Lung cancer remains the leading cause of cancer-related deaths and the second leading cause of new cancer cases in the United States. Although more commonly involving hilar nodes, the liver, adrenal glands, bones, and the brain, lung cancer can metastasize to almost any organ. Metastases, although rare in the skin may be the first sign of a lung cancer or cutaneous metastases may present as a sign of recurrent disease. The incidence of cutaneous metastases from lung cancer has been reported in approximately 1% to 12 % of cases and was associated with poor prognosis. Although cutaneous metastasis from small cell lung cancer is a rare occurrence, cutaneous metastasis involving the breast is even less common. Here, we present a case of recurrent small cell lung cancer presenting with a firm purplish cutaneous metastatic nodule in the right breast.

Internal malignancies leading to metastases in the skin are rare with a reported incidence of 2% in 5 large autopsy studies.

 Cutaneous metastasis occurs when cells from a cancer in the body spread to the skin through the lymphatic system or bloodstream, or the cancer cells may spread directly to the skin through a surgical scar. Cutaneous metastases can occur after the primary cancer has been diagnosed, or in some cases, these lesions may be the first presenting sign of the cancer. Lung cancer is likely responsible for the majority of cutaneous metastases in men and is the second leading cause of cutaneous metastases in women after breast cancer.

 The most commonly reported metastatic skin lesions originate from primary breast, lung, and colon cancers. Other cancers that have the potential for cutaneous metastasis include melanoma, and those of the kidney, oral cavity, cervix, ovaries, and pancreas. Cutaneous metastases from kidney and oral cavity cancers are more often seen in men and appear on the head and neck regions. Skin findings include fast-growing, firm, mobile, painless pink or purple lesions that may ulcerate. 

Breast cancer is the most common form of cutaneous metastasis in women because of its high prevalence rate. Lung cancer is the most common primary malignancy to metastasize to the skin in men. The incidence of cutaneous metastases from lung cancer varies between 1% to 12% of cases.

 All histological types of lung cancer may cause metastases in the skin. Metastases from lung cancer may be the first sign of lung cancer and clinically it cannot be distinguished from cutaneous metastases originating from other organs.

 The most common sites of cutaneous metastases from lung cancer are the chest, abdomen, head, and neck.

 Clinically, cutaneous metastases occur as round or oval nodules, mobile or fixed, firm, and usually skin-colored (sometimes red, dark red, purple, or black). The nodules are usually painless and sometimes can be ulcerated. They can infrequently appear in the form of solitary or grouped papules, plaque-like, zosteriform, erysipelas-like, or as cicatricial alopecia on the scalp.

 When lesions present on the chest, they may have spread directly from a lung biopsy site. Some lesions of cutaneous lung cancer metastases have been found to run parallel to the blood vessels of the rib cage. Although all different histologic subtypes of lung cancer have been linked to the development of cutaneous metastases, adenocarcinoma or large cell carcinoma of the lung are more frequently reported to metastasize in this fashion.

 The second most common primary source of metastatic skin disease involving both sexes is colorectal carcinoma. The abdomen and pelvis are the most common locations for these cutaneous metastases to appear. A Sister Mary Joseph node at the umbilicus is a hallmark sign of an underlying gastrointestinal cancer.

A 57-year-old white woman presented with a subcutaneous, purplish, 1.8-cm nodule in the lower middle of her right breast (Figure 1). Past medical history was significant for bilateral silicone breast implants 10 years ago, and a diagnosis of limited-stage small cell lung cancer treated with etoposide/cisplatin plus concurrent chest wall radiation which led to complete remission 1 year ago. In evaluation of this skin nodule, a computed tomography (CT) scan of the chest and an ultrasound-guided biopsy of the breast nodule was performed. The CT scan of the chest confirmed the presence of bilateral breast implants with a 1.8-cm breast nodule in the middle lower quadrant of the right breast, and a right axillary lymph node (Figure 2). Pathology of tissue from the breast nodule biopsy are shown in Figure 3 and Figure 4.

Further work-up with CT scans of the abdomen and pelvis revealed adenopathy in the abdomen adjacent to aorta and left adrenal gland. She was started on second-line chemotherapy with paclitaxel 175 mg/m2 and carboplatin (area under the concentration time curve of 6) given intravenously every 3 weeks. After 4 cycles of chemotherapy, the breast nodule was no longer visible or palpable on physical exam (Figure 5). Restaging CT scans showed resolution of the breast nodule and axillary and abdominal lymphadenopathy (Figures 6).

