease lymphedema rates. 

ARM is a procedure where dye (such as isosulfan blue) is injected in the ipsilateral arm intraoperatively prior to ALND to identify the lymphatics and nodes draining the arm and attempt to spare these if they are not directly involved with clinical breast cancer metastasis/drainage. A different type of dye is injected in the breast (such as radioisotope) to identify the sentinel nodes and ensure these are not the same nodes as the primary drainage of the arm.

If involved with breast cancer or drainage, then the nodes found during ARM should be removed and the afferent and efferent lymphatic channels re-approximated, if possible. The results of an ongoing phase III trial randomizing patients to ARM + ALND versus ALND alone are expected to provide important information about lymphedema rates and oncologic safety of the ARM procedure.⁷

Another technique that has been developed to decrease lymphedema rates following ALND is LVA. LVA is typically performed by a plastic surgeon using microvascular techniques. Similarly to ARM, LVA involves injection of dye into the ipsilateral arm intraoperatively prior to ALND. After ALND, transected lymphatics draining the arm are identified and anastomosed to a vein located in the axilla. Preliminary results of a randomized controlled trial from Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, showed a significant decrease in breast cancer-related lymphedema of 9.5% following LVA versus 32% without, although we are still awaiting long-term follow-up results.⁸

When to Do SLNB and ALND?

Despite these advances, the ability to de-escalate axillary surgery provides the greatest benefit to decreasing axillary surgical morbidity. 

The practice-changing American College of Surgeons Oncology Group (ACOSOG) Z0011 clinical trial demonstrated the safety of omitting ALND in patients with small-volume axillary disease (cT1-2, 1-2 positive SLNs).⁹

Axillary management has been further de-escalated with Choosing Wisely guidelines for omission of SLNB in women >70 years, as reviewed earlier.

As systemic therapies continue to improve and pCR rates increase, we have found more opportunities to de-escalate axillary surgery. Targeted axillary node dissection (TAD) is a technique where the biopsied axillary nodal metastasis is marked with a seed or wire preoperatively and removed in addition to the radioactive or blue nodes identified using standard SLNB techniques. 

TAD has been used with good results in patients with limited imaging-detected axillary nodal disease (1-2 LNs identified on imaging with no palpable nodes) who are undergoing upfront surgery with breast conservation or mastectomy and meet National Comprehensive Cancer Network (NCCN) guidelines for omission of ALND (cT1-2, 1-2 positive LNs, and planning to undergo adjuvant radiation).¹⁰

Additionally, we use TAD after neoadjuvant chemotherapy in patients with node-positive disease that convert to cN0. Removal of the clipped node has been shown to decrease false-negative rates; therefore, this is the preferred method by surgeons at City of Hope.¹¹ We perform radar seed placement in the LN metastasis prior to the start of chemotherapy, as the abnormal node is more easily identified for seed placement prechemotherapy than postchemotherapy.

The need for excision of the clipped node is a controversial topic and many institutions perform SLNB without localization of the clipped node. If the clipped node is not removed, then the surgeon should obtain three or more nodes, as this has been shown to decrease false-negative rates.¹¹ Using these techniques, we can spare ALND in patients who convert from node positive to pathologically node negative with chemotherapy. This is an additional benefit to neoadjuvant chemotherapy in tumor subtypes with a high pCR rate. 

Another successful area of axillary de-escalation is in patients with recurrent cN0 breast cancer with a history of prior breast conservation and axillary surgery, who historically would undergo ALND at time of surgery for the recurrence. Repeat SLNB has been shown to be successful in 64% to 73% of patients and highly specific with a negative predictive value of 96.5%.^12,13 The NCCN guidelines recommend proceeding with ALND in the setting of failure to map with repeat SLNB.¹⁰

Guidelines for axillary management are summarized in Figure 3.

