Seminars in Oncology
Volume 37, Issue 1 , Pages 1-10, February 2010

Residual Disease After Neoadjuvant Chemotherapy for Breast Cancer

Article Outline

 

Locally advanced breast cancer is a clinical quandary for which there is no standard treatment regimen. Often, preoperative chemotherapy regimens are chosen from proven regimens recommended for the adjuvant setting, as accepted by national panels. There are several accepted characteristics of breast tumors that may predict greater response to neoadjuvant chemotherapy, including phenotype, nuclear grade, and proliferation index. The following cases illustrate two clinical situations in which the neoadjuvant chemotherapy given yielded partial to near complete responses, yet left questions for the clinician regarding the optimum approach to best reduce the risk of recurrence.

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Case No. 1 

A 41-year-old woman presented with a 3-week history of erythema in the inner aspect of the right breast, associated with tenderness but no palpable mass or nipple discharge, no history of trauma to the breast, and no history of previous breast imaging. Family history was positive for breast cancer in her mother at age 37, and in her maternal aunt at age 80, with no family history of ovarian cancer. Examination revealed a well-defined area of light erythema measuring 13 × 16 cm, with mild tenderness and mild peau d'orange, without palpable discrete mass and no inversion of the nipple; there was no clinically palpable axillary lymphadenopathy. Bilateral mammogram and ultrasound imaging were negative for abnormality. She underwent 2 weeks of antibiotics and anti-inflammatory medication without change in the erythema. A magnetic resonance image (MRI) of the breast then revealed a spiculated mass lesion with abnormal enhancement, 3.5 × 2.0 × 1.3 cm, with multiple small satellite lesions, significant skin thickening, and edema, and axillary lymphadenopathy. A mammotome core needle biopsy of the area of erythema was positive for invasive ductal carcinoma (Figures 1A and 1B), nuclear grade 1 of 3, estrogen receptor (ER) 90% positive, progesterone receptor (PR) 30% positive, Her-2-neu–positive by immunohistochemistry, and no Her-2-neu gene amplification by fluorescence in situ hybridization (FISH). The patient underwent six cycles of neoadjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC), with complete response in the skin of the breast, and follow-up MRI showed no evidence of residual disease from the prior spiculated mass or satellite lesions and no area of skin enhancement. She underwent unilateral mastectomy that showed no evidence of disease in the primary breast specimen, but metastatic adenocarcinoma in two of nine lymph nodes, the largest measuring 0.7 cm (Figures 2A and 2B). She was offered postmastectomy radiation and adjuvant hormonal therapy.

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  • Figure 1. 

    (A) Original core biopsy at low power; hematoxylin and eosin stain (H&E), 100X. (B) Original core biopsy at high power; H&E, 400X. Courtesy of James C. Steinmetz, MD, Department of Pathology, Moses Taylor Hospital, Scranton, PA

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  • Figure 2. 

    (A) Residual ductal carcinoma in lymph node; H&E, 100X. (B) Residual ductal carcinoma in lymph node; H&E, 400X. Courtesy of James C. Steinmetz, MD, Department of Pathology, Moses Taylor Hospital, Scranton, PA.

