Hung Khong, MD, breast cancer oncologist, Moffitt Cancer Center, underscores the importance of testing for 

 mutations in patients with breast cancer. 

Results from the phase 3 OlympiA trial (NCT02032823) showed improved outcomes when the PARP inhibitor olaparib (Lynparza) was given in the adjuvant setting for patients with TNBC or estrogen receptor (ER)–positive breast cancer that harbors 

 mutations, Khong says. Most patients enrolled to the study had TNBC, although approximately 18% had ER-positive disease, and benefit was seen across both patient populations, according to Khong.

Currently, any patient under the age of 50 years will receive testing for 

 mutations, although those with TNBC are tested for the mutation under the age of 70 years, as well, Khong continues. Based on the positive results from the OlympiA trial, testing patients for 

 mutations is crucial to ensuring that they receive the regimen that could yield the most benefit for them, Khong concludes. 

Videos

Hung Khong, MD, underscores the importance of testing for BRCA mutations in patients with breast cancer. 

Dr. Khong on the Importance of BRCA Testing in Breast Cancer

Hung Khong, MD, a breast oncologist within the Chemical Biology and Molecular Medicine Program at Moffitt Cancer Center, discusses the potential benefit of combining immunotherapy with endocrine therapy in estrogen receptor (ER)–positive, HER2-negative breast cancer.

ER-positive breast cancer is thought to be less aggressive compared with HER2-positive breast cancer and triple-negative breast cancer (TNBC), Khong explains. 

However, ER-positive breast cancer is associated with a longer risk of recurrence versus HER2-positive or, in particular, TNBC, Khong adds. 

If patients with TNBC have not recurred after 5 years, it is rare that recurrence will occur. Conversely, patients with ER-positive disease have a steady risk of relapse up to 30 years after diagnosis, says Khong.

As such, combining immunotherapy with endocrine therapy may offer patients with ER-positive disease long-term disease control, concludes Khong. 

Hung Khong, MD, discusses the potential benefit of combining immunotherapy with endocrine therapy in estrogen receptor–positive, HER2-negative breast cancer.  



Dr. Khong on the Potential Benefit of IO/Endocrine Therapy in ER+ Breast Cancer 

Hung Khong, MD, a breast oncologist within the Chemical Biology and Molecular Medicine Program at Moffitt Cancer Center, discusses antiestrogen and immunotherapy combinations in ER-positive, HER2-negative breast cancer.

When immunotherapy is combined with a different drug in breast cancer, it is typically paired with chemotherapy, says Khong. The phase 2 I-SPY 2 study combined pembrolizumab (Keytruda) with paclitaxel, or other chemotherapies, followed by doxorubicin and cyclophosphamide, for patients with ER-positive disease in the neoadjuvant setting.

However, it is known that in this setting, endocrine therapy works just as well, if not better than, chemotherapy in this patient population. In the United States, there is a great deal of comfort with combining immunotherapy with chemotherapy in the neoadjuvant setting, says Khong, but many studies are demonstrating that endocrine therapy works just as well and with less toxicity. 

Different types of endocrine therapies are available, and the 2 major therapies are tamoxifen and the aromatase inhibitors. Tamoxifen has been shown to shift the T cells from a Th1 to Th2 phenotype and that will be impactful for a cancer treatment combinations, concludes Khong.

Hung Khong, MD, discusses antiestrogen and immunotherapy combinations in ER-positive, HER2-negative breast cancer.

Dr. Khong on Endocrine Therapy Combinations in ER+/HER2- Breast Cancer

Hung T. Khong, MD, medical oncologist, Moffitt Cancer Center, discusses the use of neoadjuvant endocrine therapy.

Neoadjuvant therapy is usually used to downstage tumors so that surgery can be optimally performed. In patients who require a mastectomy, downstaging the tumor can enable a lumpectomy. This can conserve the breast rather than removing the whole breast with a mastectomy. The use of neoadjuvant endocrine therapy can also convert patients with an unresectable tumor to a resectable tumor.