Cancer metastasis is an organ-selective process determined by anatomical, biological, and specific microenvironmental factors.

 The exact mechanism of lung cancer metastasis to the skin is not clearly understood. Several recent studies have suggested that unique genes and gene signatures might be involved.

Lung and breast carcinomas are the most common primary tumors that lead to cutaneous metastases in the skin in men and women, respectively. A number of cancers  demonstrate colonization preference to their regions of  origin-lung cancer to the supradiaphragmatic skin and colorectal cancer to the infradiaphragmatic skin regions. Although any histological type of lung cancer is capable of cutaneous metastasis,

 adenocarcinomas and large cell carcinomas are the most frequently reported histology in the  literature.

Small cell carcinoma of the lung seldom metastasizes to the skin.

 In a review of 4020 cases of cutaneous metastases from systemic cancers, 

 were of pulmonary origin and only 2 arose from small cell carcinoma.

 The malignant cells of small cell carcinoma often affect regional areas via lymphatic channels, but they can also disseminate widely throughout the entire body via hematogenous spread. Metastases in the skin occur when the disease has progressed and they indicate poor prognosis.

 Survival time after the appearance of cutaneous metastases can be as short as 5 to 6 months.

 Patients who present with cutaneous metastases earlier during the disease course have poorer prognosis compared with those who develop skin metastases later in the disease course.

Metastatic lesions are often found on the anterior chest, head, scalp, back, and abdomen, and less commonly on the shoulders, flank, and upper and lower extremities.

 Metastases to the breast from extramammary sites are very unusual and account for 0.4% to 2.0% of breast malignancies.

 They may present as solitary or multiple lesions with ulcerative or exudative features. Cutaneous manifestations of small cell carcinoma are variable and do not have classic pathognomonic features. Several general characteristics that have been described include nodular, mobile, fast growing, and painless. On biopsy, specimens  may appear to remain superficial, or they may invade the dermis and subcutaneous tissue.

 In the differential diagnosis of cutaneous metastasis of small cell lung cancer to the breast, primary small cell carcinoma of the breast should be excluded. Primary small cell carcinoma of the breast is a very rare entity with fewer than 30 cases reported in the English-language literature.

 The histological findings of primary small cell carcinoma of the breast and of other organs are similar, although their immunohistochemistry staining characteristics are different. The histological detection of in situ intraductal components is important in making the diagnosis of primary small cell carcinoma of the breast along with the immunohistochemical staining for estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 , thyroid transcription factor 1 (TTF-1), cytokeratin (CK) 7, CK20, chromogranin, and synaptophysin.25 Although primary small cell lung cancer is usually TTF-1-positive, this finding is nonspecific.

 It can be positive in small cell carcinoma of many primary sites, and determining the primary organ requires clinical and radiographic correlation. The histologic and immunophenotypic findings of our case were typical for small cell carcinoma, showing cells with fine chromatin, minimal cytoplasm, and nuclear molding. No associated intraductal component was present (Figure 3). Immunohistochemical stains were positive for synaptophysin and chromogranin (Figure 4). CK20 was negative, excluding Merkel cell carcinoma. 

In the advanced stage, small cell lung cancer most frequently metastases to the liver, but it can also go to the other organs. Cutaneous metastases may be the first sign or they can develop as a recurrence of previously treated disease (as it was in our case). Due to their nonspecific appearance, these skin lesions can be overlooked or misdiagnosed as benign lesions or as second primary tumors. In our case, the unusual location of this single isolated breast metastasis suggested several differential diagnostic possibilities, including silicone implant-related granuloma, angiosarcoma of the breast, primary small cell carcinoma of the breast, or Merkel cell carcinoma. The presence of cutaneous metastases signifies an advanced-stage disease and carries a poor prognosis. Clinicians should keep this uncommon but important presentation in mind and evaluate suspicious skin lesions appropriately. 

The patient had a complete clinical response to second-line chemotherapy. Her disease is being monitored closely and at the first sign of recurrence, she will be treated with ipilimumab plus nivolumab combination immunotherapy.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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Articles

Experts present a case of recurrent small cell lung cancer presenting with a cutaneous metastatic nodule in the right breast.

Recurrent Small Cell Carcinoma of the Lung  With Cutaneous Metastasis in Breast

The FDA granted accelerated approval for the combination use of nivolumab (Opdivo) plus ipilimumab (Yervoy) for the treatment of patients with hepatocellular carcinoma (HCC) who received prior treatment with sorafenib (Nexavar).

