Systemic Therapy for Breast Cancer

Historical Perspective

The term neoadjuvant therapy for breast cancer is used in a setting where systemic therapy is utilized prior to definitive surgery. Historically, this treatment approach has been reserved for patients who had clinically unresectable disease, or for locally advanced patients who require a mastectomy to appropriately resect the entire tumor. For patients desiring breast conservation, neoadjuvant chemotherapy has been used to convert from mastectomy to lumpectomy for patients who achieve sufficient response. For this purpose, the treatment had been largely limited to the administration of neoadjuvant multiagent chemo therapy and has been largely limited to serve surgical outcomes.

Current Goals of Neoadjuvant Therapy

With the advent of more targeted agents, additional goals of neoadjuvant therapy have been identified. Beyond the surgical goal of transforming a patient for mastectomy to lumpectomy or from unresectable to resectable, the goal of neoadjuvant therapy is now also to quantify the tumor’s response to neoadjuvant therapy to prognosticate short and long-term outcomes, and to delineate adjuvant therapy strategies after surgery. Based on the response achieved, the best adjuvant treatment strategy can be identified with a more aggressive approach in patients who have a suboptimal response, and sparing treatment toxicity for patients with a good response.

With the growing knowledge of the efficacy of systemic therapy for breast cancer coupled with the understanding of the more diminished role of aggressive local therapy, neoadjuvant therapy is also exploring the concept of eradicating axillary disease with systemic therapy. The goal is to minimize the need for aggressive local therapies, such as axillary dissections and comprehensive radiation therapy.

In that, studying the clinical and pathologic response to neoadjuvant therapy has become a very useful clinical trial environment to assess the efficacy of a multitude of new agents, helping us recognize the neoadjuvant treatment response as a surrogate marker for long-term disease control.

This section describes the current state-of-the-art of neoadjuvant therapy in breast cancer with its complexities of patient selection; preoperative clinical, pathologic, and radiographic evaluation; categories of neoadjuvant therapy; post-treatment assessment; and subsequent optimized adjuvant management from a medical oncologic perspective. The principles of the surgical and radiation approach in the neoadjuvant setting are deferred to other specialty-specific chapters within this book.

Primary Tumor

As discussed earlier, neoadjuvant therapy was historically utilized in patients with locally advanced disease, to aid in resectability and achievement of breast conservation. In that, the clinical and radiographic staging assessments have become critical components of our preoperative assessment, and over time have become more complex and specific. Most patients will undergo preoperative mammography and ultrasonography, and many will also benefit from the application of preoperative magnetic resonance imaging (MRI) or contrast-enhanced mammography. This is largely used to optimize the surgical approach and understand the degree of local disease advancement including multifocality, skin, chest wall, and lymph node involvement. The decision whether the patient should undergo surgery first or should be subjected to neoadjuvant therapy is typically at the discretion of a multidisciplinary team including the surgeon, medical and radiation oncologists, pathologist, and of course the patient. In our institutions, these discussions are frequently and routinely held within multidisciplinary tumor conferences or clinics, with the goal of achieving a consensus recommendation for each individual patient.

Patients with locally advanced T3 or T4 breast cancers are typically ideal candidates for the approach with neoadjuvant therapy regardless of the subtype of breast cancer, as they are often not amenable to resection and much less to breast conservation upfront. Furthermore, most of those patients will benefit from systemic therapy due to the high risk of distant disease recurrence, and giving the treatment preoperatively will thus serve both purposes.

Certain patients with more limited disease (typically T1c and T2 tumors) will usually also be referred for neoadjuvant therapy, at least in part to identify patients who would benefit from additional more intensified adjuvant therapy if a complete pathologic response is not achieved. This is particularly true for human epidermal growth factor 2 (HER2) (HER2)/neu-positive and triple-negative breast cancers, who will typically be referred for systemic therapy even in the early-stage setting. These tumors are known to have a very high rate of achievement of clinical and pathologic complete responses.