In addition, it can confer longtime survival benefit, says Khong. The side effects are very minimal compared with those seen in chemotherapy. The benefit is very similar to, and in some cases better than, chemotherapy. It’s important to note that the benefit of neoadjuvant endocrine therapy is not inferior to chemotherapy, says Khong.

Dr. Khong on the Benefit of Neoadjuvant Endocrine Therapy in ER+ Breast Cancers

	In May 2005, a 25-year-old female presented to her primary care physician complaining of a newly palpable breast mass that had grown to several centimeters over the course of a few months. A mammogram and ultrasound revealed a 3.6 x 3.4 cm left breast mass with several enlarged and suspicious lymph nodes. Adjacent soft tissue masses in the left axilla were deemed suspicious, ranging in size from 1 to 2 cm each. An ultrasound-guided core biopsy of the breast mass revealed a grade 3/3 infiltrating ductal carcinoma that was estrogen receptor/progesterone receptor (ER/PR) positive and HER2/neu 3 (ie, strongly positive). In June 2005, the patient began neoadjuvant chemotherapy with 4 treatments of dose-dense Adriamycin (doxorubicin) and Cytoxan (cyclophosphamide), followed by 2 cycles of Taxol (paclitaxel). Due to the development of severe peripheral neuropathy, her treatment regimen was changed to 2 cycles of Taxotere (docetaxel).

	The patient completed neoadjuvant chemotherapy in November 2005 and underwent a left modified radical mastectomy, with the final pathology revealing a grade 3/3 infiltrating ductal carcinoma that was 3.2 cm, with associated high-grade comedo-type ductal carcinoma in situ (DCIS). All surgical margins were negative, and final pathology revealed a single lymph node involved with metastatic breast cancer. No reconstruction was performed at that time. She recovered from her operation and then received left chest wall radiation followed by adjuvant tamoxifen and trastuzumab therapy. Deemed responsible for an asymptomatic decrease in her ejection fraction, the trastuzumab was subsequently held for 3 months. Her ejection fraction returned to normal; further investigation showed that the decrease was not due to the trastuzumab, but rather the Adriamycin and possibly the adjuvant chest wall radiation. Trastuzumab was restarted in August 2006 and completed in October 2006, and her last ejection fraction was found to be within normal limits.

	In November 2006, the patient developed new-onset midsternal pain that she described as constant and unrelenting. Analgesics and narcotics were required to achieve adequate pain control. A whole-body position emission tomography-computed tomography (PET/CT) scan revealed an area of intense hypermetabolic activity within the central and distal portion of the sternum, extending to and including the xiphoid process (

). This area was described as an expansile lytic lesion of the sternum with large areas of cortical bone destruction. A bone scan was otherwise negative. Her pain continued to increase in severity and her tamoxifen was discontinued. She was started on anastrazole, an aromatase inhibitor, and leuprolide therapy in an attempt to inhibit further growth of this likely sternal metastasis.

	In March 2007, we proceeded with surgical intervention in collaboration with our cardiothoracic and plastic surgery colleagues. We began with a midsternal skin incision followed by a complete 360-degree circumferential dissection of the mid-distal sternum. This left the manubrium and sternal notch intact as the superior aspect of the sternum was clearly uninvolved on imaging studies. A circumferential margin of 3 to 4 cm was removed with resection of the ribs. The central and distal portions of the sternum, including the xiphoid process (

), were also completely removed. Chest wall stability was maintained by leaving the uninvolved superior aspect of the sternum intact. A high-grade adenocarcinoma, which involved bone and periosseous soft tissue consistent with a mammary duct primary cancer, was revealed in a final histologic analysis of the specimen. All rib margins were negative, with the carcinoma closely approximating the deep soft-tissue margin of the surgical resection to within 0.1 mm (