 The agency’s approval is based on cohort findings from the phase I/II CheckMate-040 trial (NCT01658878), which demonstrated an objective response rate (ORR) of 33% (95% CI, 20-48) in patients who received the nivolumab and ipilimumab combination.

At a median follow-up of 28 months, 16 of 49 (33%) patients responded to treatment, with 4 (8%) experiencing a complete response (CR), and 12 (24%) demonstrating a partial response (PR). Additionally, the duration of response (DOR) ranged from 4.6 to 30.5+ months, with 88% of responses lasting at least 6 months, 56% lasting at least 12 months, and 31% of responses lasting 24 months or longer. Blinded independent central review (BICR) using modified Response Evaluation Criteria in Solid Tumors (RECIST) assessed ORR at 35% (95% CI, 22-50), with a CR reported in 12% of patients and a PR reported in 22%.

The FDA granted the approval on March 10, 2020, at a dose of 1 mg/kg of nivolumab and 3 mg/kg of ipilimumab. The treatment becomes the only dual immunotherapy approved by the FDA in this setting.

“HCC is an aggressive disease in need of different treatment approaches,” said Anthony B. El-Khoueiry, MD, lead investigator and associate professor of clinical medicine and phase I program director at the Keck School of Medicine, University of Southern California (USC) and the USC Norris Comprehensive Cancer Center, in a statement. “The ORR observed in the Opdivo plus Yervoy cohort of the CheckMate-040 trial underscores the potential of this dual immunotherapy as a possible treatment option for patients.”

Patients were randomized 1:1:1 to one of 3 dosing schedules with the combination, and treatment continued until unacceptable intolerability or disease progression. Arm A (n = 50) was given 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab every 3 weeks for 4 cycles, arm B (n = 49) was given 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 cycles, and arm C (n = 49) received nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks. Patients in arms A and B were then given a flat dose of nivolumab 240 mg intravenously every 2 weeks.

The majority of patients in all 3 arms (A, 88%; B, 85%; C, 79%) had discontinued sorafenib due to disease progression. Primary end points of the trial included safety and tolerability; key secondary end points were ORR (BICR per RECIST v1.1), DOR, and overall survival.

Serious adverse events (AEs) occurred in 59% of patients receiving the combination; treatment was discontinued in 29% of patients and delayed in 65% of patients experiencing an AE. Serious AEs reported in at least 4% of patients were pyrexia, diarrhea, anemia, increased aspartate aminotransferase, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. The most common adverse reactions (reported in ≥20% of patients) were rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), dizziness (20%), hypothyroidism (20%), and weight decreased (20%).

Since 1980, liver cancer incidence rates have more than tripled, with an estimated 42,810 new cases expected to be diagnosed in 2020. Death rates have more than doubled in the same time period.

“The incidence of liver cancer is rising in the United States, and HCC is the most common and aggressive form of the disease,” a spokesperson from Bristol Myers Squibb told 

. “Patients with advanced HCC who relapse on first-line therapy are in need of new options.”

Continued approval for this indication is contingent upon verification and description of clinical benefit in confirmatory trials.

1. U.S. Food and Drug Administration approves Opdivo (nivolumab) + Yervoy (ipilimumab) for patients with hepatocellular carcinoma (HCC) previously treated with sorafenib [news release]. Princeton, NJ: Bristol Myers Squibb; March 11, 2020. https://news.bms.com/press-release/corporatefinancial-news/us-food-and-drug-administration-approves-opdivo-nivolumab-ye-0. Accessed April 2, 2020.

2. El-Khoueiry AB, Hsu C, Kang YK, et al. Safety profile of nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 40 study. Presented at: 13th Annual Conference of the International Liver Cancer Association; September 20-22, 2019; Chicago, IL. Abstract O-13. ilca-online.org/wp-content/uploads/2019/09/ABSTRACTS-2019-min.pdf.

3. American Cancer Society. Key Statistics About Liver Cancer. American Cancer Society website. https://www.cancer.org/cancer/liver-cancer/about/what-is-key-statistics.html. Accessed April 3, 2020.

The FDA granted accelerated approval nivolumab plus ipilimumab for the treatment of advanced hepatocellular carcinoma in patients who were previously treated with sorafenib. 