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Case No. 2 

A 54-year-old woman self-palpated a left breast mass 2 months prior to presentation. Mammogram and ultrasound imaging were negative, but breast MRI showed extensive enhancement of the left breast with skin thickening and edema laterally, with spiculation in the posterior upper outer quadrant but without chest wall involvement. A core biopsy of the area showed poorly differentiated infiltrating mammary carcinoma with allomorphic lobular carcinoma (Figures 3A and 3B), grade III, and triple-negative phenotype. Physical examination revealed an 8- × 4-cm breast mass and mild inversion of the nipple, without peau dorange or palpable axillary lymphadenopathy. Metastatic workup including computed tomography (CT) and positron emission tomography scans was negative; she had no neurologic symptoms. The patient was treated with four cycles of dose-dense AC with pegfilgrastim support followed by four cycles of paclitaxel, and had a complete clinical response with no further palpable tumor. Follow-up MRI of the breast showed no evidence of residual abnormal enhancement but persistent architectural distortion. At mastectomy there was a small focus of residual invasive lobular carcinoma (Figures 4A and 4B), approximately 1 cm in diameter, grade III, with lymphovascular invasion, multiple foci of atypical lobular hyperplasia, and one of 17 lymph nodes dissected showed a minute focus of metastatic carcinoma 0.2 mm in size, classified as isolated tumor cells (Ni+) (Figures 5A and 5B). The patient was offered postmastectomy radiation to the chest wall and axillary area, concomitant with capecitabine for residual disease. Three weeks after the mastectomy, the patient presented with increased left leg pain and sciatica, decreased ability to ambulate, and failure to thrive. She was unable to undergo MRI of the CNS due to clips placed at the mastectomy site, and thus was evaluated for CNS metastasis by CT of the head and spine, which were negative. However, a lumbar puncture revealed carcinomatous meningitis.

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  • Figure 3. 

    (A) Original core biopsy at low power; H&E, 10X. (B) Original core biopsy at high power; H&E, 40X. Courtesy of Hasam Hamati, MD, Department of Pathology, Mercy Hospital Health Partners, Scranton, PA.

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  • Figure 4. 

    (A) Fibrotic breast tumor post-treatment at low power; H&E, 10X. (B) Fibrotic breast tumor post-treatment at high power; H&E, 40X. Courtesy of Hasam Hamati, MD, Department of Pathology, Mercy Hospital Health Partners, Scranton, PA.

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  • Figure 5. 

    (A) Residual ductal carcinoma in lymph node; H&E, 10X. (B) Residual ductal carcinoma in lymph node; H&E, 40X. Courtesy of Hasam Hamati, MD, Department of Pathology, Mercy Hospital Health Partners, Scranton, PA.

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Medical Oncologists' Expert Opinions 

Case No. 1 

Residual disease at the time of surgery following administration of preoperative chemotherapy presents a therapeutic dilemma for many physicians. Based on the results of many neoadjuvant trials in which subset analyses demonstrated poorer overall survival for patients that have a partial pathologic response versus complete pathologic response, many clinicians continue to question the role of postoperative therapy in this setting.

At this time, there are no practice guidelines supporting the role for postoperative chemotherapy following completion of a course of standard chemotherapy in the preoperative setting. Of course, these guidelines are exclusive of completion of a standard course of targeted therapy including trastuzumab and/or endocrine therapy.

Hopefully clinical trials such as the Dana Farber–led postoperative study of bevacizumab in conjunction with metronomic cyclophosphamide and methotrexate in patients who have residual cancer in either the breast or lymph nodes following preoperative chemotherapy will help elucidate the role of sequential preoperative and postoperative chemotherapy. This study also will be assessing the contribution of diet and exercise on breast cancer outcomes.

Although this patient remains at high risk of recurrence, at this time there is no role for postoperative chemotherapy. Postoperative radiation therapy and endocrine therapy remain the standard of care. The future focus of her care should include prevention strategies such as genetic counseling.

Case No. 2 

Meningeal carcinomatosis is a rare metastatic complication of breast cancer occurring in approximately 1% to 3% of patients.1 Standard treatment options include intraventricular chemotherapy and/or radiation therapy. Data suggest that the most important prognostic factor is the performance status. Patients with a Karnofsky performance score (KPS) >70 survived longer (range, 8–58 weeks) than those patients with a KPS <70 (range, 3–10 weeks).2, 3 Data support symptomatic treatment and palliative care for most patients in this setting. A more aggressive approach including intraventricular chemotherapy or craniospinal radiation may be more appropriate for patients with few limitations from the disease. Other prognostic factors described in the literature include cerebral spinal fluid glucose <2.5 mmol/L and protein 0.51 to 1.0 g/L may reliably predict survival times independent of therapeutic intervention.1 These clinical data were not provided but may be useful for treatment planning in patients that have a performance status flirting with a KPS of 70.