The role for neoadjuvant chemotherapy in clinically limited ER-positive disease is less clear at this time, since neoadjuvant chemotherapy typically does not yield significant and much less so complete pathologic responses in this setting. For this reason, the use of neoadjuvant endocrine therapy is currently a strong area of research. This area has interestingly been accelerated during the time of the COVID-19 pandemic, in which patients were referred for neoadjuvant therapy to delay definitive surgical intervention even in early-stage disease, as many hospital centers chose to delay nonessential surgeries.

Lymph Node-Positive Disease

Axillary dissections and comprehensive axillary radiation therapy are well known to induce short- and long-term toxicities including lymphedema and restriction of arm mobility. Another goal in utilizing neoadjuvant therapy is to minimize the need for these interventions. The standard approach to patients with lymph node involvement has been surgical and radiation management; however, with the advent of neoadjuvant therapy and effective downstaging of axillary involvement, many patients can be safely managed with limited lymph node removal or sentinel lymph node biopsy alone. This is especially true for breast cancers with a more aggressive histology (HER2/neu-positive, triple-negative) and with relatively limited lymph node involvement (cN1).

HER2/Neu-Positive Disease

HER2/neu-positive disease represents a very specific histologic subtype for the consideration of neoadjuvant therapy, as it meets all discussed criteria for referral for neoadjuvant therapy including resectability, breast conservation, and lymph node downstaging. In addition, this particular subtype of breast cancer has shown exclusive sensitivity to combination HER2/neu-targeted therapy and chemotherapy, achieving high rates of complete pathologic responses, which have been used as surrogate markers for short- and long-term survival outcomes. With that, measurable responses achieved in the neoadjuvant setting can be used to prognosticate the benefit of additional adjuvant therapy, in which setting, patients with complete pathologic responses have excellent outcomes even with de-intensified adjuvant treatment options. Conversely, patients with suboptimal response to neoadjuvant therapy can be approached with more aggressive adjuvant treatment, aiding in improved long-term outcomes. This means that the neoadjuvant arena for HER2/neu-positive disease can often be utilized as a training ground to understand the patient’s biology of the tumor, and to aid in treatment selection after surgery.

Timing of Surgery

In certain circumstances, neoadjuvant therapy can be utilized to delay definitive surgical intervention. This has especially been true in our institutions during the COVID-19 pandemic, during which elective surgeries were deferred to minimize potential exposure and preserve valuable hospital resources. Furthermore, patient-specific characteristics sometimes dictate a medical delay before a patient can safely undergo an invasive procedure (for instance, thromboembolic events / recent pulmonary emboli, pregnancy, recent myocardial infarction, etc.). In both patient- and healthcare-specific settings, neoadjuvant therapy can be utilized to effectively treat the primary malignancy while safely delaying the surgery.

Pathology

Understanding the patient’s histopathologic and immunologic pathology is paramount in predicting the patient’s likely response to neoadjuvant therapy. This includes assessment of the estrogen and progesterone receptor (PR) status, HER2/neu assessment, as well as the grade of the tumor. At our institutions, Ki-67 assessment is also the standard of care in the pathologic assessment of breast specimens. In some cases, preoperative assessment of molecular profiling (Oncotype, MammaPrint) can be useful in patients with ER-positive disease, particularly if it is unclear if the patient will or will not benefit from systemic chemotherapy (for instance, postmenopausal patients with ER-positive T1c or T2 tumors and cN0 or cN1 disease).

Radiology

The preoperative assessment of the clinical stage of breast cancer is paramount for the clinical and radiographic assessment of the stage of the disease, and should always include mammography and breast ultrasound. In most cases, pretreatment MRI is also routinely obtained in patients considered for neoadjuvant therapy in our institutions to aid in the assessment of local extent of disease and to assess for presence of multifocal disease, chest wall involvement, and more locally advanced lymph node involvement. This is especially true for patients who present with a lobular histology, as often mammography and ultrasound may underestimate the extent of this disease. It needs to be understood that pretreatment MRI is afflicted with a higher rate of false-positive findings and has shown to lead to a higher rate of mastectomy, including bilateral mastectomy, without apparent improvement in outcomes. With that, the benefit of pretreatment MRI needs to be juxtaposed to its potential risks and carefully evaluated with each patient.