FDA Approves Nivolumab Plus Ipilimumab for the Treatment of Advanced HCC

• The prognosis for patients with mCRPC has improved over the last few years due to the introduction of novel agents.
	• The optimal sequence of administering these therapeutic agents remains as a moving target and is not well established. Decisions are usually made according to patients’ clinical conditions and disease characteristics, and the safety profile and availability of new drugs.
	• Recently, cabazitaxel improved outcomes in the third-line setting after docetaxel and an ARTA. Olaparib is an additional option for second- and third-line treatment in those with alterations in BRCA1, BRCA2, and ATM.
	• Understanding the mechanisms of resistance may provide a rationale for suggesting specific strategies.
	• A subset of patients may benefit from molecularly targeted therapies, which highlights the importance of genomic testing in the castration-resistant setting.
	• Immunotherapy may provide benefit to some subsets of patients, such as those with MSI-high tumors. Studies regarding combination therapy with immune checkpoint inhibitors are ongoing.

A 69-year-old man with a past medical history of metastatic prostate cancer treated with androgen deprivation therapy (ADT) with leuprolide for 18 months presented with new lumbar pain and a prostate-specific antigen (PSA) level that increased from a nadir of 3 ng/mL to 75 ng/mL with adequate testosterone suppression. A computed tomography (CT) scan and bone scan showed new bone lesions, without visceral involvement. Therefore, the diagnosis of castration-resistant prostate cancer (CRPC) was made and he started treatment with docetaxel and zoledronic acid with clinical benefit and adequate tolerance. Response evaluation after 6 cycles showed that PSA level decreased to 7 ng/mL and there was stable disease on imaging. 

However, after 9 cycles of docetaxel, the patient complained of pain in his left hip and lumbar spine. Bone scintigraphy confirmed new bone metastases in the left iliac bone. At this time, his PSA level was 63 ng/mL. He received palliative radiotherapy to the left pelvis and started abiraterone with prednisone. He had symptomatic improvement and a biochemical response with a PSA level of 10 ng/mL. 

Six months later, disease progression was documented with a PSA level of 262 ng/mL, an increase in number of bone lesions, and new metastatic bilateral subpleural nodules (Figure 1).

What is the best treatment option for this patient?


	A. Enzalutamide
	B. Docetaxel rechallenge
	C. Cabazitaxel
	D. Radium-223
	E. Sipuleucel-T

C. Cabazitaxel improves clinical outcomes in patients with metastatic CRPC (mCRPC) previously treated with docetaxel and an androgen receptor-targeting agent (ARTA).

Prostate cancer is the second most common malignancy in men and the fifth cause of cancer death worldwide, with an estimate of more than 1.2 million new cases and over 350,000 deaths in 2018.

 In the United States, prostate cancer is the most common cancer, comprising 21% of the new cases of cancer, and the second cause of cancer death, with over 30,000 annual deaths projected for 2020.

ADT with bilateral orchiectomy or a luteinizing hormone-releasing hormone agonist or antagonist has been the backbone of treatment for metastatic castration-naÃ¯ve prostate cancer since the 1940s.

 The addition of docetaxel or an androgen rector-targeting agent (ARTA), such as abiraterone or enzalutamide, to ADT has become a standard of care for these patients based on data from randomized phase III trials showing the superiority of combined treatment over ADT alone in terms of overall survival (OS) and progression-free survival (PFS).

 Selected patients with low-volume disease may also benefit from local treatment with radiation to the primary tumor.

Despite high rates of response, virtually all patients ultimately progress to CRPC in an average time of 2 years after diagnosis.

 Over the past few years, several agents have demonstrated improved clinical outcomes in this setting: docetaxel,

 These agents can be administered to improve survival, but determining the best sequencing strategy is often challenging because of the scarcity of direct, prospective, randomized comparisons and the movement of many of these agents to use in earlier states of the disease, and cross-resistance between agents.

Sequencing strategies in (mCRPC) are influenced by the choice of first-line treatment which, in the absence of head-to-head comparisons of ARTAs and docetaxel, relies frequently on clinical characteristics of the patient (eg, disease presentation [symptomatic vs mild or asymptomatic], functional status, site of metastases [visceral vs nonvisceral], duration of response to previous treatment, presence of significant comorbidities, toxicity profile of the drug, potential interactions, cost, availability, and patient preferences).

In patients progressing after first-line docetaxel, several drugs have demonstrated improved OS. In the TROPIC trial, cabazitaxel demonstrated an OS of 15 months and a PFS of 2.8 months.

 Abiraterone was associated with an OS of 14.8 months and a PFS of 5.6 months in the COU-AA-301 trial.

 In the AFFIRM trial, enzalutamide showed an OS of 18.4 months and a PFS of 8.3 months.