Clinical benefit from intraventricular chemotherapy within 2 to 6 weeks of initiating therapy is correlated with improved survival. The patient described in this clinical scenario appears to have a KPS minimally less than 70. We do not believe that an empiric trial of intraventricular chemotherapy for several weeks would be inappropriate. Pending her clinical presentation following a 2- to 6-week trial, the patient should continue therapy or transition to hospice.

Patricia Robinson, MD

Department of Medical Oncology

Cancer Survivorship Program

Loyola University Medical Center

Shelly Lo, MD

Department of Medical Oncology

Loyola University Medical Center

Maywood, IL

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Medical Oncologists' Expert Opinions 

Locally advanced disease accounts for a significant number of breast cancer cases and is a common clinical scenario as illustrated in the patient described in case no. 1. During recent years, the treatment of locally advanced breast cancer has evolved from single-modality treatment, consisting of radical mutilating surgery and/or high-dose radiotherapy in inoperable disease to multidisciplinary management, including systemic chemotherapy and endocrine-based therapy. Neoadjuvant chemotherapy has impacted furthermore the management of locally advanced breast cancer by instituting systemic therapy upfront in the patients with a morbid risk of micrometastases. Although neoadjuvant chemotherapy has not yielded significant overall survival benefits, this approach has made breast conservation possible in a selected group of patients.4 In addition to offering the earliest treatment of micrometastatic disease, neoadjuvant chemotherapy also allows for an assessment of whether there is resistance to systemic cytotoxic chemotherapy.

From a medical oncology perspective, this 41-year-old premenopausal female (case no. 1) with a strong family history of breast cancer and with invasive ductal carcinoma, ER/PR+/Her-2-neu–negative who was given six cycles of neoadjuvant chemotherapy with TAC followed by unilateral mastectomy with 2/9 lymph node–positive disease would benefit from postmastectomy radiation therapy and adjuvant endocrine therapy. This approach has been shown to be efficacious in several studies with long-term follow-up including National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-6.5, 6 The choice of neoadjuvant chemotherapy in this situation is important, as we believe the primary goal should be to maximize response with the use of the most effective agents available, namely, both anthracyclines and taxanes. Although there is the option to provide some induction chemotherapy prior to surgery such as AC, and then a taxane after surgery, we believe that based on NSABP B-27,4 maximizing response prior to surgery portends the best survival outcomes. Clearly, this trial showed that the pathologic complete responses were more often obtained in the arm where patients received both anthracyclines and taxanes neoadjuvantly. Therefore we agree with the choice of TAC as the initial regimen to use in this patient.

The question of additional adjuvant chemotherapy remains controversial and somewhat unclear, especially in patients with residual disease after induction chemotherapy. Both the National Comprehensive Cancer Network (NCCN) and the National Cancer Institute (NCI)7, 8 recommend the consideration of additional chemotherapy primarily in the setting of a clinical trial for patients having received neoadjuvant treatment with or without adequate response. In the absence of a clinical trial, it is difficult to surmise or expect an additional benefit from more chemotherapy, and one could only estimate the potential long-term toxicities that patients may suffer, such as a risk of leukemia, etc.9, 10 Therefore, we would not recommend additional chemotherapy in this patient despite residual disease. However, the use of endocrine therapy for decreased risk of systemic relapse is highly preferred and effective. Until clinical trial data reveal benefit to additional adjuvant chemotherapy in patients treated with a neoadjuvant approach, we prefer to rely on our endocrine agents to manage the risk of residual systemic disease.