All disease identified radiographically should undergo biopsy (primary tumor, lymph node) via fine-needle aspiration or core needle biopsy. At the time of biopsy, a radiopaque clip is placed that can be traced throughout the trajectory of therapy and will be removed surgically at the time of their definitive intervention. These clips are extremely useful, especially in patients who achieve significant or complete radiographic and pathologic responses, as they guide the surgical approach but also point the pathologist to the area within the histologic specimen previously involved by cancer.

Lymph Nodes

The assessment of lymph nodal status prior to the administration of neoadjuvant therapy is useful for surgical planning and is often used to select the appropriate neoadjuvant systemic treatment. To assess the lymph nodal status, we perform a clinical assessment as well as a comprehensive axillary ultrasound of all patients with a primary breast cancer diagnosis. As discussed earlier, most of those patients also undergo pretreatment MRI at our institutions. Any suspicious axillary lymph nodal involvement will require biopsy evaluation, at which time a radiopaque clip is placed, and the affected lymph node is targeted for surgical excision at the time of definitive surgery even in the setting of complete radiographic response. For patients with lymph node involvement proven by biopsy and with a clip in place, we require that the marked lymph node is removed at the time of definitive surgery in addition to sentinel lymph node biopsy. Prospective clinical trials have shown that the removal of the marked node will lower the false-negative rate of sentinel lymph node biopsy alone. Unfortunately, the marked node is present only about 75% of the time in a routine sentinel lymph node biopsy, and with that we favor preoperative localization of the marked lymph node, either via wire localization or using newer techniques, including Savi scout.

Chemotherapy

Just like with any other neoadjuvant therapy, the purpose of neoadjuvant chemotherapy is to fulfill the goal of reducing the risk of distant recurrence, downstaging the primary malignancy, and providing clinical information of the tumor’s responsiveness to the chosen regimen, which may suggest additional adjuvant treatment options after surgery. Chemotherapy is typically employed in ER-positive/HER2/neu-negative disease and in triple-negative breast cancer; however, it needs to be recognized that neoadjuvant endocrine therapy is an evolving field that is rapidly gaining popularity. HER2/neu-positive breast cancers are approached with a combination of HER2/neu-targeted treatment and chemotherapy. Recent approvals of neoadjuvant immunotherapy in combination with chemotherapy have been achieved in triple-negative breast cancer. This is a testament to the fact that the neoadjuvant treatment arena is currently considered a very fertile area for research and the standard of care is rapidly changing and evolving.

This section is dedicated to the approach to patients who present with HER2/neu-negative breast cancer and for whom neoadjuvant chemotherapy is chosen.

The regimen selection for neoadjuvant chemotherapy for an estrogen receptor (ER)-positive but HER2/neu-negative breast cancer typically centers around one paradigm question: to utilize or not to utilize an anthracycline. This choice is typically informed by the results from the Anthracycline and Breast Cancer study, which evaluated anthracycline-based regimens in comparison to six cycles of Docetaxel and Cytoxan in the adjuvant setting. The detailed subgroup analysis of this study showed that the addition of an anthracycline typically only benefits patients with triple-negative disease or patients with four or more positive lymph nodes with ER-positive disease.

Accordingly, patients with limited (one to two axillary lymph nodes [ALNs]) disease and ER-positive presentation are typically approached with an anthracycline-free Docetaxel- and Cytoxan-based neoadjuvant approach; however, more locally advanced ER-positive patients do receive neoadjuvant Adriamycin, Cytoxan, and Taxol (administered either in the dose-dense fashion or for 12 weekly doses). However, the ECOG 1199 clinical trial showed that docetaxel given every 3 weeks is at least equivalent to the weekly administration of Taxol in the adjuvant setting and would be considered a very reasonable alternative to the typical weekly or dose-dense Taxol approach, especially in patients in whom toxicity considerations around Taxol are concerning.

The neoadjuvant treatment choice for triple-negative therapy has become more complex over the last few years, as the addition of carboplatin and immunotherapy have shown benefit in selected patients.

There is good evidence now that the addition of carboplatin to neoadjuvant therapy with taxanes and anthracycline-based regimens leads to improved complete pathologic response rates.