 These agents have not been compared head to head, so the superiority of one over another cannot be concluded. Choice of therapy is usually made on an individual basis and physician expertise.

The activity of a subsequent hormonal agent in mCRPC is limited after failure to a first-line ARTA. One prospective phase II trial in Canada compared enzalutamide after progression on abiraterone and the reverse sequence. In patients that received second-line enzalutamide after abiraterone, median time to PSA progression was 3.5 months compared with 1.7 months in those receiving second-line abiraterone after enzalutamide (HR, 0.66; 

 Both median times to PSA progression were shorter than the 10.2 months recorded in patients treated with abiraterone after docetaxel in the COU-AA-301 trial.

A post hoc analysis from the COU-AA-302 trial, in which patients received abiraterone in the first line, PFS was less than 4 months in those who given another ARTA in the second line,

 compared with 7.6 months in those given docetaxel in the second line.

 In another retrospective cohort of 546 US patients that progressed after first-line therapy with an ARTA, 340 received another ARTA and 206 received a taxane as  second-line therapy. The analysis showed that overall response rate (ORR) was greater in the group given chemotherapy compared with the group given an ARTA (44% vs 24%), but there was no difference in OS (HR, 0.90).

 Therefore, answer A (enzalutamide) may not be the best possible option for this patient since abiraterone was the prior treatment he received.

These findings suggest that the sequential use of ARTAs may lead to a lack of response due to risk of cross-over resistance, whereas docetaxel remains active, although less than when used in the first line. Retreatment with docetaxel after use in the first line has also been described. Retrospective analyses suggest that the efficacy of a rechallenge is associated with the interval between the last cycle of first-line docetaxel-based chemotherapy and progression. Some series report a PFS benefit with a treatment-free interval lasting more than 3 months

; other investigators suggest that the clinical benefit is reserved for those with a treatment-free interval lasting more than 6 months, without any benefit in OS. Furthermore, prospective data are lacking, and answer B (docetaxel rechallenge) might be best reserved for when there are no other treatments available.  

In the third-line setting, a pooled analysis of 13 retrospective studies including 1016 patients evaluated the best treatment sequencing of novel agents (ARTA-ARTA, ARTA-cabazitaxel, and cabazitaxel-ARTA) after docetaxel failure; none of these strategies showed clear superiority over another, but a sequence that included cabazitaxel suggested a possible OS advantage.

 This was later confirmed in the phase III CARD trial, which randomized 255 patients with mCRPC who progressed in less than 12 months on a prior ARTA, before or after docetaxel therapy, to receive cabazitaxel or the other ARTA (abiraterone or enzalutamide depending on which one was used previously).

 The median imaging-based PFS was 8 months with cabazitaxel versus 3.7 months with an ARTA (HR, 0.54; 

 ≤.001). Median OS was 13.6 compared with  11 months, respectively (HR, 0.64; 

 = .008). The benefit of cabazitaxel was maintained regardless of the sequence of ARTA and docetaxel. This robust prospective data suggests that cabazitaxel is now the preferred third-line therapy after docetaxel and 1 ARTA (Table 1). Therefore, answer C (cabazitaxel) is currently the best option for this patient, who has progressive disease after docetaxel and abiraterone.

Radium-223 prolongs OS in chemotherapy naÃ¯ve (unfit or refusing docetaxel) and docetaxel-treated patients and is approved in mCRPC with symptomatic bone metastasis without visceral involvement.

 Given its mechanism of action, there is no theoretical cross-resistance with taxanes and ARTAs, and it could be used in any line in candidate patients. Concomitant administration of abiraterone and radium-223 is not recommended, as data from the ERA 223 trial showed an increased risk of adverse events when both agents were used concurrently.

 Answer D (radium-223) is not appropriate because our patient currently has visceral disease.

Sipuleucel-T is an autologous active cellular immunotherapy that has shown to improve OS in mCRPC, with a benefit of 4.1 months compared with placebo.

 However, the phase III IMPACT trial excluded patients with visceral metastases, and therefore answer E (sipuleucel-T) would not be suitable for this patient.

One of the key points of sequencing treatment is to understand the mechanism of resistance to therapies. CRPC is not androgen independent and continues to rely on androgen signaling.

 Although enzalutamide and abiraterone represent breakthroughs in the treatment of mCRPC, approximately 20% to 40% of patients have no response to these agents, and among those who initially respond, virtually all will acquire secondary resistance. 