). We had decided preoperatively against placing synthetic mesh or nonautologous tissue into the resulting defect due to the uncertainty of surrounding tissue involvement and the possibility of developing recurrent disease in this area. Thus, the resulting defect measured 13 x 13 cm, and tissue reconstruction was achieved with bilateral pectoralis major muscle advancement flaps brought to the sternal midline, with the vascular pedicle based upon the thoracoacromial artery (

	Following a full recovery from her operation, the patient was again placed on anastrazole and leuprolide, and she has since completed a full year of trastuzumab therapy. She tested negative for BRCA1 and BRCA2 genetic mutations. Despite these negative genetic testing results, she wished to undergo a prophylactic mastectomy of the right breast with immediate bilateral reconstruction. In January 2008, she underwent a right breast prophylactic mastectomy, sentinel lymph node mapping of the right axilla using blue dye only, and the immediate placement of tissue expanders. Due to the patient’s prior course of radiation to the left chest wall, a left latissimus dorsi myocutaneous flap was used for reconstruction and bilateral silicone implants were inserted (

	The final pathology revealed multifocal, high-grade DCIS, intermixed areas of lobular carcinoma in situ (LCIS), and sentinel lymph nodes negative for metastatic cancer. No invasive component was identified. Interestingly, her right breast mammogram never identified an area of abnormality throughout this process. She currently continues on an aromatase inhibition and goserelin therapy every 3 months. A follow-up examination in August 2010 revealed no evidence of disease recurrence. Her recent  whole-body PET/CT scan remains negative for metastatic disease.

	The development of a solitary sternal metastasis in patients with a previous history of breast cancer is rare and represents less than 2% of all cases.1,2 Several authors note that long-term survival can be achieved with either partial or complete sternal resection (also called sternectomy) for an isolated metastasis, with a median survival of ~30 months and a 5-year overall survival of ~60%.

 There are several interesting features in this case report of a woman who developed an aggressive breast cancer at a relatively young age. Her initial diagnosis was at age 25, when she felt a growing mass in her left breast. Subsequently, she was found to have an aggressive, high-grade infiltrating ductal carcinoma with nodal involvement. She appropriately received neoadjuvant chemotherapy and underwent a modified radical mastectomy. The mass recurred as an isolated sternal metastasis within 12 months of this surgery and within 18 months of the original diagnosis of cancer in her left breast. Prophylactic right breast mastectomy revealed high-grade, multifocal DCIS with intermixed areas of LCIS. Genetic testing for BRCA1 and BRCA2 was negative.

	This is a single case in which a primary breast cancer metastasized to the sternum without apparent metastases to other solid organs or other sites of the body. Wedin and colleagues

 described the occurrence of symptomatic bone metastases in a defined population of patients with breast cancer. They identified all patients in the Stockholm Breast Cancer Database (population base 1.8 million) with a diagnosis of bone metastases from 1989 to 1994 and found a total of 641 cases of symptomatic skeletal metastasis, of which 107 (17%) were operated on. Metastases were located in long bones (77), spine (14), and pelvis (6), but none to the sternum. The median survival was 6 years after the initial diagnosis of breast cancer and 2 years after the first recurrence. The median survival from diagnosis of bone metastases was 22 months for patients with bone as the first site of metastases, 15 months for those with locoregional recurrence, and 12 months for those with soft tissue or multiple sites of recurrence.

 reported on 10 patients who received sternal resections for breast cancer recurrence. They further described various techniques of sternal resection followed by immediate tissue reconstruction with or without synthetic material. They noted a 5-year survival of 33%, with a partial resection of the sternum being well tolerated. In addition, hospitalization was short, morbidity was minimal, and local control was excellent. Lequaglie and colleagues

 reported on 88 patients who underwent sternal resections, of which 28 were for metastatic lesions from primary breast cancer. They found a similar 5-year overall survival of 41.8%, and noted that sternal resection followed by plastic reconstruction is a safe, effective treatment option that improves quality of life and can result in long-term survival.