In case no. 2, the difficulties in managing triple-negative breast cancer are clearly displayed in this 54-year-old woman with poorly differentiated infiltrating mammary carcinoma, ER−, PR−, and Her-2-neu–negative, who was treated with intensive neoadjuvant chemotherapy and found to have residual disease at mastectomy along with 1/17 positive lymph nodes (showing a minute focus of metastatic carcinoma). Despite further treatment with postmastectomy radiation and concurrent capecitabine, she unfortunately progressed with leptomeningeal disease. Although hindsight is 20/20, as stated in our initial discussion above, we would not have offered additional chemotherapy outside the setting of a clinical trial to this patient despite her residual disease after neoadjuvant therapy, especially with a complete clinical response and partial pathologic response. We acknowledge that this case demonstrates the fundamental problem with triple-negative disease, namely, sensitivity to systemic chemotherapy but also higher risk of relapse. However, we question whether any additional treatment (before or after surgery) would have prevented this patient's CNS relapse as the penetration of cytotoxic treatments to this area is reduced due to the blood-brain barrier.11 We furthermore question whether this case was limited stage at all, as it is not clear that she had a pretreatment MRI evaluation of her CNS. Regardless of her pretreatment stage, in the absence of good evidence for further adjuvant therapy, we would have closely followed this patient on observation by assessing her relapse risk with staging evaluations such as periodic PET and/or MRI scans as indicated.

As far as further therapy at this point, we believe that this patient would benefit from a targeted approach such as a poly(ADP)-ribose-polymerase (PARP)-inhibitor (on clinical trial) or an anti–vascular endothelial growth factor (anti-VEGF) treatment such as a bevacizumab-based regimen. At the 2009 Annual Meeting of the American Society of Clinical Oncology, O'Shaughnessy's plenary presentation on the efficacy of PARP-inhibitors in triple-negative metastatic breast cancer when combined with a platinum-based regimen (carboplatin and gemcitabine) was remarkable with a noted significant improvement in response rate and overall survival.12 There is also a role for angiogenesis inhibition in the treatment of patients with CNS involvement as evidence by the efficacy of this approach in glioblastoma multiforme. In this patient who progressed with initial standard chemotherapy, we believe that a targeted approach with a regimen such as paclitaxel and bevacizumab or docetaxel and bevacizumab may be quite efficacious, although enrollment on a clinical trial is highly preferred.13, 14 Hopefully, future investigations will reveal other targets in triple-negative breast cancer that will give our patients more effective and less toxic options in both the metastatic and adjuvant settings.

Thomas A. Samuel, MD

MCG Clinical Breast Cancer Program

Department of Medicine-Hematology/Oncology

Developmental Therapeutics Program, MCG Cancer Center

Medical College of Georgia

Asad A. Sheikh, MD

MCG Division of Hematology/Oncology

Medical College of Georgia

Augusta, GA

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Medical Oncologists' Expert Opinions 

In both of these cases the extent of the disease is not readily apparent in the tests or the physical examination. Inflammatory breast cancer is often likely to be metastatic even when the usual tests are negative. In the second case, the tragic course of events and development of carcinomatous meningitis was certainly not evident initially. Aggressive therapy is indicated in both of these cases. Since the first patient had ER+ disease, the adjuvant hormonal treatment is certainly reasonable. Sometimes years of disease suppression can be obtained with hormone treatment. The fact that in case no. 1 the patient is 41 years old will influence the type of treatment. A selective estrogen receptor modulator (SERM) is indicated in the premenopausal group and an aromatase inhibitor in the postmenopausal groups. If there was a question, hormone levels could be checked along with a follicle-stimulating hormone (FSH) level. It has not been routine practice to use ovarian suppression in premenopausal patients.

Three randomized prospective studies have clearly shown that administering several cycles of two non–cross-resistant regimens preoperatively increases the pathologic complete remission rate from 20% to 30%. Postoperatively, endocrine therapy (ER+ disease), herceptin (Her2-neu–positive disease), and radiation therapy remain the standard of care. There are no data available to support the use of adjuvant therapy in the setting of a primary complete remission after neoadjuvant chemotherapy and surgical resection. If there is discernable residual disease after primary preoperative systemic chemotherapy, preoperative radiation therapy followed by surgery is a reasonable treatment strategy. These patients have a worse prognosis compared with patients who obtain a pathologic complete remission after neoadjuvant chemotherapy. It is becoming more apparent that different types of breast cancer will respond differently to neoadjuvant chemotherapy. For example, ER+ neoplasms have lower clinical and pathologic responses as compared with ER− tumors. The long-term survival of the ER− tumors is better.