One of the most studied mechanisms of resistance is the presence of androgen receptor splice variants (AR-Vs). Antonarakis et al

 demonstrated an association between AR-V 7 (AR-V7) in circulating tumor cells and poor prognosis and resistance to enzalutamide and abiraterone in patients with CRPC. However, in the absence of prospective trials designed to test the predictive value of AR-V7 expression when choosing between taxane- and ARTA-based treatment, its detection only has prognostic value. 

Genomic studies have identified another potential driver of resistance in ERG rearrangements that involve genes like 

 that are transcribed by androgen receptors.

 These findings could represent potential therapeutic targets in the future.

CRPC is molecularly heterogeneous, as up to 23% of mCRPC harbor DNA repair pathway aberrations, and 8% harbor germline findings .

 Loss-of-function alterations in homologous recombination repair genes are associated with a response to poly (ADP-ribose) polymerase inhibition.

 The phase III PROfound trial compared olaparib versus enzalutamide or abiraterone in patients with mCRPC with somatic alterations in any of 15 predefined genes with a role in homologous recombination repair whose disease had progressed on a prior ARTA.

 Radiologic PFS in cohort A (included alterations in 

) was 7.3 months in the olaparib group versus 3.5 months in the control group (HR, 0.43; 

 = .0001), and ORR was 33% versus 2.3%. OS results are immature, but an interim analysis suggested a benefit with olaparib (HR, 0.64) despite crossover.

Finally, microsatellite instability-high (MSI-high) and mismatch repair deficient (MRD) tumors are found in 2% to 3% of patients with mCRPC.

 The immune checkpoint inhibitor pembrolizumab is approved for the treatment of patients with solid tumors that harbor these markers. In a prospective trial carried out at Memorial Sloan Kettering Cancer Center, 11 patients with mCRPC with MSI-high disease were treated with anti-programmed cell death protein 1  (PD-1) or programmed cell death-ligand 1(PD-L1) therapy. More that 50% of patients achieved a PSA response and 45% were still on therapy for up to 89 weeks.

 In patients without MSI-high or MRD features, responses to pembrolizumab are more modest. In the phase II KEYNOTE-199 trial that enrolled patients with mCRPC with progression after docetaxel and at least 1 targeted endocrine therapy, ORR was 5% in PD-L1-positive patients and 3% in PD-L1-negative patients. Among a third cohort of patients with bone-predominant disease regardless of PD-L1 status, 22% achieved disease control.

 Pembrolizumab is also being studied in combination with other therapies. In a preliminary report from the KEYNOTE-365 trial, pembrolizumab plus olaparib demonstrated a 9% PSA response rate, a radiographic PFS of 4 months, and an OS of 14 months.

The potential of molecularly targeted treatment in patients with mCRPC highlights the importance of genomic testing in this population. Our patient was advised to be tested to expand his treatment options. 

The patient started treatment with cabazitaxel at 25 mg/m

 every 3 weeks. Currently, he has received 2 cycles of chemotherapy with mild toxicity (grade 1 peripheral neuropathy) and his PSA level decreased more than 50%. A control CT scan and bone scan to evaluate response are pending.

1. International Agency for Research on Cancer. Global Cancer Observatory. International Agency for Research on Cancer website. http://globocan.iarc.fr. Published 2018. Accessed March 30, 2020.

2. American Cancer Society. Cancer Facts & Figures 2020. American Cancer Society website.. www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf. Published 2020. Accessed March 30, 2020.

3. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1(4):293-297.

4. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-746. doi: 10.1056/NEJMoa1503747.

5. Fizazi K, Tran N, Fein L, et al; LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360. doi: 10.1056/NEJMoa1704174.

6. Davis ID, Martin AJ, Stockler MR, et al; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. doi: 10.1056/NEJMoa1903835.

7. Parker CC, James ND, Brawley CD, et al; Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomized controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366. doi: 10.1016/S0140-6736(18)32486-3.

8. Tannock IF, de Wit R, Berry WR; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512. doi: 10.1056/NEJMoa040720.

9. de Bono JS, Oudard S, Ozguroglu M, et al ; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147-1154. doi: 10.1016/S0140-6736(10)61389-X.

10. de Bono JS, Logothetis CJ, Molina A, et al; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005. doi: 10.1056/NEJMoa1014618.

11. Ryan CJ, Smith MR, de Bono JS, et al; COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-148. doi: 10.1056/NEJMoa1209096.

12. Scher HI, Fizazi K, Saad F, et al; AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-1197. doi:10.1056/NEJMoa1207506.

13. Beer TM, Armstrong AJ, Rathkopf DE, et al; PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424-433. doi: 10.1056/NEJMoa1405095.