Impact of ALND on Adjuvant Systemic Therapy

As we de-escalate axillary management, the information regarding THE number of positive LNs is limited, as we are favoring radiation for management of potential microscopic LN involvement in non-sentinel nodes. This has the potential to affect patient eligibility for adjuvant systemic therapies, including chemotherapy and cyclin-dependent kinase (CDK) 4/6 inhibitors such as palbociclib, abemaciclib, or ribociclib. CDK 4/6 inhibitors have been shown to improve invasive disease-free survival and distant relapse-free survival in patients with high-risk ER-positive, HER2-negative breast cancers (≥4 positive LNs or 1-3 LNs and grade 3 and/or tumor size ≥5 cm).¹⁴ Therefore, it is important to ensure joint decision-making with the medical oncologists, although ALND should not be performed for the sole reason for determining adjuvant systemic therapy eligibility.¹⁵

Oncoplastic Surgery

Multiple studies during the past decade have shown a breast cancer-specific survival improvement with breast-conserving surgery (BCS) and radiation when compared with mastectomy (with or without radiation). This was initially thought to be due to selection bias of patients; however, additional studies and analyses have shown a survival benefit even when adjusting for tumor stage, subtype, grade, education level, family income, and country of birth.^16,17

This survival improvement has stimulated the field of oncoplastic surgery, which uses plastic surgery techniques to remove a larger volume of tissue and improve cosmetic outcomes after BCS. By mobilizing and advancing adjacent breast tissue, up to 50% of the breast parenchyma can be resected, depending on breast size and location of the area of resection, while limiting contour deformity. These techniques increase the number of patients who are eligible for BCS. Patients frequently require a contralateral symmetry procedure if larger volumes of breast tissue are removed. 

There are many different techniques for oncoplastic surgery ranging from more basic full-thickness breast tissue re-approximation to reduction mammoplasty.

I favor a staged approach to large oncoplastic surgery procedures and schedule the reduction with a plastic surgeon approximately 2 weeks after the initial BCS and nodal surgery, to ensure negative margins on final pathology prior to large tissue rearrangements, which could make it difficult to identify the affected margin and result in need for mastectomy. 

The timing of the contralateral symmetry procedure depends on the plastic surgeon and patient preferences as there are pros and cons to each option:

• The contralateral symmetry procedure can be performed at the same time as the oncoplastic reduction; however, the ipsilateral breast may further decrease in size after radiation, resulting in future asymmetry.
• Contralateral reduction can be delayed for 6-12 months after completion of radiation, resulting in an initial asymmetry, but improved long-term symmetry after postradiation changes have occurred. 

Emerging Technologies and Future Directions

While there have been impressive advances in the field of breast surgery over the past few decades, there are still opportunities to further decrease the morbidity of our interventions and further improve outcomes. Numerous exciting areas are currently being studied in clinical trials, several of which are reviewed here.

Robotic Mastectomy

Nipple-sparing mastectomies (NSM) have gained popularity due to improvement in aesthetic outcomes. While there are no randomized controlled trials studying NSM versus skin-sparing mastectomy, studies of NSM for prophylaxis and treatment of early breast cancers have shown comparable oncologic outcomes and low recurrence rates. 

A known side effect of NSM is decreased sensation of the nipple and often permanent numbness.  This is thought to be secondary to transection of the nerves that supply sensation to the nipple, in addition to further injury during retraction on the skin flaps during the NSM procedure. During open NSM, the entire breast is removed through a small incision while maintaining perfusion to the skin flaps and nipple. 

This approach has ergonomic implications for the surgeons, who are often trying to maintain visualization under the skin flaps through small incisions. These factors make the concept of robotic NSM appealing since excellent visualization can be maintained using robotic instruments.

Additionally, the surgery can be performed through a hidden 3-cm incision along the anterior axillary line, and there is a question of improved sensation in the flaps and nipples, thought to be potentially related to the benefit of CO2 insufflation instead of manual retraction on the flaps. A criticism of the robotic NSM approach is the question of whether the skin flaps are thicker and if improved sensation is due to the presence of a higher amount of residual breast tissue.