With that, there is emerging evidence that these improved response rates also translate into improved long-term outcomes including event-free survival, as seen for instance in the double-blind phase III BrighTNess trial, where the 4-year event-free survival improved from 69% to 79% with the addition of carboplatin. However, it needs to be noted that the addition of carboplatin also provides higher hematologic toxicities and higher treatment discontinuation rates. Interestingly, the addition of other chemotherapeutic agents to our backbone of Adriamycin, Cytoxan, and Taxol (for instance, gemcitabine, capecitabine, and bevacizumab) has not translated into clinically meaningful improvements and is not routinely recommended at our institutions.

The very recent addition of checkpoint inhibitor-based immunotherapy to chemotherapy in the neoadjuvant therapy for triple-negative breast cancer has shown significant improvements in desired outcomes, leading to the recent US Food and Drug Administration (FDA) approval of pembrolizumab in this setting. This is discussed in more detail below in the immunotherapy section.

HER2/neu-Targeted Therapy

The previously discussed narrow surgical indications for neoadjuvant therapy do not necessarily apply in the HER2/neu-positive setting, as the response achieved in the neoadjuvant setting significantly influences the choice for treatment after surgery. The achievement of a complete pathologic response is associated with long-term improvement in outcomes, in that it is both prognostic and predictive. In sum, administration of neoadjuvant therapy in HER2/neu-positive disease can help clarify the need for additional intensified (or de-intensified) adjuvant therapy.

In the early-stage setting, neoadjuvant HER2/neu-targeted combination therapy is still indicated for patients desiring breast conservation, who are not initially candidates due to the size of the tumor relative to the size of the breast. Furthermore, patients will benefit from the application of neoadjuvant therapy even in the setting of limited nodal extent in the axilla, in which scenario patients often achieve complete pathologic remission, sparing the need for full axillary dissection. Beyond those two indications for surgical downstaging, neoadjuvant HER2/neu-targeted combination therapy is often used to assess the need for postoperative therapy with trastuzumab emtansine (TDM1), which is only indicated if patients do not achieve complete pathologic responses.

The standard neoadjuvant therapy regimen for HER2/neu-positive disease is six cycles of trastuzumab, pertuzumab, Docetaxel, and carboplatin (TCHP). Owing to the known cardiotoxicity of both monoclonal antibodies, concurrent or sequential anthracycline-based regimens have fallen out of favor, even in patients who have ER-negative disease. Due to the high toxicity afflicted with TCHP, and the high rate of achievement of complete pathologic responses, multiple clinical trials are currently ongoing that are investigating the de-escalation of this regimen. One of those trials is the COMPASS trial, which is investigating four cycles of Docetaxel, trastuzumab, and pertuzumab only, at which time patients are taken to surgery and then further adjuvant therapy is tailored to the degree of response achieved. Our institutions are participating in this trial.

Screen shots demonstrating how this regimen is selected in the EMR are shown in the following seven figures:

New formulations of the monoclonal antibodies targeting the HER2 domain have recently been developed and FDA approved, and are readily available in our pharmacies. These products are available for subcutaneous injection as single-agent preparations for trastuzumab, or as combination preparations for trastuzumab and pertuzumab. These formulations are considered interchangeable to the IV formulations and have quickly become part of our repertoire for patients in the neoadjuvant and adjuvant setting.

An example of the pathway that can be used in this setting is shown below:

Endocrine Therapy

The approach to neoadjuvant therapy with endocrine agents has been studied in both the premenopausal and postmenopausal setting, with significant and notable differences. Much of the comparison of the neoadjuvant approach in treatment (principally chemotherapy vs. endocrine therapy) is based on the toxicity profile and response rates achieved, and many clinical trials are designed around these two endpoints and do not give a lot of information in regard to long-term outcomes such as event-free or OS.

Several clinical trials have shown that neoadjuvant endocrine therapy is inferior in producing high rates of clinical and pathologic response in premenopausal patients. However, this is in contrast to other data that show quite comparable response rates and breast-conservation rates in postmenopausal patients receiving either neoadjuvant endocrine therapy or neoadjuvant chemotherapy, as demonstrated in a meta-analysis including almost 3500 patients. Based on this available data, one can anticipate a response rate to neoadjuvant endocrine therapy in the 60–70% range; however the complete pathologic response rate is only 1–3% after 3 months of exposure. This does not differ significantly from neoadjuvant chemotherapy outcomes for these ER-positive postmenopausal patients. Long-term follow-up in this clinical dataset shows no significant difference in local recurrences, and toxicity rates are significantly improved with endocrine therapy compared to chemotherapy, which is of course not surprising.