14. Kantoff PW, Higano CS, Shore ND, et al; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422. doi: 10.1056/NEJMoa1001294.

15. Parker C, Nilsson S, Heinrich D, et al; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223. doi: 10.1056/NEJMoa1213755.

16. Caffo O, Maines F, Kinspergher S, Veccia A, Messina C. Sequencing strategies in the new treatment landscape of prostate cancer. Future Oncol. 2019;15(25):2967-2982. doi: 10.2217/fon-2019-0190.

17. Khalaf DJ, Annala M, Taavitsainen S, et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicenter, randomized, open-label, phase 2, crossover trial. Lancet Oncol. 2019;20(12):1730-1739. doi: 10.1016/S1470-2045(19)30688-6.

18. Smith MR, Saad F, Rathkopf DE, et al. Clinical outcomes from androgen signaling-directed therapy after treatment with abiraterone acetate and prednisone in patients with metastatic castration-resistant prostate cancer: post hoc analysis of COU-AA-302. Eur Urol. 2017;72(1);10-13. doi: 10.1016/j.eururo.2017.03.007.

19. de Bono JS, Smith MR, Saad F, et al. Subsequent chemotherapy and treatment patterns after abiraterone acetate in patients with metastatic castration-resistant prostate cancer: post hoc analysis of COU-AA-302. Eur Urol. 2017;71(4):656-664. doi: 10.1016/j.eururo.2016.06.033.

20. Oh WK, Miao R, Vekeman F, et al. Real-world characteristics and outcomes of patients with metastatic castration-resistant prostate cancer receiving chemotherapy versus androgen receptor-targeted therapy after failure of first-line androgen receptor-targeted therapy in the community setting. Clin Genitourin Cancer. 2018;16(1):50-57. doi:10.1016/j.clgc.2017.06.004.

21. Thomas C, Brandt MP, Baldauf S, et al. Docetaxel-rechallenge in castration-resistant prostate cancer: defining clinical factors for successful treatment response and improvement in overall survival. Int Urol Nephrol. 2018;50(10):1821-1827. doi: 10.1007/s11255-018-1963-1.

22. Loriot Y, Massard C, Gross-Goupil M, et al. The interval from the last cycle of docetaxel-based chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer. Eur J Cancer. 2010;46(10):1770-1772. doi: 10.1016/j.ejca.2010.04.010.

23. Maines F, Caffo O, Veccia A, et al. Sequencing new agents after docetaxel in patients with metastatic castration-resistant prostate cancer. Crit Rev Oncol Hematol. 2015;96(3):498-506. doi:10.1016/j.critrevonc.2015.07.013.

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25. Robinson D, van Allen DM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-1228. doi: 10.1016/j.cell.2015.05.001.

26. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(3):408-419. doi: 10.1016/S1470-2045(18)30860-X.

Experts discuss the case of a 69-year-old man with a history of metastatic prostate cancer previously treated with androgen deprivation therapy with leuprolide. 

69-Year-Old Man With Castration-Resistant Prostate Cancer Progressing After Docetaxel and Androgen Receptor-Targeting Agent

With the development of immunotherapy and targeted agents, the treatment landscape for patients with breast cancer has evolved immensely, progressing from one-size-fits-all surgeries to the current state of individualized precision medicine. 

 recently sat down with Joyce A. O’Shaughnessy, MD, to discuss the recent trends in breast cancer treatment and the avalanche of agents moving through the development pipeline that have the potential to redefine the accepted standards of care.

What are the major trends in breast cancer today? Do you think there is an overarching theme that is going to be reflected at the breast cancer conferences this year? 

Yes. At all the breast cancer conferences, the novel therapeutics are basically all focused on the molecular drivers of the cancer. For every subtype of breast cancer, there are multiple agents being developed that [target that. So, those are always highlighted because they go hand in hand with…any data on the new agents. Besides that, other things highlighted at the congresses will be advances in immunotherapy for breast cancer. We are kind of new in breast cancer in the immunotherapy space, but we do have exciting data emerging, particularly in the curative setting with triple-negative breast cancer. We also have a new approval in the metastatic setting for triple-negative breast cancer that is programmed cell death protein-ligand 1-positive with atezolizumab (Tecentriq). Everybody is keenly interested in checkpoint inhibitor therapy in the breast cancer space. At all of our congresses, we also highlight locoregional control. There is a trend towards doing less surgery over time, and probably radiation therapy has become a bit more comprehensive for the high-risk patients, but [it is a] shorter course. And even more limited is partial breast irradiation, not whole breast irradiation for lower risk patients. Radiation therapy is becoming personalized. The surgery is becoming personalized. So, we spend a lot of time, because those are very rapidly evolving areas, in locoregional control.