W. Edward Jordan, III, MD

Lisa C. Thomas, MD

Hematology & Oncology Associates of NE PA, PC

Dunmore, PA

The Commonwealth Medical College

Scranton, PA

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Radiation Oncologist's Expert Opinion 

Postmastectomy radiation therapy (PMRT) to the chest wall and supraclavicular nodes is considered standard in patients with four or more positive axillary nodes. It is recommended for many patients with one to three positive nodes or with T3 primary tumors.15 In patients with one to three positive nodes, the recommendation for PMRT may be based on patient and clinical factors such as age, number of dissected nodes, presence of extranodal extension, positive deep margins, lymphovascular invasion, or use of systemic therapy, all of which influence the risk of locoregional recurrence. PMRT reduces locoregional recurrence by up to 75%. A >10% benefit in locoregional control leads to a measurable improvement in 15-year survival.6 The risks of modern-day PMRT are rarely serious, but it does increase the risk of fibrosis, which may lead to shoulder and arm mobility problems and/or increased risk of arm edema. In older studies with less attention to technique, survival benefit was countered by increased risk of cardiovascular death.

Neoadjuvant chemotherapy may obscure many of the pathological factors physicians use in making a decision for PMRT. In a good responder, the primary may be small or absent. The number of involved nodes in the axillary dissection may not represent the original axillary status. Inflammatory changes may disappear. Do pathological data obtained after neoadjuvant chemotherapy reflect the true risk of locoregional recurrence after mastectomy? Most physicians would agree that a poor response to neoadjuvant chemotherapy would suggest a role for PMRT. The M.D. Anderson Cancer Center,16 with a large database of patients treated with neoadjuvant chemotherapy, found that both initial clinical stage and pathological stage were important predictors of locoregional recurrence without PMRT. PMRT reduced the 10-year risk of locoregional recurrence from 22% to 8%, including patients with a complete histological response in the mastectomy and axillary dissection specimen.

In the first case, the patient was young; age under 35 or 40 years is associated with a higher risk of locoregional recurrence. She had a large mass on clinical examination and multifocal disease on MRI. There were skin changes suggestive of lymphatic obstruction on clinical and MRI examination. Despite a complete response in the primary, there were two positive axillary nodes. Based on these pretherapy features and the positive axillary nodes, the recommendation for PMRT was appropriate. The second case has a similar story with like pathological features but older age. There was a large mass on presentation, lymphovascular invasion, a good response to chemotherapy, and evidence of axillary involvement, although technically pN0. She presented with a triple-negative grade 3 infiltrating mammary carcinoma. The residual cancer was lobular, a histology that is less likely to respond to neoadjuvant chemotherapy. The recommendation of capecitibine with PMRT is not standard. Its concomitant use, based on data from gastrointestinal malignancies, is often done for unresectable or medically inoperable primary or recurrent disease when the total radiation dose may be limited. Unfortunately, the patient failed rapidly in the CNS, considered a sanctuary site from chemotherapy and more often associated with ER- and PR-, or Her2-neu–positive tumors. As local and distant control improves in the treatment of high-risk breast cancer patients, this phenomenon is increasingly observed and will require study for early intervention in high-risk patients.17

Krystyna D. Kiel, MD

Radiation Oncology

Rush University Medical Center

Chicago, IL

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Radiation Oncologist's Expert Opinion 