Based on this data, neoadjuvant endocrine therapy is typically reserved for patients who are treated in the postmenopausal setting. In the rare setting of a premenopausal patient presenting to our institutions with indication for neoadjuvant endocrine therapy, we typically strive to utilize ovarian suppression (OFS) with aromatase inhibitor (Ai)-based endocrine therapy as our treatment approach.

It is well understood that the full benefit of neoadjuvant endocrine therapy may not be achieved until at least 3–4 months of therapy, and in many instances not until even later. At our institutions, we typically administer neoadjuvant endocrine therapy in the appropriate setting for at least 4 months, and in many settings much longer. Much of the data that was accumulated more recently during the COVID-19 pandemic was driven by the fact that definitive surgical interventions had to be delayed to spare ventilator use in the operating room, and to delay patient exposure to the hospital setting. In that, we have used neoadjuvant endocrine therapy in patients that may otherwise not have qualified for neoadjuvant therapy (e.g., smaller tumors, node-negative disease) and have seen quite significant responses even in small tumors. With that, the indication for neoadjuvant endocrine therapy has broadened and is typically utilized in patients who meet criteria for endocrine therapy and do not have clinical, pathologic, or molecular evidence of benefiting from chemotherapy (Oncotype, MammaPrint), but would benefit from a neoadjuvant treatment approach based on disease extent or based on a desire to delay definitive surgical intervention. The treatment we utilize are AIs, which we use essentially interchangeably in this setting (anastrozole, letrozole, exemestane). Although there is some preliminary data on the efficacy of fulvestrant, this is not routinely used at our institutions in the neoadjuvant setting.

Immunotherapy

The addition of immunotherapy to neoadjuvant treatment has been explored in multiple settings and achieved FDA approval based on the KEYNOTE-522 trial in June 2021.

This trial showed that the addition of pembrolizumab to neoadjuvant multiagent chemotherapy containing Taxol, carboplatin, Adriamycin, and Cytoxan improves the pathologic complete response rates from 51% to 65%, regardless of the PD-L1 status. This translated to a 37% improvement in event-free survival at the subsequent updated analysis, and a measurable benefit was seen across patients with either node-positive or node-negative presentation. With this data emerging, the KEYNOTE-522 regimen has become the standard of care at our institutions, and at this time is considered for all patients fit for this treatment and considered to be good candidates for neoadjuvant therapy in the triple-negative setting.

The IMpassion031 clinical trial utilized atezolizumab in addition to nab-paclitaxel, Adriamycin, and Cytoxan in the neoadjuvant setting, and showed very promising results with respect to improvement in complete pathological response rates that increased from 41% to 58%. This clinical trial was not powered to assess long-term differences in event-free survival rates. This stands in contrast to the NeoTRIPaPDL1 trial, which showed no improvement with the addition of atezolizumab to carboplatin and nab-paclitaxel-based neoadjuvant chemotherapy. With that, atezolizumab is not currently the standard of care in the neoadjuvant triple-negative breast cancer setting at our institutions.

As much as immunotherapy has very recently changed the paradigm in the treatment of neoadjuvant therapy for triple-negative breast cancer, it has also created some additional complexities, including questions in the adjuvant setting after surgery. The KEYNOTE-522 regimen utilizes additional therapy with pembrolizumab in the adjuvant setting, and that competes with other current standards of care that include the recommendation for adjuvant therapy with Xeloda in patients having significant residual disease after neoadjuvant treatment (CREATE-X trial), and adjuvant poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor therapy for patients carrying the BRCA mutation (Olympia trial). This means that adjuvant therapy in triple-negative disease is highly individualized after neoadjuvant therapy followed by surgery. The treatment selection is based on multiple disease and patient-specific characteristics, and is typically managed in consultation with the multidisciplinary team that includes a surgeon, radiologist, radiation oncologist, medical oncologist, geneticist, pathologist, and often a plastic surgeon.