When you talk about “less breast cancer surgery,” are you referring to the trend toward neoadjuvant therapy to see if tumors can be shrunk instead of surgically removed?

 Yes, and so [we are] able to do a lumpectomy instead of a mastectomy because [we] shrunk [the tumor] down, but also less axillary surgery which is very important. [We are] taking out fewer axillary lymph nodes and decreasing the risk of lymphedema.

What are some of the more important recent treatment breakthroughs, and which studies in particular are you looking forward to learning about or hearing about this year? 

 We just recently had the FDA approval [of trastuzumab deruxtecan (Enhertu)], and a lot of these data came out at [the] San Antonio [Breast Cancer Symposium]. All these [results] are so new that it is very important to have our congresses to help bring clinicians up to speed on the data. 

We [can also] expect FDA approval very soon of the oral HER2 tyrosine kinase inhibitor, tucatinib, and for metastatic breast cancer, oral neratinib (Nerlynx). We already have neratinib approved in the extended adjuvant setting for patients with HER2-positive breast cancer. Now we are waiting for neratinib to be approved in the metastatic setting. Hope[fully] later this year we will see approval by the FDA [for margetuximab], another agent for HER2-positive breast cancer, a molecularly enhanced form of trastuzumab.

With regard to triple-negative breast cancer, we are looking forward, we hope, to the FDA approval of the antibody-drug conjugate, sacituzumab. We are waiting for that. Then we are really keeping our fingers crossed, crossed, crossed. We will have to see what additional data show, but we are keeping our fingers crossed for the preoperative pembrolizumab (Keytruda) trial [KEYNOTE-522] in triple-negative breast cancer to continue with further follow-up [and demonstrate] improvement in event-free survival. [If so, it] should lead to FDA approval. 

The other thing [that] we are waiting for [are data from] some of the adjuvant cyclin-dependent kinase (CDK) 4/6 inhibitor trials…in [patients with] high-risk, estrogen receptor (ER)-positive breast cancer, such as the PENELOPE-B trial which…should [have results] later this year. [In that trial,] patients with ER-positive breast cancer received preoperative [chemotherapy], they still have residual disease at surgery, then they [were given] endocrine therapy, and [finally,] they were randomized to receive 1 year of palbociclib or placebo. [Data] should be [available] soon. [Data are expected from] a couple of other adjuvant CDK4/6 inhibitor trials…within the next year, we hope. That could lead to FDA approvals of CDK4/6 inhibitors in the curative setting, which will be very exciting.

Do you believe that a lot of the recent progress has to do with gaining a better understanding of the molecular mechanisms behind breast cancer?

 Yes, and being able to choose the right patient populations. You could have a great agent, but if you do not choose the right patient population, it [will not] have the level of effectiveness it needs [to be granted] FDA approval.

On the community level, is matching treatments and sequencing tumors widespread or is it an area that still requires more education?

 We have had a sea change in breast cancer just within the last 6 months with the FDA approval of alpelisib (Piqray). It is the first PI3K alpha-specific inhibitor. [However,] it is for ER-positive breast cancers that have the 

 mutation, and that is about 40% of ER-positive breast cancers. And it is for [patients with] metastatic [disease]. So, you have…to now go looking [for the mutations]. You have…to sequence the breast cancer. You can also get circulating tumor DNA [through] a blood test, because many times you will find the 

 mutation in the blood or in the tumor. For the first time, we have a definite reason for [patients with] ER-positive metastatic [breast cancer] to get next-generation sequencing (NGS). 

ONCOLOGY® recently sat down with Joyce A. O’Shaughnessy, MD, to discuss the recent trends in breast cancer treatment and the avalanche of agents moving through the development pipeline that have the potential to redefine the accepted standards of care.

ONCOLOGY Vol 34 Issue 4 | Oncology

Recurrent Small Cell Carcinoma of the Lung With Cutaneous Metastasis in Breast

FDA Approves Nivolumab Plus Ipilimumab for the Treatment of Advanced HCC

69-Year-Old Man With Castration-Resistant Prostate Cancer Progressing After Docetaxel and Androgen Receptor-Targeting Agent

Advancing the Field of Breast Cancer Care

HPV and the Immune System in Head and Neck Cancers: Therapeutic Considerations

Oncology in the Time of COVID-19