Given these questions, the safety, oncologic outcomes, and patient-reported outcomes are currently being studied in an ongoing prospective, multicenter randomized controlled trial, Robotic versus Open NSM for Early Stage Breast Cancer (NCT05720039).

This trial is sponsored by Intuitive Surgical, and the robotic procedure is performed using the da Vinci Single Port Surgical System. Patients undergo NSM, standard LN evaluation, and reconstruction through a single anterior axillary line incision. Reconstruction is per plastic surgeon preference and can be direct-to-implant or tissue expander placement, followed by later exchange to implant.

Case Report – Figure 4 shows photographs (A) preoperative and (B) postoperative following bilateral robotic NSM with direct-to-implant prepectoral implant placement. This patient is a premenopausal woman who presented with a 1.8-cm right ER 6%, PR-negative, HER2-negative breast cancer diagnosed after self-palpating a mass in the breast. She underwent neoadjuvant chemotherapy plus pembrolizumab with an excellent clinical response.

The patient underwent bilateral robotic NSM with immediate prepectoral implant reconstruction and right SLNB with a pCR. She had an uncomplicated postoperative course and is currently in follow-up per clinical trial guidelines. We are excited to see the results of this clinical trial to determine oncologic safety of the robotic NSM procedure and guide future directions for robotic breast and axillary surgeries.

Tumor Ablation

Cryoablation is a minimally invasive percutaneous technique that uses extreme cold to kill tumor cells under ultrasound guidance. Cryoablation is approved by the US Food and Drug Administration (FDA) for the management of fibroadenomas less than 4 cm in size, as an alternative treatment option to surgical resection or surveillance. 

At this time, ablative techniques are not FDA approved for the treatment of breast cancers, but several techniques are currently in clinical trials. Cryoablation has been shown to be highly effective for treatment of breast cancers <1 cm in a multicenter phase II trial that evaluated cryoablation followed by surgical resection of the primary tumor. All <1 cm tumors were completely ablated, as were 92% of tumors ≤2 cm.

Cryoablation is currently being studied as an alternative to surgical resection for small breast cancers in ICE3, a multicenter, single-arm, non-randomized trial of women ≥60 years old with unifocal, ultrasound-visible invasive ductal carcinoma ≤1.5 cm with favorable features (ER-positive, HER2-negative, low-to-intermediate grade) who underwent treatment with cryoablation instead of surgery. Interim analysis at 3 years showed low ipsilateral breast tumor recurrence of 2%.¹⁸

Long-term follow-up and the results of ongoing randomized controlled trials are needed to further evaluate cryoablation as an alternative to surgery for early breast cancers.

In addition to direct killing of the cancer, tumor ablation has been shown to enhance anti-tumor immune responses. This is currently being studied as another method to harness the immune system against cancer.

Other types of ablation also are being studied, including laser ablation.

Future Directions

Advances in immunotherapy, molecular profiling, targeted therapies, and personalization of cancer care have propelled the field and improved outcomes for nearly every type of cancer. These advances have made the multidisciplinary coordination of cancer care even more important, as the different treatment types fit together like a puzzle to improve patient outcomes. 

There is more room to grow to minimize treatment morbidity, further tailor therapy to each patient, and continue to decrease rates of recurrence and cancer-related deaths. Despite major improvements in outcomes for breast cancer over the past few decades, as many as 25%–30% of patients diagnosed with early breast cancer develop recurrence. Ongoing research focuses on how to further harness the immune system to target circulating tumor cells and residual microscopic disease that can result in future local and distant recurrences. 

As surgeons, we are often the first specialist that breast cancer patients see, and our involvement in the multidisciplinary approach to treatment, advancement of surgical techniques, development of less-invasive treatments, and optimization of systemic therapies has the potential to further propel the oncology field forward in our goal of continuing to improve survival and quality of life for breast cancer patients.

Dr. Jamie Rand is a surgical oncologist at the City of Hope Comprehensive Cancer Center in Duarte, California, specializing in breast cancer treatment. 

References

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