Case No. 1 

This patient presents with the classic clinical milieu of inflammatory breast carcinoma. The standard of care would consist of neoadjuvant chemotherapy, modified radical mastectomy, chest wall and regional node radiotherapy, and hormone therapy. This comprehensive treatment plan addresses the patient's advanced disease and multiple avenues for failure. The use of neoadjuvant chemotherapy allows for an in vivo assessment of the tumor's sensitivity to a given cytotoxic regimen and it generally facilitates the subsequent resection. It has been demonstrated that those patients who achieve a pathologic complete response (pCR) have a better prognosis than those who do not.18, 19 The percentage of patients who achieve a pCR varies among series, but for those with T4 primary tumors, is in the general range of 5% to 15%.19, 20 Perhaps counterintuitive, trials comparing neoadjuvant to adjuvant chemotherapy did not reveal differences in the ability to control eventual distant metastatic disease or survival.18, 21 With inflammatory presentations, neoadjuvant chemotherapy remains the preferred standard.

In patients who demonstrate a response to neoadjuvant chemotherapy, modified radical mastectomy is generally performed, followed by chest wall and regional node radiotherapy. The risk of locoregional recurrence is affected by both the pretreatment clinical stage as well as the post neoadjuvant chemotherapy pathologic stage. Data from M.D. Anderson Cancer Center demonstrate that patients with locally advanced breast cancer treated with neoadjuvant chemotherapy followed by mastectomy had significant benefit from radiotherapy in terms of locoregional control as well as survival. Among patients with stage IIIB or IIIC disease, those receiving radiotherapy had locoregional recurrence rates of 15% versus 51% in patients not receiving radiotherapy. Ten-year cause-specific survival rates were also similarly favorably impacted by radiotherapy for patients with T4 disease, stage IIIB or IIIC, or those with four or more positive nodes. On multivariate analysis, the hazard ratio of not receiving radiotherapy were 4.7 for locoregional control (95% confidence interval [CI], 2.7–8.1; P <.0001) and 2.0 for cause-specific survival (95% CI, 1.4–2.9; P <.0001), respectively.22

A “spectrum of disease” model proposed by Dr Samuel Hellman and others attempts to combine both Halstead (aggressive local control) as well as Fisher (breast cancer is systemic prior to presentation) hypotheses. This model suggests that achieving local control of some breast cancers will improve survival by preventing subsequent metastasis. Other breast cancers may have spread hematogenously at diagnosis, and local control in these patients will likely have little impact on survival.23 The “spectrum of disease” hypothesis was validated by the most recent Oxford overview meta-analysis. In this update, we clearly see that better local control at 5 years leads to significant improvements in both cause-specific and overall survival at 15 years. Radiotherapy, chemotherapy, and hormone therapy all impact favorably on local control and this translates into a survival advantage over the long term. In the meta-analysis, the addition of radiotherapy after mastectomy in node-positive patients led to a three- to fourfold reduction in 5-year local recurrence, which translated into a 15-year absolute breast cancer mortality advantage of 5.4% and an overall survival advantage of 4.4%.6 In addition to the contribution of systemic chemotherapy and hormone therapy to reducing local recurrence, these agents given adjuvantly have been shown to decrease metastatic disease and improve survival.24 Therefore, in summary, this patient warrants both aggressive local and systemic therapy to maximize disease-free and overall survival.

Case No. 2 

This patient has the unfortunate diagnosis of carcinomatous meningitis. This diagnosis can be seen in up to 5% of all patients with cancer.25 She presented with a locally advanced breast cancer, and was appropriately offered neoadjuvant chemotherapy for her cT3, clinically node-positive, triple-negative breast cancer. She demonstrated an excellent pathologic response at mastectomy and was being evaluated for postmastectomy radiotherapy to reduce recurrence and improve overall survival. She rapidly declined after mastectomy and was admitted for failure to thrive and decreased function. She had overt evidence of CNS involvement, and this was confirmed pathologically by the positive lumbar puncture.

There is no uniform standard of care treatment regimen for patients with carcinomatous meningitis, but these patients are usually managed by a combination of corticosteroids, analgesics, radiotherapy, and chemotherapy. The details and sequencing of these therapies are variable. All patients warrant corticosteroids to minimize edema and analgesia to address pain. The modalities used are dependent on the performance status of the patient, and the extent of her systemic disease burden. Craniospinal axis imaging with a contrast enhanced MRI is preferred to assess disease burden. In those unable to undergo MRI, contrast enhanced CT would be recommended.