 more specifically performed an in-depth analysis of patients with metastatic breast cancer to clarify whether solitary skeletal metastasis has clinical significance compared with multiple skeletal metastases. They examined 703 patients who developed metastatic bone lesions after beginning treatment for their breast cancer, and further subdivided them into those who had solitary (41%) or multiple (59%) metastatic bone lesions. Of those with solitary metastases, the highest incidence involved the sternum (98 of 289; 34%), while other skeletal sites were more prevalent in patients who had multiple metastatic lesions (

 <.001). Interestingly, they showed that an isolated sternal lesion remains a sole site of metastasis significantly longer than other solitary skeletal metastatic bone lesions. Finally, those patients with a solitary bony metastasis lived significantly longer than those with multiple metastatic bone lesions. This provides additional evidence that a solitary metastatic bone lesion is an independent, favorable prognostic factor in breast cancer patients with skeletal metastasis.

 published a series of 11 patients—4 of whom had recurrent breast cancer&mdash;who underwent sternal tumor resection and immediate chest wall repair with both primary and metastatic tumors. All underwent sternal and partial rib resection and immediate reconstruction with either polytetrafluoroethylene (PTFE) and/or a sandwich of polypropylene with a pedicled musculocutaneous flap. Four of the 5 patients underwent curative surgical intent and the overall survival ranged from 5 to 58 months.

 describe a similar case of a patient who underwent a left modified radical mastectomy for breast cancer and developed a solitary metastatic lesion within the sternal body 4.5 years after her original operation. The patient received radiation therapy and the lesion recurred after 18 months; it was then treated with oral chemotherapy, but the lesion returned 15 months later. At that point, surgical resection was undertaken and a “no-touch” technique was used that involved partial rib removal with 2-cm margins. Reconstruction was completed with a prosthetic chest wall created from methyl methacrylate (MMA) sandwiched between 2 layers of Prolene mesh. The investigators also concluded that excellent local control along with long-term survival is achieved in select cases.

 performed a 25-year retrospective study examining long-term outcomes of 68 patients who underwent a sternectomy for recurrent breast cancer (17 of 68 patients). They found a 5-year overall survival of 37%, which was well within the range of other studies cited. Careful patient selection is important when such cases are approached for curative intent, with palliative resection reserved for those with large, painful lesions. The authors also stressed the role of the multidisciplinary team for optimal medical and surgical outcomes.

	This is a report on a single case of a patient who developed a solitary sternal metastasis following a modified radical mastectomy for a high-grade infiltrating ductal carcinoma of the breast. She underwent a partial sternectomy with 4-cm resection margins followed by immediate reconstruction with bilateral pectoralis muscle advancement flaps to the midline. No synthetic material or mesh was used. The patient fully recovered and has since undergone a second operation with a prophylactic right breast mastectomy with insertion of bilateral tissue expanders followed by breast implants. She has completed her trastuzumab therapy and is more than 5 years from her original diagnosis of breast cancer and more than 3 years from her partial sternectomy. She is currently without evidence of recurrent or distant metastatic disease.

Articles

In May 2005, a 25-year-old female presented to her primary care physician complaining of a newly palpable breast mass that had grown to several centimeters over the course of a few months.

Hung T. Khong, MD

Articles

Dr. Khong on the Importance of BRCA Testing in Breast Cancer

Dr. Khong on the Potential Benefit of IO/Endocrine Therapy in ER+ Breast Cancer

Dr. Khong on Endocrine Therapy Combinations in ER+/HER2- Breast Cancer

Dr. Khong on the Benefit of Neoadjuvant Endocrine Therapy in ER+ Breast Cancers

Resection and Reconstruction of a Solitary Sternal Metastasis After Mastectomy for Breast Cancer: A Case Report and Review of the Literature