The median survival for these patients is around 3 months, but this varies with performance status, bulk of systemic disease, and primary site. Patients presenting with limited CNS symptoms and systemic disease with a good performance status have a much better prognosis, both in terms of efficacy of palliation as well as survival, than those with advanced disease and poor performance status. For those in the former category, aggressive therapy is warranted to maximize palliation as well as meaningful survival. For these patients, I would recommend tumor-directed radiotherapy in combination with chemotherapy.26, 27 Prior to administering these agents, a nuclear medicine cerebrospinal fluid (CSF) flow study should be done to evaluate any areas of CSF flow obstruction that may warrant radiotherapy targeting. The chemotherapy can range from intrathecal agents, or high systemic doses given with the goal of CNS penetration (ie, methotrexate). This patient is Her-2-neu–negative so trastuzumab would be of little to no benefit. The radiotherapy is generally given first, before chemotherapy, as radiotherapy is more effective at rapidly decreasing symptoms. I recommend focal radiotherapy directed at bulky sites of CNS disease, areas of obstructed CNS flow, or symptomatic sites. This generally involves whole brain and/or partial spine radiotherapy. The usual dose is 30 Gy in 10 fractions, followed by intrathecal chemotherapy. If for some reason the patient cannot receive chemotherapy, then craniospinal radiotherapy would be warranted.

For patients with a poor performance status where a very short survival is expected (ie, <1 month), it is reasonable to treat with corticosteroids and analgesics in hospice care and withhold tumoricidal therapy. These decisions must be made in multidisciplinary fashion with medical and radiation oncologists, primary care physicians, and neurologists with clear communication to the patient and family as to the goals of care.

Christopher A. Peters, MD

Northeast Radiation Oncology Center

Department of Medicine

The Commonwealth Medical College

Scranton, PA

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Summary and Assessment 

These cases illustrate a spectrum of disease response to neoadjuvant chemotherapy, and the need to consider further treatment if there is residual disease, despite predictors of response. In the above cases, there are differential expressions of the broad phenotypes of breast cancers, with greater initial response expected by those tumors which are negative for ER and/or PR, but whose growth is driven by other aggressive cell cycle and transcription signals such as Her-2-neu overexpression, p53 expression, epidermal growth factor receptors, and proliferation index.18 Preliminary preoperative therapy has been patterned after historical NSABP studies, which have demonstrated improved responses after combinations of anthracycline and taxanes have been administered prior to surgery.28, 29, 30 Clinical trials that have sought to incorporate trastuzumab into preoperative treatments for Her-2–positive breast cancers have borne a new standard of care for this subtype.31, 32, 33 However, further clinical trials have attempted to address either new combinations,34, 35 or additional options for those breast tumors that fail to respond to conventional chemotherapy approaches.36 How these treatment regimens may be further chosen and tailored to individuals is a focus of promising research using genomic methods such as chemosensitivity assays,37, 38 molecular profiling,39, 40 and specific molecular expressions.41, 42, 43 These will hopefully add to already existing pathologic criteria for response and prediction of survival thereof.44, 45

The above cases demonstrate the need for further treatment options in the event of residual disease in order to ensure adequate disease control at the microscopic and molecular level. This is the focus of research questions that will employ molecular tools for the individualization of care in the near future. There are currently no additional guidelines for further therapy for triple-negative breast cancer after standard chemotherapy, but incorporation of platinum agents and epidermal growth factor receptor inhibitors have been currently investigated. Further understanding of the biology of this phenotype may stimulate research into specifically targeted therapy.

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PII: S0093-7754(09)00226-7

doi:10.1053/j.seminoncol.2009.12.001

Seminars in Oncology
Volume 37, Issue 1 , Pages 1-10, February 2010

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